2. Combination Therapy for Type 2 Diabetes Paul Davidson, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia Presented in Dalton, GA on Aug 14, 2003

3. ACE / AACE Targets for Glycemic Control HbA 1c < 6.5 % Fasting/preprandial glucose< 110 mg/dL Postprandial glucose< 140 mg/dL ACE / AACE Consensus Conference, Washington DC August 2001

4. Goals of Intensive Diabetes Management A Normal HbA1c Is Not Everything. It Is the Only Thing!

5. TYPE 2 DIABETES... A PROGRESSIVE DISEASE Natural History and Treatment 0 Years of Diabetes Relative  -Cell Function Plasma Glucose Insulin resistance Insulin secretion 126 mg/dL Fasting glucose Post-meal glucose Wt Loss Sensitizes Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota Secretors Insulin Exercise -10 -20102030

6. TYPE 2 DIABETES... A PROGRESSIVE DISEASE Progressive Decline of  -Cell Function in the UKPDS 0 20 40 60 80 100  10 99 88 77 66 55 44 33 22 11 0123456 Years  -Cell Function (%  ) Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:1249-1258. 6-4

7. Basal vs Mealtime Hyperglycemia in Diabetes Riddle. Diabetes Care. 1990;13:676-686. Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 18002400 Type 2 Diabetes 0600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal  AUC from normal basal >1875 mgm/dL. hr; Est HbA1 c >8.7%

8. When Basal Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 900 mgm/dL. hr; Est HbA1 c 7.2%

9. When Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 1425 mgm/dL. hr; Est HbA1 c 7.9

10. When Both Basal & Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 225 mgm/dL. hr; Est HbA1 c 6.4%

11. Step Therapy l Diet l Exercise l Sulfonylurea or Metformin l Add Alternate Agent l Add hs NPH l Switch to Mixed Insulin bid l Switch to Multiple Dose Insulin Utilitarian, Common Sense, Recommended Prone to Failure from Misscheduling and Mismanagement

12. Stumble Therapy l YAG Diet l Golf Cart Exercise l Sample of the Week Medication –Interupted, –Not Combined l Poor Understanding of Goals l Poor Monitoring HbA1c >8% (If Seen) Informed Patient Refers Self Elsewhere

13. PETS Therapy Step--Spelled Backwards All at once, nothing first, Just like bubbles, when they burst. l Start with Fast to Glucose <126 mg/dL –IV Insulin l Feed PSMF Diet l Add SU, MF, TZD, Repaglanide + prn Lispro for BG <150 l “Normal” BG from Day 1 l Monitor BG qid l See Patient Monthly, HFP l HbA1c Bimonthly GI Problems: Cut MF Hypoglycemia: Cut SU Hypoglycemia Again: Cut Repaglinide Allow 2 Month to See TZD Effect

14. Mean Hemoglobin A1C PETS Rx

15. Insulin The agent we have to control glucose only most powerful

16. Comparison of Human Insulins / Analogues Insulin Onset ofDuration of preparations action Peak action Regular30–60 min2–4 h6–10 h Lispro/aspart5–15 min1–2 h 4–6 h NPH/Lente1–2 h4–8 h10–20 h Ultralente2–4 hUnpredictable16–20 h Glargine1–2 hFlat~24 h

17. 400 350 300 250 200 150 100 Meal SC injection 50 0 03060 Time (min) 90120180210150240 Regular Lispro 500 450 400 350 300 250 150 50 200 100 0 050100 Time (min) 150200300250 Plasma insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506. Short-Acting Insulin Analogs Lispro and Aspart Plasma Insulin Profiles Regular Aspart

18. Short-Acting Analogs Lispro and Aspart l Convenient administration immediately prior to meals l Faster onset of action l Limit postprandial hyperglycemic peaks l Shorter duration of activity –Reduce late postprandial hypoglycemia –Frequent late postprandial hyperglycemia l Need for basal insulin replacement revealed

19. Limitations of NPH, Lente, and Ultralente l Do not mimic basal insulin profile –Variable absorption –Pronounced peaks –Less than 24-hour duration of action l Cause unpredictable hypoglycemia –Major factor limiting insulin adjustments –More weight gain

20. 15 10 15202530 1 5101520 Asp Gly Arg Extension Substitution Arg Insulin Glargine A New Long-Acting Insulin Analog l Modifications to human insulin chain –Substitution of glycine at position A21 –Addition of 2 arginines at position B30 l Gradual release from injection site l Peakless, long-lasting insulin profile

21. Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 6 5 4 3 2 1 0 010 Time (h) after SC injection End of observation period 2030 Glargine NPH Glucose utilization rate (mg/kg/h) Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp

22. Glucose Infusion Rate n = 20 T1DM Mean ± SEM SC insulin 4.0 3.0 2.0 1.0 0 24 20 16 12 8 4 0 04812162024 Time (hours) mg/kg/min µmol/kg/min Lepore M, et al. Diabetes. 2000;49:2142–2148. NPH Ultralente Glargine CSII

23. Treat to Target Study: NPH vs Glargine in DM2 patients on OHA l Add 10 units Basal insulin at bedtime (NPH or Glargine) l Continue current oral agents l Titrate insulin weekly to fasting BG < 100 mg/dL - if 100-120 mg/dL, increase 2 units - if 120-140 mg/dL, increase 4 units - if 140-160 mg/dL, increase 6 units - if 160-180 mg/dL, increase 8 units

24. Treat to Target Study; A1C Decrease

25. Patients in Target (A1C < 7%)

26. Bedtime Glargine vs NPH, With Mealtime Regular 4 3 2 1 0 48 36 24 12 0 Nocturnal Hypoglycemia Weight Gain * ** Weight (kg) NPH Glargine Patients (%) *P <.0007 **P <.02 (compared to NPH) Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100. 6-52

27. Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA l 57% had HbA1c <7% l Nocturnal Hypoglycemia reduced by 42% in the Glargine group l 33% had HbA1c <7% without any nighttime hypoglycemia in glargine group l Results significantly better than with NPH

28. Overall Summary: Glargine l Insulin glargine has the following clinical benefits –Once-daily dosing because of its prolonged duration of action and smooth, peakless time-action profile –Comparable or better glycemic control (FBG) –Lower risk of nocturnal hypoglycemic events –Safety profile similar to that of human insulin

29. Goals of Intensive Diabetes Management l Near-normal glycemia –HbA1c less than 6.5% l Avoid short-term crisis –Hypoglycemia –Hyperglycemia –DKA l Minimize long-term complications l Improve QOL

30. Type 2 Diabetes … A Progressive Disease Over time, all patients will need insulin to control glucose

31. Insulin Therapy in Type 2 Diabetes Indications l Significant hyperglycemia at presentation l Hyperglycemia on maximal doses of oral agents l Decompensation –Acute injury, stress, infection, myocardial ischemia –Severe hyperglycemia with ketonemia and/or ketonuria –Uncontrolled weight loss –Use of diabetogenic medications (eg, corticosteroids) l Surgery l Pregnancy l Renal or hepatic disease

32. MIMICKING NATURE WITH INSULIN THERAPY All persons need both basal and mealtime insulin (endogenous or exogenous) control to control glucose 6-19

33. Starting Basal Insulin l Continue oral agent(s) at same dosage –May later reduce l Add single insulin glargine dose (Wt# x 0.1 units) –Usually at bedtime l Adjust dose to normalize fasting SMBG l Increase insulin dose q 3 d as needed –Increase 4 U if FBG > 140 mg/dL –Increase 2 U if FBG = 110 to 140 mg/dL l Treat to target (usually < 110 mg/dL)

34. Advancing to Multiple Dose Insulin l Indicated when FBG acceptable but –HbA1c > 6.5% l Insulin options –Add mealtime lispro/aspart l Oral agent options –Stop sulfonylurea –Continue metformin for weight control –Continue glitazone for insulin sensativity

35. Goals in Management of Type 2 Diabetes l Fasting BG <126 mg/dl –Less Than 4 Months l HbA1c <7.0% –Less Than 8 Months i.e. 6%

36. Managing Type 2 Diabetes Four Months or Less to Goal 1

37. Managing Type 2 Diabetes Goal 2 (HbA1c <7.0%)

39. GEMS--Glargine Evening Mealtime Secretagogue l Basal Dosing –(Weight in #`s x 0.1) Glargine hs l Prior to Meals –Short Acting Secretagogue Rapaglinide 2 mg Nateglinide 120 mg –Glimepiride 2 mg

40. Routine Hospital Care for Type 2 Diabetes The Case for GEMS l Usually metformin contra-indicated l Glargine insulin required for normal am glucose –Stress or steroids l Interrupted and/or unreliable food intake l Nursing routine problems –Lispro insulin at time of tray –Reluctance to give lispro with normoglycemia l Supplemental lispro with elevated glucose l Short-acting secretagogue in half hour before tray –Little risk of hypoglycemia if limited intake

41. Infections in Diabetes l One BG >220 mg/dl results in 5.8 times increase in nosocomial infection rate l Two hours hyperglycemia results in impaired WBC function for weeks Pomposelli, New England Deaconess, J Parenteral and Enteral Nutrition 22:77-81,1998

42. DIGAMI Study Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction(1997) l Acute MI With BG >200 mg/dl l Intensive Insulin Treatment l IV Insulin For >24 Hours l Four Insulin Injections/Day For >3 Months l Reduced Risk of Mortality By 28% Over 3.4 Years 51% in Those Not Previous Diagnosed Malmberg BMJ 1997;314:1512

43. Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Malmberg, et al. BMJ. 1997;314:1512-1515. All Subjects (N = 620) Risk reduction (28%) P =.011 Standard treatment 0.3.2.4.7.1.5.6 01 Years of Follow-up 2345 Low-risk and Not Previously on Insulin (N = 272) Risk reduction (51%) P =.0004 IV Insulin 48 hours, then4 injections daily 0.3.2.4.7.1.5.6 01 Years of Follow-up 2345 6-11

44. ICU Survival l 1548 Patients l All with BG >200 mgm/dl l Randomized into two groups –Maintained on IV insulin –Conventional group (BG 180-200) –Intensive group (BG 80-110) l 1.74 X mortality in conventional group Van den Berghe NEJM 2001;345:1359

45. Protocol for Insulin in Hospitalized Patient l Glucommander While NPO l hs: Wt(#) x 0.1 Glargine l Meals Eaten: 1.5 units per 15 Gm CHO eaten l BG >150: (BG-100) / CF CF = 7000 / Wt(#) l Do Not Use Sliding Scale Only l Any BG <80: D50 (100-BG) x 0.3 ml Maintain INT l Do Not Hold Insulin When BG Normal

46. If HbA 1c is Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l Diet –accurate CHO counting –appropriate CHO/insulin bolusing l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG

47. If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

48. Improvement in HbA 1c with Increased BG Testing

49. If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

50. Median slope = 2.82 Data: file: IPDC020510A1cCIRs2, 127 pts CARBOHYDRATE TO INSULIN RATIO CIR = 2.8 * BW# / TDD

51. If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 22.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

52. Correction of Hypoglycemia with Glucose 100-BG X 0.15 Grams

53. If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

54. Correction Factor The 1700 Rule CF = 1724 / TDD n = 166

55. Future of Diabetes Management Improvements in Insulin & Delivery l Insulin analogs and inhaled insulin l External pumps l Internal pumps l Closed-loop systems

56. Conclusion Intensive therapy to target is the only way to treat patients with diabetes 4. Insulin Pump 3. Glargine + Lispro/Aspart 2. Glargine + Glinide or Sulfonylurea 1. Metformin + Glinide or Sulfonylurea