Type 2 Diabetes Mellitus -

Role of InsulinGayotri Goswami, MD, FACE

Assistant Clinical Professor of MedicineDivision of Endocrinology &

Metabolism

November 9, 2009

Stages of Type 2 Diabetes Related to Beta-Cell

Function

Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).

2­12 ­2­10 ­6 0 6 10 14

Beta­Cell­Function­

(%)

0

50

100

75

25

Type­2Phase­1IGT

Years­from­Diagnosis

Type­2Phase­2

Type­2Phase­3

Postprandial

Hyperglycemia

Contributions of FPG and PPG to Overall Glycemia in T2DM

PPG­+­FPG­=­A1C­(%)

01020304050607080

1 2 3 4 5

A1C­Quintiles

Contribution­(%)

PPG

FPG

FPG = fasting plasma glucose. PPG: Post prandial glucoseAdapted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.

<7.3 7.3- 8.4 8.5 - 9.2 9.3- 10.2 >10.2

7

Targets for Glycemic Control*Normal Goal

American­Diabetes­Association1

A1C (%)Preprandial plasma glucose (mg/dL) Peak postprandial plasma glucose (mg/dL)

<6.0<110

<7.070-130<180

European­Diabetes­Policy­Group2

A1C (%)Preprandial plasma glucose (mg/dL) Postprandial glucose (mg/dL)

<6.0<110

<6.5<110<135

American­Association­of­Clinical­Endocrinologists3

A1C (%)Preprandial plasma glucose (mg/dL) Postprandial glucose (mg/dL)

<6.0<110

<6.5<110<140

*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.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

Plasma­Plasma­Insulin­Insulin­((µU/mL)­U/mL)­

4:004:00

2525

5050

7575

8:008:00 12:0012:00 16:0016:00 20:00­­20:00­­ 24:0024:00 4:004:00

Breakfast Lunch Dinner

Time

8:008:00

Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.

PlasmaInsulin(U/mL)

Time

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Breakfast Lunch Dinner

Ideal Basal/Bolus Insulin – elementary principal

75

50

25

0

GlucoseBolus­InsulinBase­Insulin

Skyler­J,­Kelley’s Textbook of Internal Medicine­2000.

Hours­After­Glucose­Ingestion

Patients­With­Type­2­DiabetesHealthy­Subjects

Plasma­Insulin

0

20

40

60

–1 0 1 2 3 4 5

90

180

270

360

–1 0 1 2 3 4 5

Plasma­Glucose

Mitrakou A, et al. Diabetes. 1990;39:1381–1390.

Loss of Early Insulin Release Leads to Postprandial

Hyperglycemia

(mU/L)(mg/dL)

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) 1-2 (2-6)– Novolog (aspart) 1-2 (2-6)– Glulisine (epidra) 1-2 (2-6)

• SHORT-ACTING- Regular 2 - 4 (3-6)

• INTERMEDIATE-ACTING

– NPH (Neutral Protamine Hegedron)

6-12 (10-24) • LONG ACTING

– Lantus / glargine none (10-24)– Levemir / detemir -­

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

Long­Acting­Analogs

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

Short­Acting­Analogs

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

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

Change­in­serum­insulin­

­­Baseline­Level

Theoretical­representation­of­expected­insulin­release­in­nondiabetic­subjects

Human Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

Regular­insulin­(human)

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Regular­Insulin­(human)

Change­in­serum­insulin­

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

­­Baseline­Level

Theoretical­representation­of­expected­insulin­release­in­nondiabetic­subjects

Change­in­serum­insulin­

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­rapid-acting­Insulin­Analog

Change­in­serum­insulin­

Rapid-Acting­Insulin­Analog

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

QD­(basal)­Analog­Insulin

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Basal­Analog­Insulin

Change­in­serum­insulin­

Human Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

Human­Premix­70/30­(70%­NPH­&­30%­Regular)

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Human­Premix­70/30

Change­in­serum­insulin­

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Insulin­Analog­Premix

Change­in­serum­insulin­

Insulin­Analog­Premix

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 HyperglycemicTreatment – 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 trialPREDICTIVE 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

LANTUS­Vs­NPH­+­Oral­agents­(Treat­to­Target­Trial)

Riddle­et­al.Diabetes­Care;2003:3080-3086

Large multicenter trial, patients had A1cBetween 8-10%, 24 weeks duration with eitherLantus/NPH + 2 oral agents to bring FBG to<100mg/dL

Adverse effects

4T Study (Three year efficacy of complex insulin

regimens )• 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 groups1. Biphasic aspart2. Aspart pre-meals TID3. 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 66:193-20Haak T et al.2005.Diabetes Obes metab.7:56-64Hermansen 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 within-subject day-to-day control and less weight gain

Questions ????