Combined Therapy with Insulin Plus Oral Agents. Is there Any Advantage?

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1 Combined Therapy with Insulin Plus Oral Agents Is there Any Advantage? Matthew C. Riddle, M.D. Professor of Medicine Oregon Health & Science University Portland, Oregon

2 Is there Any Advantage in Combined Therapy? Gewiss! Yes! Vraiment! Most patients with type 2 diabetes need combination therapy to reach usual glycemic targets... including those who need insulin

3 The Clinical Problem Loss of Control with Monotherapy in the UKPDS 9 Conventional (diet) Intensive (SU or insulin) Median HbA 1c (%) Years From Randomization UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:

4 Monotherapy in the UKPDS Obese Substudy Percent with HbA1c < 7% on monotherapy 3 years 6 years 9 years Diet Sulfonylurea Metformin Insulin Turner RC et al. UKPDS 49. J Am Med Ass 1999;21:2005

5 Monotherapy in the UKPDS Obese Substudy The majority of patients need multiple therapies to attain these target goals in the longer term. Turner RC et al. UKPDS 49. J Am Med Ass 1999;21:2005

6 Why combine oral agents with insulin? Pharmacology Physiology Clinical trials

7 Why combine oral agents with insulin? Pharmacology The ratio of desired to undesired effects may be improved

8 Dose-response Relationships for Effects of Treatments Desired effect % of maximal effect 100 % incidence 100 Undesired effect % of maximal dose

9 Dose-response Relationships for Metformin HbA1c reduction GI symptoms % of maximal effect % incidence h h h h h %?20-30% Mg metformin daily 2500 Garber AJ et al. Am J Med 1997;102:491

10 Dose-response Relationships for Glimepiride HbA1c reduction Hypoglycemia % of maximal effect % incidence 100 h h h Mg glimepiride daily Goldberg RB et al. Diabetes Care 1996;19: 849

11 Why combine oral agents with insulin? Physiology Glycemic variability and hypoglycemia can be reduced by enhancing the effectiveness of endogenous insulin

12 Three Main Oral agent + Insulin Combinations Sulfonylureas + Insulin Metformin + Insulin Thiazolidinediones + Insulin

13 Smooth Transition to Insulin while Continuing Glimepiride Placebo + 70/30 insulin titrated to 140 mg/dl Glimepiride + insulin 300 mg/dl * FPG 100 Units/Day * * * * 75 * * * Insulin Dosage * P <.001 Weeks of treament * P <.001 P <.05 Riddle MC et al. Diabetes Care. 1998;21: Weeks of treament Quicker control with 37% less injected insulin

14 Metformin or Glitazone + CSII in T2DM Effect on Plasma Glucose Continuous insulin infusion Continuous insulin infusion plus metformin Continuous insulin infusion Continuous insulin infusion plus troglitazone mg/dl 150 Metformin 150 Troglitazone Yu et al. Diabetes 1999;48: Time of day Time of day Equivalently excellent glycemic control

15 Metformin or Glitazone + CSII in T2DM Effect on Plasma Insulin Continuous insulin infusion Continuous insulin infusion plus metformin Continuous insulin infusion Continuous insulin infusion plus troglitazone pmol/l 1000 Metformin 1000 Troglitazone % insulin dose reduction % insulin dose reduction Time of day Yu et al. Diabetes. 1999;48: Time of day Reduced exogenous insulin requirement due to enhanced response to endogenous insulin

16 Variability of FPG in 2 Studies of glibenclamide and evening insulin SD of sequential FPG measurements Placebo/Ins Glibenclamide/Ins Bedtime NPH 1.7 ± ± 0.1 Riddle MC et al. P < 0.05 Diabetes Care 1989;12:623-9 Suppertime 70/ ± ± 0.1 Riddle MC et al. P < 0.05 Am J Med Sci 1992;:303: and 43% less variability with combination therapy

17 Glibenclamide is no longer a suitable choice as secretagogue Higher incidence of severe hypoglycemia in a populationbased study 1 Glibenclamide 5.60 per 1000 patient-year Glimepiride 0.86 Interference with cardiac ischemic preconditioning 2 Glibenclamide Glimepiride Abolished preconditioning No effect on preconditioning Higher mortality in a population taking a secretagogue with metformin 3 Glibenclamide 8.7 % per year Repaglinide 3.1 Gliclazide 2.1 Glimepiride Holstein A et al. Diab/Metab Res Rev 2001;17: Lee T-M & Chou T-F. J Clin Endocrinol Metab 2003;88: Monami M et al. Diab/Metab Res Rev 2006;22:

18 Summary of physiologic studies Secretagogues increase the proportion of insulin from endogenous secretion Sensitizers increase the response to endogenous insulin... both improve the effectiveness of remaining endogenous insulin

19 Why combine oral agents with insulin? Clinical trials Better glycemic control achieved Less weight gain

20 Improvement of Glycemic Control with Combination Therapy Previously insulin-treated T2DM patients Regimen Glycated Hb reduction vs insulin alone (despite insulin dose reductions) Insulin + sulfonylurea - 0.4% 7 studies Insulin + metformin - 1.3% 4 studies Insulin + TZD - 1.3% 2 studies Yki-Jarvinen H. Diabetes Care 2001;24:

21 Initiation of Bedtime NPH Insulin ± Glipizide N = 18 T2DM Baseline on Glipizide 20 mg/d After bedtime NPH titrated to FPG 120 mg/dl FPG 248 mg/dl % HbA 1c % 0 Bedtime NPH Bedtime NPH + glipizide 6 Bedtime NPH Bedtime NPH + glipizide Shank M et al. Diabetes. 1995;44: Better control with combination therapy

22 Metformin + Intensified N + R Insulin Insulin + Placebo Insulin + Metformin N = 22 N = 21 Insulin dosage (U/d) Baseline months Weight (kg) Baseline months HbA1c (%) -3 kg Baseline months Aviles-Santa et al. Ann Intern Med 1999;131: % Better control and no weight gain with combination therapy

23 Intensive Insulin Therapy ± Metformin 390 type 2 patients on insulin or insulin + metformin Mean age 61 yr, duration 13 yr, BMI 30, A1c 7.9% Randomized to Insulin 2 to 4 injections + Placebo Insulin 2 to 4 injections + metformin mg Endpoints At 48 months CV morbidity and mortality At 16 weeks glycemic control An early report after 16 weeks:... unexpected favorable effects of metformin Wulffele MG et al. Diabetes Care 2002;25:

24 Intensive Insulin Therapy ± Metformin Insulin + placebo Insulin + metformin Insulin u/d Metformin mg/d A1c % Endpoint Placebo adj < Weight kg Placebo adj < Hypoglycemia/pt-mo NS Wulffele MG et al. Diabetes Care 2002;25:

25 Unanswered questions Will limitation of weight-gain accompanying insulin treatment improve CV outcomes? What are the roles of pramlintide and exenatide combined with insulin? Will using all available agents to get to A1c 6% improve outcomes?

26 Pramlintide + Basal-prandial Insulin in T2DM Open-label clinical experience study 230 Baseline 6 Months 210 Glucose mg/dl * * * * * * * acb pcb acl pcl acd pcd hs *P <0.05 Karl D et al. Diabetes 2005; 54(S1):A12; in press Diab Res Clin Pract

27 The ACCORD Trial Can we get to 6% A1c and will that improve outcomes? 10,000 type 2 patients -- to be followed ~ 5.5 yr Primary endpoint -- major cardiovascular events Double 2x2 factorial design Intensive vs standard glycemic policy (n=10,000) Intensive vs standard blood pressure policy (n=5800) Statin treatment with or without added fibrate (n=4200) HbA1c target for intensive glycemic arm -- 6%, using any combination of agents, including intensive insulin