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Type 2 Diabetes Mellitus - Role of Insulin

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. Beta ­ Cell Function (%). 50. Type 2 Phase 1. IGT.

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Type 2 Diabetes Mellitus - Role of Insulin

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  1. Type 2 Diabetes Mellitus - Role of Insulin GayotriGoswami, MD, FACE Assistant Clinical Professor of Medicine Division of Endocrinology & Metabolism November 9, 2009

  2. Stages of Type 2 Diabetes Related to Beta-Cell Function 100 75 Beta­Cell Function (%) 50 Type 2Phase 1 IGT Type 2Phase 3 25 PostprandialHyperglycemia Type 2Phase 2 0 ­12 ­10 ­6 ­2 0 2 6 10 14 Years from Diagnosis Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).

  3. Contributions of FPG and PPG to Overall Glycemia in T2DM <7.3 7.3- 8.4 8.5 - 9.2 9.3- 10.2 >10.2 FPG = fasting plasma glucose. PPG: Post prandial glucose Adapted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.

  4. Targets for Glycemic Control* *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.

  5. “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.

  6. 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

  7. 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

  8. 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)

  9. Ideal insulin therapy • One which replicates physiologic insulin secretion • Maintains near-normal glycemia • Minimizes long term complications • Improves quality of life

  10. 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 24:00 4:00 8:00 Time Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.

  11. Ideal Basal/Bolus Insulin – elementary principal 75 50 25 0 Breakfast Lunch Dinner Glucose Bolus Insulin Base Insulin Plasma Insulin (U/mL) 8:00 12:00 16:00 20:00 24:00 4:00 8:00 4:00 Time Skyler J, Kelley’s Textbook of Internal Medicine 2000.

  12. 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 5 0 1 2 3 4 –1 Hours After Glucose Ingestion Healthy Subjects Patients With Type 2 Diabetes Mitrakou A, et al. Diabetes. 1990;39:1381–1390.

  13. Components of a daily regimen • Basal: maintains interprandial and overnight glycemic control • Bolus /Nutritional/Prandial: controls the post meal glucose surge

  14. 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.

  15. 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-

  16. 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

  17. Insulin delivery devices

  18. Long Acting Analogs

  19. 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

  20. 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

  21. 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. .

  22. NPH- formulary • Neutral ProtamineHegedron: 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

  23. Short Acting Analogs

  24. 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

  25. Aspart (Novolog) • The AA , B28, which is normally proline , is substituted with an aspartic acid residue

  26. Human Insulin Time-Action Patterns Normal insulin secretion at mealtime Change in serum insulin Theoretical representation of expected insulin release in nondiabetic subjects Baseline Level Time (hours) SC injection

  27. Normal insulin secretion at mealtime Human Insulin Time-Action Patterns Regular insulin (human) Change in serum insulin Theoretical representation of profile associated with Regular Insulin (human) Baseline Level Time (hours) SC injection

  28. Normal insulin secretion at mealtime Analog Insulin Time-Action Patterns Change in serum insulin Theoretical representation of expected insulin release in nondiabetic subjects Baseline Level Time (hours) SC injection

  29. Normal insulin secretion at mealtime Analog Insulin Time-Action Patterns Rapid-Acting Insulin Analog Change in serum insulin Theoretical representation of profile associated with rapid-acting Insulin Analog Baseline Level Time (hours) SC injection

  30. Normal insulin secretion at mealtime Analog Insulin Time-Action Patterns QD (basal) Analog Insulin Change in serum insulin Theoretical representation of profile associated with Basal Analog Insulin Baseline Level Time (hours) SC injection

  31. Normal insulin secretion at mealtime Human Premix 70/30 (70% NPH & 30% Regular) Human Insulin Time-Action Patterns Theoretical representation of profile associated with Human Premix 70/30 Change in serum insulin Baseline Level Time (hours) SC injection

  32. Normal insulin secretion at mealtime Analog Insulin Time-Action Patterns Insulin Analog Premix Change in serum insulin Theoretical representation of profile associated with Insulin Analog Premix Baseline Level Time (hours) SC injection

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. Titration • For titrating prandial insulin pre-meal BG and 2 hour post meal BG is needed and doses are adjusted according to the goals

  42. Glycemic Control

  43. 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

  44. Adverse effects

  45. 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 groups • Biphasic aspart • Aspart pre-meals TID • Basal Detemir once daily (twice if needed) Holman et al.NEJM.2009,361,18

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