Type 2 Diabetes Mellitus Incretin Based Therapy

Transcription

1 Type 2 Diabetes Mellitus Incretin Based Therapy Michael T. McDermott MD Director, Endocrinology and Diabetes Practice University of Colorado Hospital Michael.mcdermott@ucdenver.edu Type 2 Diabetes Mellitus Pathophysiology Glucose Production Insulin Resistance CNS Role Hyperglycemia Insulin Resistance Insulin Glucagon Incretin Effect 1

2 Metformin Type 2 Diabetes Mellitus Pathophysiology Based Therapy Bromocriptine Sulfonylurea Meglitinide Glucose Production Insulin Resistance CNS Effect Euglycemia Insulin Resistance Insulin Glucagon Incretin Effect Thiazolidinedione Thiazolidinedione GLP-1 Analog DPP4 Inhibitor Type 2 Diabetes Medications Personalized Medication Choice BG Target Other Key Features Fasting BG Metformin Weight Neutral, Inexpensive Thiazolidinedione Hypoglycemia Rare Basal Insulin Most Effective Postprandial BG GLP-1 Analog Weight Loss, Hypoglycemia Rare DPP4 Inhibitor Weight Neutral, Hypoglycemia Rare Sulfonylurea Rapid Acting, Inexpensive Meglitinide Rapid Acting Pramlintide Weight Loss, Hypoglycemia Rare 2

3 Normal Response to Meals Insulin Increases and Glucagon Falls mg/dl ( - ) Glucose Insulin 15 pm ( - ) 2 Glucagon 75 ng/l ( - ) Minutes After Meal Ingestion Woerle HJ, Am J Physiol Endocrinol Metab 23; 284:E716 E725 Response to Meals in Type 2 Diabetes Abnormal Insulin and Glucagon Dynamics Glucose, mg % Meal Type 2 diabetes Normal patients Insulin, µ/ml Glucagon, µµ/ml Müller WA, N Engl J Med 197; 283:19 15 (minutes) 3

4 Type 2 Diabetes Mellitus Lost First-Phase Insulin Response to IV Glucose 12 Normal 12 Type 2 Diabetes Plasma Insulin, µu/ml Plasma Insulin, µu/ml Time, min Time, min Pfeifer MA, Am J Med 1981; 7: Type 2 Diabetes Mellitus Lack of Glucagon Suppression Postprandial Hyperglycemia 216 Non-suppressed glucagon Suppressed glucagon Glucose, mg/dl Time, min Shah P, J Clin Endocrinol Metab 2; 85:

5 Incretin Effect Normal Subjects Plasma Glucose (mg/dl) 2 1 Oral Glucose IV Glucose C-peptide (nmol/l) Incretin Effect Time (min) Time (min) Nauck MA, J Clin Endocrinol Metab 1986; 63: Impaired Incretin Effect Type 2 Diabetes Mellitus Oral Glucose IV Glucose Healthy Subjects Incretin Effect 9 Type 2 Diabetes Incretin Effect Insulin (µu/ml) 6 3 Insulin (µu/ml) Time (min) Time (min) Perley M, J Clin Invest 1967; 46:

6 GLP-1 Stimulates Insulin Secretion and Suppresses Glucagon Secretion in Glucose Dependent Manner Type 2 Diabetes Glucose (mg/dl) Insulin (pmol/l) Glucagon (pmol/l) Time (min) Time (min) Time (min) Placebo GLP-1 Infusion Glucose Dependent Effects on Insulin and Glucagon Nauck MA, Diabetologia 1993; 36:741-4 Incretin Physiology Glucose Production Insulin Glucagon Gastric Emptying Satiety Appetite Glucose Dependent L-Cells GLP-1 T1/2 = 2 min GLP-1 = Glucagon Like Peptide-1 6

7 Incretin Based Therapy GLP-1 (7-36) T ½ : 1-2 min Dipeptidyl Peptidase 4 [DPP4] GLP-1 (9-36) Inactive GLP-1 Analog / Agonist Resistant to DPP4 Action Prolonged Duration of Action DPP4 Inhibitor Prevents Native GLP-1 Breakdown Prolongs Duration of Action of Native GLP-1 Incretin Based Therapy GLP-1 Analog / Agonist Exenatide (Byetta) Liraglutide (Victoza) Exenatide QW (Bydurion) DPP4 Inhibitor Sitagliptin (Januvia) Saxagliptin (Onglyza) 7

8 GLP-1 Agent Therapy Glycemic Effects GLP-1 Agents A1C FPG PPBG % (mg/dl) (mg/dl) Exenatide Liraglutide Exenatide QW Buse J, Diabetes Care 24; 27: Kendall D, Diabetes Care 25; 28: DeFronzo R, Diabetes Care 25; 28:192-1 Drucker D, Lancet 28;372: Klonoff DC, Curr Med Res Opin 28;24: Apovian C, Am J Med 21; 123:468 Diamant M, Lancet 21; 375: Bergenstal R, Lancet 21; 376:431-9 Marre M, Diabetes Med 29; 26: Nauck M, Diabetes Care 29; 32:84-9 Garber A, Lancet 29; 373: Zinman B, Diabetes Care 29; 32: Russell-Jones D, Diabetologia 29;52: Buse JB, Lancet 29; 374:39-47 GLP-1 Agent Therapy Weight Effects GLP-1 Agents Weight (kg) Exenatide Liraglutide Exenatide QW Buse J, Diabetes Care 24; 27: Kendall D, Diabetes Care 25; 28: DeFronzo R, Diabetes Care 25; 28:192-1 Drucker D, Lancet 28;372: Klonoff DC, Curr Med Res Opin 28;24: Apovian C, Am J Med 21; 123:468 Diamant M, Lancet 21; 375: Bergenstal R, Lancet 21; 376:431-9 Marre M, Diabetes Med 29; 26: Nauck M, Diabetes Care 29; 32:84-9 Garber A, Lancet 29; 373: Zinman B, Diabetes Care 29; 32: Russell-Jones D, Diabetologia 29;52: Buse JB, Lancet 29; 374:

9 DPP4 Therapy Glycemic and Weight Effects DPP4 Inhibitors A1C FPG PPBG % (mg/dl) (mg/dl) Sitagliptin Saxagliptin.5-.8 DPP4 Inhibitors Weight (kg) Sitagliptin No Δ Saxagliptin No Δ Goldstein B, Diabetes Care 27;3: Nauck M, Diab Obes Metab 27; 9: Raz I, Current Med Res Opin 28; 24:537-5 Visboll T, Diabetes Obes Metab 21; 12: Exenatide vs Sitagliptin Post-Prandial BG Control 28 Primary Endpoint PP Glucose (mg/dl) 24 2 Sitagliptin 28 Baseline Exenatide Standard Meal Time (min) DeFronzo R, Curr Med Res Opin 28; 24:

10 Liraglutide vs Sitagliptin: A1C 665 DM2 Subjects (on Met) Liraglutide 1.2 mg (221) Liraglutide 1.8 mg (218) Sitagliptin 1 mg (219) A1C 26 Weeks Liraglutide 1.2 Liraglutide 1.8 Sitagliptin Δ A1C Pratley R, Lancet 21; 375: Exenatide in Pre-Diabetes Obese / Pre-DM: N = 152, Age 46, Wt 18 kg, BMI 39.6, 82% F RCT: Exenatide (73) vs Placebo (79) x 24 weeks Weight Weight Intake IGT/IGF (Kg) (Kcal) Normalized Exenatide % Placebo % Rosenstock J, Diabetes Care 21, 33:

11 Exenatide Effect on Beta Cell Function Exe Exe Exe During Treatment (1 Year) 1 st Phase Insulin 2 nd Phase Insulin After Treatment Back to Baseline Bunck M, Diabetes Care 29; 33: Sitagliptin Plus Insulin Type 2 DM treated with Insulin RCT: Add on Sitagliptin (35) vs Placebo (312) x 24 weeks A1C FPG mg/dl 2 Hr PPG mg/dl +5.2 % % P < P < P <.1 Sitagliptin No Δ in Body Weight Placebo Visboll T, Diabetes Obes Metab 21; 12:

12 Exenatide Plus Basal Insulin DM2: 261 Adults on Glargine +/- Metformin or Pioglitazone (A1C: %) RCT: Add Exenatide BID vs Placebo A1C Buse J, Ann Intern Med 211; 154:13-12 Exenatide Plus Basal Insulin DM2: 261 Adults on Glargine +/- Metformin or Pioglitazone (A1C: %) RCT: Add Exenatide BID vs Placebo Body Weight 7 Point Profile Buse J, Ann Intern Med 211; 154:

13 Incretin Therapy Plus Basal Insulin Add on Sitagliptin or Exenatide to Insulin + Metformin Mean Blood Glucose Insulin + Metformin Insulin + Metformin + Sitagliptin N = 16 each group Insulin + Metformin + Exenatide Arnolds S, Diabetes Care 21; 33: Exenatide Therapy for 3 Years Cardio-Metabolic Effects Type 2 Diabetes Subjects (217) 3 Year Open Label Extension: Exenatide vs Placebo Chol LDL HDL TG SBP DBP +24% -5% -6% -3.5 mm -3.3 mm C/W Placebo -12% P.7 <.1 < <.1 Klonoff D, Curr Med Res Opin 28;24:

14 Exenatide vs Glargine Therapy for 1 Year Cardio-Metabolic Effects DM2 Subjects on Metformin (69) RCT: Added Exenatide vs Glargine x 1 Year Body Waist Total Truncal Weight Size Fat Fat hscrp +12% -6% -5% -11% -13% Adiponectin C/W Glargine: All Statistically Significant -61% Bunck M, Diabetes Care 21;33: GLP-1 Agent Therapy Cardio-Metabolic Effects GLP-1 Agents SBP DBP LDL TG (mmhg) (mmhg) (mg/dl) (mg/dl) Exenatide Liraglutide Exenatide QW Blonde L, Diabetes Obes Metab 26; 8: Drucker D, Lancet 28;372: Klonoff DC, Curr Med Res Opin 28;24: Apovian C, Am J Med 21; 123:468 Zinman B, Diabetes Care 29; 32: Buse JB, Lancet 29; 374:39-47 Bergenstal R, Lancet 21; 376:431-9 Verge D, Curr Diab Rev 21; 6:

15 GLP-1 Agent Therapy CV Risk Markers GLP-1 Agents Biomarker Ref Exenatide ApoB 1 Exenatide hscrp 61% Adiponectin 12% 2 Liraglutide PAI-1 29% BNP 38% 3 Liraglutide hscrp 23% BNP 12% 4 Exenatide QW hscrp 24 BNP 23% 5 1. Buse J, Diabetes Care 24; 27: Bunck M, Diabetes Care 21;33: Courreges J, Diabet Med 28; 25: Plutzky J, Eur Heart J 29; 3 (suppl): Bergenstal R, Lancet 21; 376: Verge D, Curr Diab Rev 21; 6:191-2 Exenatide and Postprandial Lipemia 35 Subjects: IGT (2) or Type 2 DM (15) Single Injection: Exenatide or Placebo Followed by High Fat Meal (5384 KJ) Triglycerides P <.1 Apo-B48 P <.1 Remnant Lipoprotein Triglycerides P <.1 Remnant Lipoprotein Cholesterol P <.1 Schwartz E, Atherosclerosis 21; 212:

16 Exenatide and Postprandial Lipemia 35 Subjects: IGT (2) or Type 2 DM (15) Single Injection: Exenatide or Placebo Followed by High Fat Meal (5384 KJ) Apo-CIII P <.1 Schwartz E, Atherosclerosis 21; 212: Exenatide and Endothelial Function 28 Subjects: IGT (16) or DM2 (12) Single Injection of Exenatide Followed by High Fat Meal PAT Index Postprandial Endothelial Function Improvement in DM2 Subjects Related to Postprandial TG Rise Koska J, Diabetes Care 21; 33:128 16

17 GLP-1 Infusion Endothelial and Vasoactive Effects GLP-1 Infusion (Healthy Subjects): 5% Endothelium Dependent Vasodilation (acetylcholine induced) No Δ Endothelium Independent Vasodilation (nitroprusside induced) GLP-1 Infusion (DM2, Stable CAD): Post-Ischemic Flow Mediated Dilation in the Brachial Artery Nystrom T, Am J Physiol Endocrinol Metab 24; 287:E Basu A, Am J Physiol Endocrinol Metab 27; 293:E Cardiovascular Events Exenatide Retrospective Database (LifeLink) Analysis (25-29) DM2 without CVD event in past 9 months. Exenatide (N=39,218 subjects) vs Non-exenatide (N=381,218 subjects) CVD Events Exenatide HR.81 ( ) P =.1 Best JH, Diabetes Care 211; 34:

18 Acute Pancreatitis Exenatide and Sitagliptin Retrospective Cohort Study, Claims Database (786,656 Patients) Diabetes vs Non-Diabetes Pancreatitis DM vs Non-DM HR 2.1 ( ) Garg R, Diabetes Care 21; 33: Acute Pancreatitis Exenatide and Sitagliptin Retrospective Cohort Study, Claims Database (786,656 Patients) Exenatide vs Sitagliptin vs Diabetes Controls Pancreatitis Exenatide HR.9 (.6-1.5) Sitagliptin HR 1. (.7-1.3) Garg R, Diabetes Care 21; 33:

19 Liraglutide and Medullary No Caption Found Thyroid Cancer Calcitonin Copyright 211 The Endocrine Society Hegedus L, J Clin Endocrinol Metab 211; 96:853-6 Liraglutide and Medullary No Caption Found Thyroid Cancer Calcitonin Copyright 211 The Endocrine Society Hegedus L, J Clin Endocrinol Metab 211; 96:

20 Summary GLP-1 insulin secretion and glucagon secretion in glucose dependent manner GLP-1 appetite and gastric emptying GLP-1 Analogs provide long-acting GLP-1 activity Reduce blood glucose and promote weight loss Reduce SBP and improve lipid profile May reduce CV risk profiles and events DPP4 Inhibitors prolong activity of native GLP-1 Reduce blood glucose and are weight neutral GLP-1 Analogs and DPP4 Inhibitors are effective alone, in combination with Oral Agents or with Insulin Thank You 2