Effective Use of Insulin in Diabetes: Update for 2007

Thomas M. Flood, MD Director Georgia Center for Diabetes Atlanta, 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

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Faculty Disclosure



Dr Flood

has no relevant financial relationships with any commercial interests to disclose.

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

AACE EASD ADA

A1C Target (%)

<6.5

<6.5

<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.

Key Question

What percentage of patients with diabetes achieve the AACE goal of A1C <6.5%?

1.

25% 2.

3.

4.

35% 55% 75%

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State of Diabetes in America: Blood Sugar Control Across the United States as Measured by A1C National average = 67% above goal (A1C



6.5%) OR 64.2

CA 34.5

WA 68.4

NV 67.3

N >157,000 ID 63.3

UT 72.4

AZ 67.3

MT 55.2

WY 63.0

CO 67.1

NM 68.6

ND 29.7

SD 24.6

NE 56.5

TX KS 67.0

67.7

OK 65.6

MN 59.3

IA 58.9

MO 66.2

W 24.2I

IL 72.6

AR 69.6

LA 71.3

MS 72.8

MI 65.4

IN 66.4

TN 65.6

KY 66.8

AL 71.3

OH 71.7

WV 69.5

GA 69.3

SC 66.3

NY 71.1

PA 70.9

VT NH ME 27.2

MA CT NJ DE RI VA 67.7

NC 65.7

FL 63.9

Top 10 Highest

AACE.

State of Diabetes in America.

May 2005. Available at: http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf

VT = 26.7

NH = 20.4

MA = 29.5

CT = 28.4

RI = 29.5

NJ = 67.3

DE = 66.4

MD= 68.1

Diabetes Demographics in the United States Population Aged ≥20 Years Male Female White Black Mexican Total Physician-Diagnosed Diabetes (%) 1998-1994

5.4

5.4

5.0

8.6

9.7

5.4

2001-2004

7.6

7.1

6.2

11.4

11.8

7.3

Undiagnosed Diabetes (%) 1998-1994

3.5

2.6

2.6

4.2

4.7

3.0

2001-2004

4.3

1.8

2.8

3.1

3.3

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.

No A1C Threshold in Type 2 Diabetes

80 60

Epidemiologic Data From the UKPDS

Myocardial infarction Microvascular end points

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

50 NHANES III, n = 1204

44.3% 37.0%

NHANES 1999-2000, n = 370

48.2% P <.001

40 30

29.0% 35.8% 33.9%

20 10

5.2% 7.3%

0

A1C <7% BP <130/80 mm Hg TC <200 mg/dL Good control*

*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%

100 75 50

Monotherapy Combination oral therapy Insulin

25

Type 2 Diabetes Phase I Type 2 Diabetes Phase II Phase III

0 -12 -10 -6 -2 0 2 6

Years From Diagnosis

Based on data of UKPDS 16. UKPDS Group.

Diabetes.

1995;44:1249-1258.

10 14

Stepwise Management of Type 2 Diabetes

Biggest Clinical Hurdle?

+ + +

Adapted from Williams G.

Lancet.

1994;343:95-100.

Key Question

What is the approximate amount that A1C can be lowered through use of oral agents?

1.

1% 2.

3.

4.

2% 3% 4%

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Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C

Acarbose Nateglinide Sitagliptin Rosiglitazone Pioglitazone Repaglinide Glimepiride Glipizide GITS Metformin Insulin

0 -0.5

-1.0

Reduction in A1C (%)

-1.5

-2.0

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

9

Conventional therapy Insulin therapy Sulfonylurea ± insulin therapy

8 7 6

ULN = 6.2%

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% 9.1%

9

8.6% 8.8%

8

ADA Goal

7

Sulfonylurea Combination Diet/Exercise 2.5 Years 2.9 Years

Brown JB et al.

Diabetes Care.

2004;27:1535-1540.

Metformin 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 Failing oral therapy

58% of patients believe using insulin means they have failed OAD therapy

Needle phobia

Fear associated with early experiences

Reality

OAD failure is due to progressive nature of type 2 diabetes; insulin is best agent to control disease 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 Hypoglycemia is prevalent with insulin use Insulin use increases atherosclerosis There is weight gain with insulin use Patients have a negative attitude regarding insulin use Reality

Severe hypoglycemia is very uncommon in patients with type 2 diabetes, occurring at 10% the rate in patients with type 1 diabetes Studies indicate no exacerbation of cardiovascular disease Weight gain is modest and can be controlled with diet and exercise 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.

UKPDS Group.

Lancet.

1997;314:1512-1515; Romano G et al. 1998;352:837-853.

Diabetes.

1997;46:1601-1606;

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 Glucose 300 200 100 Normal 120 100 80 60 40 20 T2DM Insulin 6:00 10:00 14:00 B L 18:00 22:00 D Time 2:00 6:00 6:00 10:00 14:00 18:00 22:00 B L D Time 2:00

B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.

Polonsky KS et al.

N Engl J Med.

1988;318:1231-1239.

6:00

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  75/25 NPL insulin/insulin lispro Analog premixes NPA = neutral protamine aspart; NPL = neutral protamine lispro.

Idealized Profiles of Human Insulin and Basal Insulin Analogs

NPH Detemir Glargine 0:00 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 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.

Open-Label, Twice-Daily Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n = 549) Exenatide 5 μg bid 1st 4 weeks, then 10 μg bid Insulin glargine 10 U/d, titrated to target FPG <100 mg/dL 240 220 200 180 160 140 120 100 Prebreakfast Prelunch Baseline (week 0) Endpoint (week 26) Predinner 3 AM 240 220 200 180 160 140 120 100 Prebreakfast Prelunch Baseline (week 0) Endpoint (week 26) 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% 3 AM

Heine RJ et al.

Ann Intern Med.

2005;143:559-569.

Steps in Transition From Basal to Basal-Bolus Insulin Therapy in T2DM

STEP 1 Above target: A1C >7.0% FPG >110 mg/dL Glargine, Detemir, or NPH HS

• •

Weekly titration based on FPG All oral agents continued STEP 2 STEP 3 Above target Add insulin Main meal Above target Add insulin Next largest meal STEP 4 Above target Add insulin Last meal A1C <7.0%, FPG <110 mg/dL

HS = at bedtime.

Adapted with permission from Karl DM.

Curr Diab Rep.

2004;4:352-357.

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/m 2 ; 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.

2.

3.

4.

NPH at bedtime Glargine once daily Twice-daily premixed 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)

≥180 140 – 180 120 – 140 100 – 120

Increase of insulin dosage (U/d)

4 2 8 6 Hermansen K et al.

Diabetes Care.

2006;29:1269-1274; 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 NPH Glargine NPH 200 150 100 0 4 8 12 16 20 Weeks of Treatment 24 9 8.5

8 7.5

7 6.5

6 0 4 8 12 16 20 Weeks of Treatment 24

*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

350 300 250 200 150 100 50 0 Hypoglycemia by Time of Day Basal insulin

* * * * * * *

Insulin glargine NPH insulin 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 Time

*P

<.05 (between treatment).

Riddle MC et al.

Diabetes Care.

2003;26:3080-3086.

Detemir vs NPH Insulin in T2DM (n = 476)

A1C (%) 10.0

9.0

8.0

7.0

6.0

Detemir NPH -2 0 4 8 12 16 20 24 Study Week 400 350 300 250 200 150 100 50 0 0 2 4 Detemir NPH 8 12 16 20 24 Study Week

*All reported events, including symptoms only.

Hermansen K et al.

Diabetes Care.

2006;29:1269-1274.

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 detemir 2

FPG (mg/dL)

120-140 

Insulin Dose (U/d)

2 140-160 160-180 >180 4 6 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.

3. Davies M et al.

Diabetes.

2006;29:1259-1271.

2004;53(suppl 2):1980.

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.

2.

3.

4.

Keep increasing the insulin dose Go to twice-daily premixed Switch to exenatide Send patient for gastric bypass consult

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Treat-to-Target Trial

50 Units 40 33 28 30 20 10 10 21 37 42 45 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

Decision Point

What do you do now?

1.

2.

3.

4.

Increase glargine Switch to twice-daily premixed Switch to 4-shot basal-bolus program Increase monitoring to AC and HS, and have patient report after 2 weeks

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AC = before meals; HS = at bedtime.

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Case Study (cont’d)

 Because the patient’s FPGs are good and post prandial glucose levels are high, the decision is made to switch to twice-daily premixed insulin  The patient is encouraged to increase daily monitoring to adjust insulin dose

At Lower A1C Levels, PPG Contributes More to Overall A1C Than FPG

80 70 60 50 40 30 20 10 0 PPG FPG (<7.3%) 1 (7.3%-8.4%) 2 (8.5%-9.2%) 3 A1C Quintile (9.3%-10.2%) 4

PPG = postprandial glucose.

Reprinted with permission from Monnier L et al.

Diabetes Care.

2003;26:881-885.

(>10.2%) 5

Prandial Excursions Are Evident, Especially Around a Single Key Meal: Insulin Glargine vs Premixed (n = 209) 350 Premixed † Glargine 300 250 200 150 * * Baseline * * * Week 28 100 50 BB B90 BL L90 BD Time of Day D90 Bed 3 AM

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.

Case Study (cont’d)

Daily Blood Glucose Diary

Week Ending

Monday Tuesday Wednesday Thursday Friday Saturday Sunday Breakfast Dose Blood Sugar

147 138 140 166

Lunch Dose Dinner Blood Sugar Dose

110 112 90 105

Blood Sugar

153 170 155 134

Dose MS Blood Sugar

185 164 205 213 March 24

Middle of Night

57 48 60

Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25)

–

Aspart Mix (70/30)

Breakfast Lunch Dinner 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.

Idealized Profiles: Rapid-Acting Insulin Analogs

Rapid-acting Inhaled insulin* Regular insulin 0:00 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.

Case Study (cont’d)

 Decision is made to switch to basal-prandial therapy to reduce hypoglycemia and postprandial highs  60% of patient’s total daily insulin dose is given as basal insulin – 54 U glargine qhs titrated to FPG 100-110 mg/dL  Before the main meal, a rapid-acting analog is added: glulisine, initiated at 5 units, up-titrated using a treat-to-target algorithm  Patient continues to self-monitor glucose

Meal Insulin: Rapid-Acting Analogs (Lispro, Aspart, Glulisine) vs Regular

Analog insulin 10 8 6 4 RHI 2 Timing of food absorbed 0 0 1 2 3 4 5 6 Hours 7 8

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.

Decision Point

The best time to use a rapid-acting insulin analog is:

1.

Before a meal 2.

3.

After a meal Either works well

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Pre- and Postmeal Efficacy of Insulin Glulisine vs Regular Human Insulin

Significant reduction in A1C with pre- and postmeal glulisine P <.05

P <.05

P <.05

Baseline 8.00

7.73

7.70

7.58

7.64

7.46

7.52

7.50

Endpoint 7.00

6.50

6.00

Premeal insulin glulisine Postmeal insulin glulisine Premeal RHI

Significant A1C reduction with premeal glulisine compared to premeal human insulin Garg SK et al.

Endocr Pract

. 2005;11:11-17; Garg SK et al. Poster presented at ADA 64th Annual Scientific Sessions, June 4-8, 2004,

Diabetes

. 7:529P.

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

PCE Takeaways

PCE Takeaways: Basal-Prandial Insulin Replacement

1.

2.

3.

An effective insulin treatment strategy provides both basal and postprandial insulin coverage 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 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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