Effective Use of Insulin in Diabetes: Update for 2007 Charles F. Shaefer, Jr, MD Assistant Clinical Professor of Medicine Medical College of Georgia Augusta, Georgia Key.
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Slide 1
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 2
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 3
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 4
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 5
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 6
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 7
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 8
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 9
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 10
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 11
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 12
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 13
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 14
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 15
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 16
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 17
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
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?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 18
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 19
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 20
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 21
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 22
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 23
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 24
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 25
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
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Slide 26
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 27
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 28
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 29
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 30
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 31
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 32
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 33
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 34
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 35
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 36
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 37
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 38
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 39
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 40
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 41
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 42
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 43
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 44
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 45
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 46
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 47
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 48
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 49
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 50
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 51
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 2
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 3
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 4
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 5
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 6
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 7
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
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Slide 8
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 9
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 10
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 11
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 12
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 13
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 14
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 15
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 16
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 17
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 18
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 19
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 20
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 21
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 22
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 23
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 24
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 25
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 26
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 27
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 28
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 29
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 30
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 31
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 32
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
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Slide 33
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 34
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 35
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 36
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 37
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 38
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 39
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 40
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 41
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 42
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 43
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 44
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 45
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 46
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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Slide 47
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
?
Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 48
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 49
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
?
Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
?
Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
?
Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
Use your keypad to vote now!
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
?
Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 50
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
Use your keypad to vote now!
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
Use your keypad to vote now!
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
Use your keypad to vote now!
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
Use your keypad to vote now!
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Slide 51
Effective Use of Insulin in Diabetes:
Update for 2007
Charles F. Shaefer, Jr, MD
Assistant Clinical Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Key Question
How comfortable are you with initiating insulin
therapy in your patient population?
1.
2.
3.
4.
Completely comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
?
Faculty Disclosure
Dr Shaefer: speakers bureau: Pfizer Inc,
sanofi-aventis Group.
Learning Objectives
State current management goals for diabetes
Identify barriers to optimal use of insulin, and
how to overcome them
Discuss the roles of short-, intermediate-, and
long-acting insulins in the management of
diabetes
A1C Targets Suggested
by Different Organizations
Optimal target: A1C <6% (normal range)
Organization
A1C Target (%)
AACE
<6.5
EASD
<6.5
ADA
<7 (general)
<6* (individual patient)
*As close to normal (<6%) without significant hypoglycemia.
AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association;
EASD = European Association for the Study of Diabetes.
State of Diabetes in America:
Blood Sugar Control Across
the United States as Measured by A1C
National average = 67% above goal (A1C 6.5%)
WA
68.4
OR
64.2
CA
34.5
MT
55.2
ID
63.3
NV
67.3
UT
72.4
AZ
67.3
WY
63.0
CO
67.1
ND
29.7
W
24.2I
SD
24.6
IA
58.9
NE
56.5
KS
67.0
OK
65.6
NM
68.6
TX
67.7
N >157,000
ME
27.2
MN
59.3
MI
65.4
VT
NY NH
71.1 MA
CT RI
PA
OH
70.9
IL
IN 71.7
MD
72.6 66.4
WV VA
KY 69.5 67.7
MO
66.8
66.2
NC
TN
65.7
65.6
AR
SC
69.6
66.3
MS AL
GA
72.8 71.3 69.3
LA
71.3
FL
63.9
NJ
DE
Top 10 Highest
AACE. State of Diabetes in America. May 2005. Available at:
http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf
VT =
NH =
MA =
CT =
RI =
NJ =
DE =
MD=
26.7
20.4
29.5
28.4
29.5
67.3
66.4
68.1
Diabetes Demographics in the United States
Population Aged ≥20 Years
Physician-Diagnosed
Diabetes (%)
Undiagnosed Diabetes
(%)
1988-1994
2001-2004
1988-1994
2001-2004
Male
5.4
7.6
3.5
4.3
Female
5.4
7.1
2.6
1.8
White
5.0
6.2
2.6
2.8
Black
8.6
11.4
4.2
3.1
Mexican
9.7
11.8
4.7
3.3
Total
5.4
7.3
3.0
3.0
Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on
Trends in the Health of Americans. Hyattsville, Md: 2006.
Adjusted Incidence per 1000
Person-Years (%)
No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
60
AACE Goal
40
20
?
0
5
6
7
8
9
Updated Mean A1C (%)
UKPDS = United Kingdom Prospective Diabetes Study.
Stratton IM et al. BMJ. 2000;321:405-412.
10
11
Risk Factor Control in Adults With Diabetes:
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n = 1204
50
Patients (%)
40
NHANES 1999-2000, n = 370
48.2%
44.3%
P <.001
37.0%
35.8%
33.9%
29.0%
30
20
10
5.2%
7.3%
0
A1C <7%
BP
TC <200 mg/dL Good control*
<130/80 mm Hg
*Achieved all 3 indicated goals.
BP = blood pressure; NHANES = National Health and Nutrition Examination Survey;
TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.
Stages of Type 2 Diabetes:
Criteria for Advancing to Next Stage?
A1C not at target: 7.0%
β-Cell Function
(% β)
100
Monotherapy
75
Combination oral
therapy
50
Insulin
25
Type 2
Diabetes
Phase I
0
-12 -10
-6
-2
0
Type 2
Diabetes
Phase II
2
Phase III
6
Years From Diagnosis
Based on data of UKPDS 16.
UKPDS Group. Diabetes. 1995;44:1249-1258.
10
14
Key Question
What is the approximate amount that A1C
can be lowered through use of oral agents?
1. 1%
2. 2%
3. 3%
4. 4%
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Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
0
-0.5
-1.0
-1.5
-2.0
Reduction in A1C (%)
Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber
AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld M
et al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288;
Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs.
1995;50:263-288.
UKPDS: Early Initiation of Insulin
Therapy Improves A1C Control
Conventional therapy
Insulin therapy
Sulfonylurea ± insulin therapy
9
A1C (%)
8
7
ULN = 6.2%
6
5
0
0
1
2
3
4
Years From Randomization
ULN = upper limit of A1C nondiabetic range.
Wright A et al. Diabetes Care. 2002;25:330-336.
5
6
Clinical Inertia: “Failure to Advance
Therapy When Required”
Last A1C Value Before Abandoning Treatment
10
9.6%
Mean A1C at Last Visit (%)
9.1%
9
8.6%
8.8%
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
2.2 Years
2.8 Years
Key Question
What are the barriers for your patients with
type 2 diabetes regarding initiation of
insulin therapy?
1. Concern that insulin use is “forever”
2. Fear of injection
3. Equating insulin use with worsening diabetes
and complications
4. Fear of weight gain
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Patient Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Failing oral therapy
58% of patients believe using
insulin means they have failed
OAD therapy
OAD failure is due to progressive nature
of type 2 diabetes; insulin is best agent to
control disease
Needle phobia
Fear associated with early
experiences
Current needles considered painless;
easy-to-use injection systems are available
Fear of complications
Common association of insulin
with diabetic complications
Complications are due to uncontrolled,
progressive disease; insulin actually results
in reduction of vascular damage
OAD = oral antidiabetic drug.
Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.
Clinician Barriers to Insulin Use:
Perception vs Reality
Perception
Reality
Hypoglycemia is prevalent
with insulin use
Severe hypoglycemia is very uncommon in
patients with type 2 diabetes, occurring at
10% the rate in patients with type 1
diabetes
Insulin use increases
atherosclerosis
Studies indicate no exacerbation of
cardiovascular disease
There is weight gain with
insulin use
Weight gain is modest and can be
controlled with diet and exercise
Patients have a negative
attitude regarding insulin use
Insulin is a “positive” approach to achieving
glycemic control
Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65;
Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606;
UKPDS Group. Lancet. 1998;352:837-853.
Information and Patient Education
Links for Healthcare Professionals
American Association of Diabetes Educators
(www.diabeteseducator.org)
American Association of Clinical Endocrinologists
(www.aace.com)
American Diabetes Association (www.diabetes.org)
International Diabetes Federation (www.idf.org)
National Diabetes Education Initiative (www.ndei.org)
National Diabetes Education Program (ndep.nih.gov)
National Institute of Diabetes and Digestive and
Kidney Diseases (www2.niddk.nih.gov)
Next Steps…
What do we do for the patient who has failed on 1 or
2 oral agents?
Basal Insulin Therapy
Usual first step when beginning insulin therapy
Continue OAD and add basal insulin to optimize FPG
A1C of up to 9.0% often brought to goal by addition of basal
insulin therapy to OADs
Easy and safe: patient-directed treatment algorithms with
small risk of serious hypoglycemia
ADA and EASD recommended: “Although 3 OADs can be
used, initiation and intensification of insulin therapy is
preferred based on effectiveness and expense”
FPG = fasting plasma glucose.
ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement.
Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Rationale for Basal Insulin Therapy:
Insulin and Glucose Patterns
Basal insulin
400
Normal
Glucose
T2DM
Insulin
120
100
μU/mL
mg/dL
300
200
80
60
40
100
20
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
6:00 10:00 14:00 18:00 22:00 2:00 6:00
B
L
D
Time
B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Options for Initiating Insulin Therapy
Basal insulin
NPH insulin (at bedtime)
Insulin detemir (once or twice daily)
Insulin glargine (once daily)
Premixed insulin preparations
70/30 NPH insulin/regular insulin
50/50 NPL insulin/insulin lispro
70/30 NPA insulin/insulin aspart
Analog premixes
75/25 NPL insulin/insulin lispro
“Premixed insulins are not recommended during
adjustment on doses” 1
NPA = neutral protamine aspart; NPL = neutral protamine lispro.
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Plasma Insulin Levels
Idealized Profiles of Human Insulin
and Basal Insulin Analogs
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082;
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154.
Twice-Daily Split-Mixed Regimens or
Lispro Mix (75/25)–Aspart Mix (70/30)
Breakfast
Lunch
Dinner
Insulin Action
Glucose levels
Insulin levels
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel
Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.
Blood Glucose (mg/dL)
Open-Label, Twice-Daily Exenatide vs
Once-Daily Insulin Glargine: Self-Monitoring
Blood Glucose Profiles (n = 549)
Exenatide
Insulin Glargine
5 μg bid 1st 4 weeks, then 10 μg bid
10 U/d, titrated to target FPG <100 mg/dL
240
240
220
220
200
200
180
180
160
160
140
140
Baseline (week 0)
Endpoint (week 26)
120
100
Prebreakfast
Prelunch
Predinner
3 AM
120
Baseline (week 0)
Endpoint (week 26)
100
Prebreakfast
Prelunch
Predinner
Both medications lowered A1C from 8.2% to 7.1% from baseline
Weight change: exenatide –2.3 kg, glargine +1.8 kg
Nausea: exenatide 57.1%, glargine 8.6%
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
3 AM
Steps in Transition From Basal to
Basal-Bolus Insulin Therapy in T2DM
Glargine,
Above target:
Detemir,
A1C >7.0%
FPG >110 mg/dL
or NPH
HS
• Weekly
titration
based on
FPG
• All oral
agents
continued
STEP 3
STEP 2
STEP 1
Above
target
Add insulin
Main meal
Above
target
Add insulin
STEP 4
Above
target
Next
largest
meal
A1C <7.0%, FPG <110 mg/dL
HS = at bedtime.
Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.
Add insulin
Last meal
Case Study
Case Study: Initiating Insulin Therapy
60-year-old man: 10-year history of T2DM and hypertension
Current T2DM medications: metformin 1000 mg bid, rosiglitazone
8 mg AM, and glimepiride 8 mg qd
Hypertension medications: 40 mg lisinopril, 10 mg amlodipine,
12.5 mg HCTZ
Dyslipidemia medication: 10 mg atorvastatin
Physical exam: weight = 245 lb (10-lb increase); height = 6’0”;
BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg
Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL;
LDL = 90 mg/dL
A1C = 8.9%; plasma glucose in the office = 198 mg/dL
Creatinine 1.1 mg/dL, normal LFTs
HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function
tests; BMI = body mass index.
Case Study (cont’d)
Patient agrees to basal insulin therapy, however:
Expresses
feelings of failure at inability to control
glycemia with OADs
Displays anxiety about injections
You explain the progressive nature of diabetes:
Convey that insulin injections are the best way
to achieve glycemic control
Describe injection options (“painless” needles,
injector pens, etc)
Indicate that you and the patient will be a “team”
in getting to the A1C goal
Decision Point
Which insulin would you use?
1. NPH at bedtime
2. Glargine once daily
3. Twice-daily premixed
4. Detemir at bedtime
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Treat-to-Target Trial: Oral Agents +
Glargine or NPH at Bedtime
Patients (n = 756) with inadequate glycemic control (A1C >7.5%)
taking 1 or 2 oral agents
Started with 10 U/d bedtime basal insulin and adjusted weekly to
target FPG 100 mg/dL:
Mean self-monitored FPG values from
preceding 2 days (mg/dL)
Increase of insulin dosage
(U/d)
≥180
8
140 – 180
6
120 – 140
4
100 – 120
2
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Oral Agents + Glargine
or NPH at Bedtime (n=756): Efficacy Results
Glargine
Glargine
NPH
NPH
9
200
A1C (%)
FPG (mg/dL)
8.5
150
8
7.5
7
6.5
100
6
0
4
8
12
16
20
24
Weeks of Treatment
0
4
8
12
16
20
24
Weeks of Treatment
*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively,
by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Treat-to-Target Trial: Timing and
Frequency of Hypoglycemia
Hypoglycemia Episodes
(PG 72 mg/dL)
Hypoglycemia by Time of Day
350
Insulin glargine
Basal
insulin
* *
300
*
250
200
NPH insulin
*
*
*
150
*
100
50
0
B
L
D
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00
*P <.05 (between treatment).
Time
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
Detemir vs NPH Insulin in T2DM
(n = 476)
Detemir
NPH
10.0
Detemir
NPH
9.0
8.0
7.0
6.0
Hypoglycemia Events*
400
A1C (%)
350
300
250
200
150
100
50
0
-2 0
4
8 12 16 20 24
Study Week
*All reported events, including symptoms only.
Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
024
8 12 16 20 24
Study Week
Case Study (cont’d)
10 U glargine is added to OADs
Patient is sent home with the “2, 4, 6, 8 algorithm” with a target
FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be
used with detemir2
FPG (mg/dL)
Insulin Dose (U/d)
120-140
2
140-160
4
160-180
6
>180
8
Alternative strategy: increase basal insulin dose by 2 units every
3 days until FPG 100 mg/dL*3
*Certain populations (children, pregnant women, and the elderly) require special considerations.
1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.
3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.
Case Study (cont’d)
Patient is seen 1 month later
FPG
still above 200 mg/dL, using up to
30 U daily
Patient is frustrated and feels the insulin
does not work
Decision Point
What do you do now?
1. Keep increasing the insulin dose
2. Go to twice-daily premixed
3. Switch to exenatide
4. Send patient for gastric bypass consult
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Treat-to-Target Trial
Total Daily Dose (U)
50
45
Units
42
37
40
33
28
30
21
20
10
10
0
0
1
2
3
4
5
6
7
8
Weeks in Study
N = 756.
Riddle MC et al. Diabetes Care. 2003;26:3080-3086.
10 12 15 18
21
Case Study (cont’d)
Patient is taking 75 U with FPG controlled
(<100 mg/dL to rarely >110 mg/dL) since last
visit 4 months ago
Patient’s last A1C = 6.9%, monitoring occasional
postprandial blood sugars
Patient finds insulin injections painless and after
speaking with you, feels that he is now a partner in
his therapy program
Case Study (cont’d)
Over the next 3 years, patient seen for routine
follow-up every 3 to 4 months
Remains medically stable, with A1C values 6.5%
to 7.2%
3.25 years after adding basal insulin glargine, A1C
has increased to 8.2%, however, FPG checks
remain <120 mg/dL
At Lower A1C Levels, PPG Contributes
More to Overall A1C Than FPG
PPG
Contribution (%)
80
FPG
70
60
50
40
30
20
10
0
(<7.3%)
1
(7.3%-8.4%)
2
(8.5%-9.2%)
3
(9.3%-10.2%)
4
A1C Quintile
PPG = postprandial glucose.
Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
(>10.2%)
5
Plasma Glucose (mg/dL)
Prandial Excursions Are Evident,
Especially Around a Single Key Meal:
Insulin Glargine vs Premixed (n = 209)
Premixed†
350
Glargine
300
250
Baseline
200
150
*
*
*
*
*
Week 28
100
50
BB
B90
BL
L90
BD
D90
Bed
3 AM
Time of Day
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)
*Denotes statistically significant difference between treatment groups at specific times.
†Premixed = BIAsp 70/30.
Raskin P et al. Diabetes Care. 2005;28:260-265.
Plasma Insulin Levels
Idealized Profiles:
Rapid-Acting Insulin Analogs
Rapid-acting
Inhaled insulin*
Regular insulin
NPH
Detemir
0:00
Glargine
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
*Inhaled dry human insulin (Exubera®) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY:
Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes
Care. 2005;28:1077-1082.
Decision Point
The best time to use a rapid-acting insulin
analog is:
1. Before a meal
2. After a meal
3. Either works well
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Meal Insulin: Rapid-Acting Analogs
(Lispro, Aspart, Glulisine) vs Regular
Analog insulin
Insulin Activity
10
8
6
4
RHI
Timing of
food
absorbed
2
0
0
1
2
3
4
5
6
7
8
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.
9
10
11
12
Advantages of Rapid-Acting Analogs
Short duration of action—fewer between-meal “hypos”
than regular insulin
Flexible mealtime dosing
More consistent kinetics
Day to day
Across anatomical sites
With large doses
Slightly faster onset of glulisine action (compared
to lispro) in obese and morbidly obese subjects
(independent of BMI)*
Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183.
Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.
*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
Case Study (cont’d)
At 6-month follow-up patient is doing well with
70 U glargine and 10 U to 17 U glulisine at supper
Actual dose adjusted by
Meal carbohydrate content
Activity
Insulin supplement of additional 1 U for every
25 mg/dL above 130 mg/dL (prandial glucose)
A1C = 6.3%
He feels well, has infrequent “hypos,” and is pleased
with his blood glucose control
Q&A
PCE Takeaways
PCE Takeaways: Basal-Prandial Insulin
Replacement
1. An effective insulin treatment strategy provides
both basal and postprandial insulin coverage
2. Initially, prandial insulin may be needed only at the
largest meal of the day, with coverage at other
meals added based on prandial glucose levels
3. Rapid-acting insulin analogs closely match normal
mealtime insulin patterns
Key Question
How much more comfortable do you now
feel you will be initiating insulin therapy in
your patient population?
1.
2.
3.
4.
Much more comfortable
Somewhat comfortable
Slightly comfortable
Not comfortable at all
Use your keypad to vote now!
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