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 Is there Any Advantage in Combined Therapy? Yes ! Gewiss! Vraiment! Most patients with type 2 diabetes need combination therapy to reach usual glycemic targets . . . including those who need insulin The Clinical Problem Loss of Control with Monotherapy in the UKPDS Conventional (diet) Intensive (SU or insulin) Years From Randomization
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. Monotherapy in the UKPDS Obese Substudy Percent with HbA1c < 7% on monotherapy Sulfonylurea Metformin
Turner RC et al. UKPDS 49. J Am Med Ass 1999;21:2005
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
Why combine oral agents with insulin? Pharmacology Physiology Clinical trials Why combine oral agents with insulin? Pharmacology The ratio of desired to undesired effects may be improved Dose-response Relationships for Effects of Treatments Desired effect Undesired effect % of maximal effect % incidence % of maximal dose Dose-response Relationships for Metformin HbA1c reduction GI symptoms % of maximal effect % incidence Mg metformin daily Dose-response Relationships for Glimepiride HbA1c reduction Hypoglycemia % of maximal effect % incidence Mg glimepiride daily
Goldberg RB et al. Diabetes Care 1996;19: 849
Why combine oral agents with insulin? Physiology Glycemic variability and hypoglycemia can be reduced by enhancing the effectiveness of endogenous insulin Three Main Oral agent + Insulin Combinations Sulfonylureas + Insulin Metformin + Insulin Thiazolidinediones + Insulin Smooth Transition to Insulin while Continuing Glimepiride Placebo + 70/30 insulin titrated to 140 mg/dL Glimepiride + insulin Insulin Dosage Units/Day * P <.001 Weeks of treament * P <.001 Weeks of treament † P <.05 Quicker control with 37% less injected insulin
Riddle MC et al. Diabetes Care. 1998;21:1052-57
Metformin or Glitazone + CSII in T2DM Effect on Plasma Glucose Continuous insulin infusion Continuous insulin infusion Continuous insulin infusion plus metformin Continuous insulin infusion plus troglitazone Metformin Troglitazone Time of day Time of day Equivalently excellent glycemic control Metformin or Glitazone + CSII in T2DM Effect on Plasma Insulin Continuous insulin infusion Continuous insulin infusion Continuous insulin infusion plus metformin Continuous insulin infusion plus troglitazone Metformin Troglitazone 31% insulin 53% insulin dose reduction dose reduction Time of day Time of day Reduced exogenous insulin requirement due to enhanced response to endogenous insulin Variability of FPG in 2 Studies of glibenclamide and evening insulin SD of sequential FPG measurements Placebo/Ins Glibenclamide/Ins Bedtime NPH 1.7 ± 0.2 1.1 ± 0.1 Riddle MC et al. P < 0.05 Diabetes Care 1989;12:623-9 Suppertime 70/30 1.4 ± 0.3 0.8 ± 0.1 Riddle MC et al. P < 0.05 Am J Med Sci 1992;:303:151-6 35 and 43% less variability with combination therapy Glibenclamide is no longer a suitable choice as secretagogue Higher incidence of severe hypoglycemia in a population- based study1 Glibenclamide per 1000 patient-year Glimepiride Interference with cardiac ischemic preconditioning2 Glibenclamide Abolished preconditioning Glimepiride No effect on preconditioning Higher mortality in a population taking a secretagogue with metformin3 Glibenclamide % per year Repaglinide Gliclazide Glimepiride
1 Holstein A et al. Diab/Metab Res Rev 2001;17: 467-732 Lee T-M & Chou T-F. J Clin Endocrinol Metab 2003;88: 531-73 Monami M et al. Diab/Metab Res Rev 2006;22: 477-82
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 Why combine oral agents with insulin? Clinical trials Better glycemic control achieved Less weight gain Improvement of Glycemic Control with Combination Therapy Previously insulin-treated T2DM patients Glycated Hb reduction vs insulin alone (despite insulin dose reductions) Insulin + sulfonylurea 7 studies Insulin + metformin 4 studies Insulin + TZD 2 studies
Yki-Jarvinen H. Diabetes Care 2001;24: 738-67
Initiation of Bedtime NPH Insulin ± Glipizide N = 18 T2DM Baseline on Glipizide 20 mg/d After bedtime NPH titrated to FPG 120 mg/dL Bedtime NPH Bedtime NPH Bedtime NPH Bedtime NPH + glipizide + glipizide Better control with combination therapy Metformin + Intensified N + R Insulin Insulin + Placebo Insulin + Metformin Insulin dosage (U/d) Baseline Weight (kg) Baseline HbA1c (%) Baseline Better control and no weight gain with combination therapy
Aviles-Santa et al. Ann Intern Med 1999;131:182-8
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 850-2550 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: 2133-40
Intensive Insulin Therapy ± Metformin Insulin + placebo Insulin + metformin Insulin u/d Metformin mg/d Endpoint Placebo adj ∆ <0.0001 Weight kg Placebo adj ∆ <0.0001 Hypoglycemia/pt-mo
Wulffele MG et al. Diabetes Care 2002;25: 2133-40
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? Pramlintide + Basal-prandial Insulin in T2DM Open-label clinical experience study Baseline *P <0.05 Karl D et al. Diabetes 2005; 54(S1):A12; in press Diab Res Clin Pract 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
Name___________________________________Period________Date_________ MULTIPLE CHOICE. Choose the one alternative that best completes the statement or answers the question. 1) Stress-inoculation therapy is one type of ________ therapy. 2) Showing a client how his or her irrational and self-defeating beliefs are causing problems is MOST characteristic of ________ ther
CONFEDERATION EUROPEENNE DE VOLLEYBALL 16. FREEDOM OF LIBERO - TEST RULE TO BE APPLIED The team may consist of 12 players with up to 2 Liberos within this number thereby respecting the below mentioned rules. The details below explain how this is to be accomplished, i.e. through the Rules and the Specific Sports Regulations for the event. The Rule(s) and interpretations for