Transcript Slide 1

Type 2 Diabetes Mellitus Role of Insulin
Gayotri Goswami, MD, FACE
Assistant Clinical Professor of Medicine
Division of Endocrinology & Metabolism
November 9, 2009
Stages of Type 2 Diabetes Related to
Beta-Cell Function
100
75
BetaCell
Function 50
(%)
Type 2
Phase 1
IGT
25
Postprandial
Hyperglycemia
0
12 10
6
2
Type 2
Phase 3
Type 2
Phase 2
0
2
6
Years from Diagnosis
Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).
10
14
Contributions of FPG and PPG to
Overall Glycemia in T2DM
Contribution (%)
PPG + FPG = A1C (%)
PPG
FPG
80
70
60
50
40
30
20
10
0
1
<7.3
2
7.3- 8.4
3
4
8.5 - 9.2
9.3- 10.2
A1C Quintiles
5
>10.2
FPG = fasting plasma glucose. PPG: Post prandial glucose
Adapted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
Targets for Glycemic Control*
Normal
Goal
<6.0
<110
<7.0
70-130
<180
<6.0
<110
<6.5
<110
<135
<6.0
<110
<6.5
<110
<140
American Diabetes Association1
A1C (%)
Preprandial plasma glucose (mg/dL)
Peak postprandial plasma glucose (mg/dL)
European Diabetes Policy Group2
A1C (%)
Preprandial plasma glucose (mg/dL)
Postprandial glucose (mg/dL)
American Association of Clinical
Endocrinologists3
A1C (%)
Preprandial plasma glucose (mg/dL)
Postprandial glucose (mg/dL)
*More stringent goal of <6.0% should be considered for individual patients. Generally, A1C goal for each
patient is an A1C as close to normal as possible without significant hypoglycemia.
A1C = glycosylated hemoglobin A1C.
7
1. ADA. Diabetes Care. 2006;29(suppl 1):S4-S42. 2. European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730.
3. Feld S. Endocr Pract. 2002;8(suppl 1):40-82.
“Although insulin therapy has not
traditionally been implemented
early in the course of Type 2
diabetes, there is no reason why it
should not be…”
Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.
Metabolic Management of type 2 DM
Nathan et al, A Consensus Statement from the American Diabetes Association and the
European Association for the Study of Diabetes. Diabetes Care,29:759-764,2006
Insulin
• Insulin is composed of 2 polypeptide chains the
A and B linked together by disulphide bonds
• Among most species the A chain consists of 21
AA and the B of 30 AA
• Although the AA sequences differ in species
there are certain segments of the molecule that
are highly conserved
Insulin
• Most affective agent, when used in adequate doses to
decrease any level of A1c to therapeutic goal
• Relatively large doses are used in Type 2 insulin
resistant patients when compared to Type 1
• Has beneficial effects on TG and HDL but can cause
weight gain
• Important side effect is hypoglycemia (can be reduced
by education, peakless and short acting insulins)
Ideal insulin therapy
• One which replicates physiologic insulin
secretion
• Maintains near-normal glycemia
• Minimizes long term complications
• Improves quality of life
Physiologic Blood Insulin Secretion Profile
75
Breakfast
Lunch
Dinner
50
Plasma
Insulin
(µU/mL)
25
4:00
8:00
12:00
16:00
20:00
Time
Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine.
June 2003;113(6):30-36.
24:00
4:00
8:00
Ideal Basal/Bolus Insulin –
elementary principal
75
Breakfast
Lunch
Dinner
Glucose
Bolus Insulin
Base Insulin
Plasma
Insulin 50
(U/mL)
25
0
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Skyler J, Kelley’s Textbook of Internal Medicine 2000.
Loss of Early Insulin Release Leads to
Postprandial Hyperglycemia
Plasma Insulin
Plasma Glucose
60
360
270
40
(mg/dL)
(mU/L)
180
20
90
0
–1
0
1
2
3
4
5
–1
Hours After Glucose Ingestion
Healthy Subjects
Patients With Type 2 Diabetes
Mitrakou A, et al. Diabetes. 1990;39:1381–1390.
0
1
2
3
4
5
Components of a daily regimen
• Basal:
maintains interprandial and overnight
glycemic control
• Bolus /Nutritional/Prandial:
controls the post meal glucose surge
What are insulin analogs?
• An insulin analog is an altered form of insulin.
• Through genetic engineering of the underlying
DNA,the amino acid sequence of insulin is
changed to alter its absorption, distribution,
metabolism and excretion.
INSULINS
•
•
•
Peak (duration) hrs
RAPID-ACTING INSULIN ANALOGS
– Humalog (lispro)
– Novolog (aspart)
– Glulisine (epidra)
SHORT-ACTING
- Regular
1-2
1-2
1-2
2-4
(3-6)
INTERMEDIATE-ACTING
– NPH (Neutral Protamine Hegedron)
•
(2-6)
(2-6)
(2-6)
LONG ACTING
– Lantus / glargine
– Levemir / detemir
6-12
none
(10-24)
-
(10-24)
Fixed dose insulin mixes
HUMULIN (NPH/REG)
–70/30
–50/50
HUMALOG (Prot-lispro/free lispro)
–75/25
NOVOLIN (NPH/REG)
–70/30
NOVOLOG MIX (Prot-aspart/aspart)
–70/30
Insulin delivery devices
Long Acting Analogs
Lantus (Glargine)- formulary
• Two positively charged arginine molecules are added to
the C-terminus of the B-chain, asparagine at position 21
in the A-chain is replaced by glycine
Lantus
• Upon injection into the subcutaneous space(pH
7.4), the acidic (4.0) glargine solution is
neutralized and it forms an amorphous
suspension
• resulting in delayed absorption and an extended
duration of action.
• Reduced incidence of hypoglycemia compared
with NPH
Levemir (Detemir)
.
• To the Lysine AA at position B29 a fatty acid
(myristic acid ) is bound.
• After it is absorbed it binds to albumin through
the fatty acid at position B29 and the slowly
dissociates from this complex.
NPH- formulary
• Neutral Protamine Hegedron: is a suspension of
crystalline zinc insulin combined with a
polypeptide protamine
• Intermediate acting and the most commonly
used basal insulin
• Half life is 8 hours and reaches a
peak concentration at 4-6 hrs
Short Acting Analogs
Lispro (Humalog)- formulary
• Lysine and proline residues on the C-terminal
end of the B-chain are reversed
Insulin Glulisine (Apidra)
•The AA asparagine at position B3 is
replaced by lysine and the lysine in position
B29 is replaced by glutamic acid
Aspart (Novolog)
• The AA , B28, which is normally proline , is
substituted with an aspartic acid residue
Human Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Theoretical representation of
expected insulin release in
nondiabetic subjects
Baseline
Level
Time (hours)
SC injection
Human Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Regular insulin (human)
Theoretical representation of
profile associated with Regular
Insulin (human)
Baseline
Level
Time (hours)
SC injection
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Theoretical representation of
expected insulin release in
nondiabetic subjects
Baseline
Level
Time (hours)
SC injection
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Rapid-Acting Insulin Analog
Theoretical representation of
profile associated with rapid-acting
Insulin Analog
Baseline
Level
Time (hours)
SC injection
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
QD (basal) Analog Insulin
Theoretical representation
of profile associated with
Basal Analog Insulin
Baseline
Level
Time (hours)
SC injection
Human Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Human Premix 70/30
(70% NPH & 30% Regular)
Theoretical representation of
profile associated with Human
Premix 70/30
Baseline
Level
Time (hours)
SC injection
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Insulin Analog Premix
Theoretical representation of
profile associated with Insulin
Analog Premix
Baseline
Level
Time (hours)
SC injection
Advantages of rapid acting insulin analogs
• Restores the early insulin peak in combination
with meal ingestion
• Prevents the hyperinsulinemia resulting from the
late absorption of regular insulin and thereby
protects against hypoglycemia
OPTIONS………
•
•
Once daily background or basal insulin if
fasting BG is elevated but glucose values
remain stable during the day
A simple and practical approach is to
implement once daily basal insulin and
continue OAD therapy, titrating according to
FBG *
•INSIGHT(Implementing New Strategies with Insulin Glargine for Hyperglycemic
Treatment – Gerstein et al 2006.Diab.Med.23:736-742
OPTIONS………
•
Once daily or twice daily pre-mixed insulin
analogue, orally administered drugs may or
may not be continued
•
Basal bolus therapy…..first initiate basal along
with 1 bolus injection before the largest meal
and eventually at each meal if needed
OAD and Insulin
• Proven to be effective in a review of 20 RCT
• Provides comparable glycemic control to insulin
monotherapy
• Reduction in total daily insulin requirements
• Reduces weight gain and helps glycemic control
by peripheral insulin sensitization and inhibiting
hepatic gluconeogenesis
Dosing
• Glargine is effectively administered either in the
morning or evening, provided the timing of
injection is consistent each day
• Detemir is administered both once and twice
daily
• NPH is usually administered twice daily, in the
morning and at bedtime
Dosing
• Short acting analogs are given 5-15 minutes
before a meal while Apidra or Glulysine can be
given upti 20 minutes after start of a meal
• RI is given atleast 20-30 minutes before a meal
• A short acting analog can be started as 10% of
the TDD (basal insulin can then be decreased by
10%) and can be added to the heaviest meal
What doses to start with……..
•
•
•
•
•
With HbA1c <8%, begin 0.1U/Kg body weight
HbA1c 8-10%, start 0.2U/kg body weight
HbA1c >10%, start 0.3U/Kg body weight
10 units /day
With pre-mixes can divide the total dose by 2 if
used twice a day
• With insulin glargine, adjust dose every 3-7 days
until target fasting dose is reached
Bergenstal Endocrine Practice,Jan 2006
Titration
• Forced weekly titration (physician led)
Treat to Target Trial
(Glargine/NPH) & (Detemir BID/NPH)
• Patient- led titration (usually every 2-3 days
according to BG goal)
AT.LANTUS trial
PREDICTIVE trial
Titration
• For titrating prandial insulin pre-meal BG and 2
hour post meal BG is needed and doses are
adjusted according to the goals
Glycemic Control
LANTUS Vs NPH + Oral agents (Treat to Target Trial)
Large multicenter trial, patients had A1c
Between 8-10%, 24 weeks duration with either
Lantus/NPH + 2 oral agents to bring FBG to
<100mg/dL
Riddle et al.Diabetes Care;2003:3080-3086
Adverse effects
4T Study
(Three year efficacy of complex insulin regimens )
•
•
•
•
•
1.
2.
3.
3 year open label, multicenter trial
708 patients with A1c levels between 7-10%
On Metformin and a SFU
Outcomes – A1c , hypoglycemia & weight gain
Randomly assigned to 3 groups
Biphasic aspart
Aspart pre-meals TID
Basal Detemir once daily (twice if needed)
Holman et al.NEJM.2009,361,18
Results
• Median A1c was similar in biphasic (7.1%)
prandial (6.8%) and basal (6.95)
• Median rates of hypoglycemia per patient per
year were lowest in the basal (1.7), biphasic (3.0),
and prandial (5.7), p<0.001 for overall
comparison
• Mean weight gain was higher in the prandial
group(5.7kg±0.5) than either biphasic (6.4±0.5)
or basal (3.6 ±0.5)
Adverse effects
• Detemir has been associated with less
weight gain when compared with NPH at
equivalent glycemic control
• Detemir also had significantly less weight
gain when compared with glargine
(Detemir 3kg; glargine 3.9kg,P<0.012)
Raslova et al, 2004.Diabetes.Res.Clin.Pract 66:193-20
Haak T et al.2005.Diabetes Obes metab.7:56-64
Hermansen K et al 2006.Diabetes Care 29;1269-1274
Conclusions
• The insulin analogues offer improved
pharmacokinetic and pharmacodynamic profiles
compared to NPH and RI and therefore offer
advantages with respect to safety,efficacy and
variability
• These advantages may help Type 2 Diabetics
overcome some of the barriers associated with
insulin initiation, hypoglycemia and weight gain
Conclusions
• Lantus offers a consistent 24 hour profile and
predictability and a lower risk of hypoglycemia
when compared with NPH and therefore
facilitates more aggressive titration
• Detemir is associated with equivalent glycemic
control, less risk of hypoglycemia lower withinsubject day-to-day control and less weight gain
Questions ????