Review of Diabetes Therapies: Key Drivers of Disease Progression

Review of Diabetes Therapies: Key Drivers of Disease Progression David M. Kendall, MD Medical Director and Chief of Clinical and Professional Services Associate Professor of Medicine University of Minnesota Minneapolis, MN

Diabetes Therapies and Disease Progression: Discussion Outline Disease progression in Type 2 diabetes The role of beta cell function and insulin resistance Clinical consequences of disease progression Glycemic control and treatment failure Specific therapies effect on diabetes progression Diabetes prevention vs. disease progression A Glimpse of the Future Implications for Treatment Early intervention and diabetes treatment response Impact on the risk of complications

The Pathophysiology of Type 2 Diabetes Impaired Incretin Effect Insulin Resistance Relative Insulin Deficiency 2008. All rights reserved

Natural History of Type 2 Diabetes Glucose (mg/dl) 350 300 250 200 150 100 50 Diabetes diagnosis Postmeal Glucose Fasting glucose Relative amount 250 200 150 100 50 0-15 β cell function Incretin effect Insulin resistance Insulin level -10-5 0 5 10 15 20 25 30 Onset Diabetes Years Kendall DM, Cuddihy, RM, Bergenstal RM 2008. All rights reserved

Diabetes Disease Progression: β cell Dysfunction and Early Hyperglycemia Ferrannini E. J Clin Endocrinol Metab 90: 493 500, 2005

Diabetes Disease Progression: Clinical Consequences Implications of disease progression Progressive deterioration in glycemic control (UKPDS) Increasing risk of complications Stepped, failure-based therapeutic approach delay in Rx HbA 1c (%) 9 8 Interval Before Rx Change 7 25 20 15 10 5 Conventional (7.9%) 14.5 20.5 Intensive therapy (7.0%) Brown JB, et al. Diabetes Care. 2004;27:1535-1540. UKPDS 33. Lancet 352: 837 53, 1998 6 0 Metformin only (n = 513) Sulfonylurea only (n = 3394) 0 3 6 9 12 15 Years from randomization

Clinical Impact of Diabetes Therapy Diabetes Prevention and Disease Progression

Diabetes Disease Progression: Impact of Specific Therapies Therapy Improved Insulin Secretion Increased β cell mass Diabetes Prevention Disease Modification Lifestyle (MNT) Metformin Sulfonylurea Insulin Measures of fasting insulin Stimulated insulin response Beta cell mass Insulin content and mrna Stimulated (maximal) insulin secretion Prevent increase in FPG Maintain or restore normal glucose response Diabetes prevention Stability of glycemic control Limit need for added therapies AGI TZD Incretin based Rx

Diabetes Prevention Program (DPP) Prevention of Diabetes Placebo (n=1082) Metformin (n=1073, p<0.001 vs. PBO) Lifestyle (n=1079, p<0.001 vs. Met and PBO) 31% 58% The DPP Research Group, NEJM 346:393-403, 2002

The STOP-NIDDM Study: Effect of Acarbose Therapy 100 Cumulative Probability (%) 0.90 0.80 0.70 0.60 0.50 Placebo Acarbose 25% Relative Risk Reduction 0.40 0 200 400 600 800 1000 1200 Days After Randomization Chiasson JL et al. Lancet 2002;359:2072 and JAMA 2003;290:486

Durability of Glycemic Control with Sulfonylurea Therapy 1 Change in A1C (%) 0-1 Glimepiride Gliclazide Glyburide Glyburide Hanefeld (n=500) Charbonnel (n=630) Glyburide CHICAGO (n=462) ADOPT (n=2897) UKPDS (n=1573) -2 0 1 2 3 4 5 6 10 Time (yrs) Mazzone T. JAMA. 2006;296:2572-2581. Hanefeldd M. Cur Med Res Opin. 2006;22:1211-1215. Nissen SE. JAMA. 2008;299:1567-1573. UKPDS Study Group. Lancet.1998;352:837-853 Charbonnel B. Diabetoogia. 2005;48(6):1093-1104.

Intensive Treatment of Type 2 Diabetes: UKPDS HbA 1c (%) 9 8 7 6 UKPDS 33. Lancet 352: 837 53, 1998 UKPDS 16. Diabetes 44:1249 1258, 1995 Conventional (7.9%) Metformin Intensive therapy (7.0%) SU or insulin 0 3 6 9 12 15 Years from randomization 80 60 40 20 0 HOMA β-cell Function (%)

Diabetes Disease Progression: Impact of Specific Therapies Therapy Improved Insulin Secretion Increased β cell mass Diabetes Prevention Disease Modification Lifestyle (MNT) Metformin Sulfonylurea Insulin AGI TZD Incretin based Rx

Thiazolidinediones A Closer Look at β Cell Function and Diabetes Disease Progression

Effect of Early TZD Use on A1C

DREAM: Investigation of Diabetes Prevention or Delay Rate of new-onset diabetes or death 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 Follow-up (years) Placebo Rosiglitazone 60% RRR HR 0.40 (0.35 0.46) P < 0.0001. at risk Placebo 2634 2470 2150 1148 177 Rosiglitazone 2635 2538 2414 1310 217 DREAM Trial Investigators. Lancet 368(9541):1096-105, 2006

ADOPT Cumulative Incidence of Treatment Failure 40 Rosi vs metformin, 32% RRR P<0.001 Rosi vs glyburide, 63% RRR P<0.001 Glyburide Cumulative Incidence of Monotherapy Failure (%) 30 20 10 Improved estimates of β cell function Metformin Rosiglitazone 0 0 1 2 3 4 5 Years. at risk Rosiglitazone 1393 1207 1078 957 844 324 Metformin 1397 1205 1076 950 818 311 Glyburide 1337 1114 958 781 617 218 Kahn SE, et al. N Engl J Med 2006;355:2427 2443.

ADOPT Impact of Initial Therapy on A1C Glycated Hemoglobin (%) 8.0 7.6 7.2 6.8 6.4 6.0 Rosiglitazone vs metformin, -0.13% P=0.002 Rosiglitazone vs glyburide, -0.42% P<0.001 Annualized slope (95% CI) Rosiglitazone, 0.07 (0.06 to 0.09) Metformin, 0.14 (0.13 to 0.16)* Glyburide, 0.24 (0.23 to 0.26)* 0 0 1 2 3 4 5 Years. of Patients 4012 3308 2991 2583 2197 822 *Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment. Kahn SE, et al. N Engl J Med 2006;355:2427 2443.

Durability of Glycemic Control with Thiazolidindiones 1 Hanefeld (n=250) Tan (n=270) PERISCOPE (n=178) Chicago (n=232) ADOPT (n=1456) Change in A1C (%) 0-1 PIO PIO PIO PIO Rosiglitazone -2 0 1 2 3 4 5 6 Time (yrs) Kahn SE. N Engl J Med. 2006;355:2427-2443. Mazzone T. JAMA. 2006;296:2572-2581 Hanefeld M. Cur Med Res Opin. 2006;22:1211-1215. Tan MH. Diabetes Care. 2005;28:544-550 Nissen SE, et al. JAMA. 2008;299:1567-1573.

Incretin Based Therapy with GLP-1 Potential Impact on Disease Progression Excess food intake CNS: promotes satiety and reduction of appetite Excess glucose production Liver: glucagon reduces hepatic glucose output Glucagon excess Alpha cell: glucagon secretion post-meal Impaired β-cell function Beta cell: enhances glucosedependent insulin secretion and β cell mass Stomach: regulates gastric emptying Rapid substrate delivery Flint A et al. J Clin Invest. 1998;101:515-520. Larsson H et al. Acta Physiol Scand. 1997;160:413-422 Nauck MA et al., Diabetologia. 1996;39:1546-1553. Drucker DJ. Diabetes. 1998;47:159 169.

Exenatide Improves Phasic Insulin Secretion in Type 2 Diabetes

Incretin Based Therapies and Disease Progression Impact of Exenatide Over 3 Years Change in A1c (%) Change in Body Weight (kg) 10 1 9 0 8-1.1 ± 0.1% -1.0 ± 0.1% -1-2 7-3 6 5 54% % achieving A1C 7% 46% 4 0 26 52 78 104 130 156 Treatment (wk) -4-5.3 ± 0.4 kg -5-6 -7 0 26 52 78 104 130 156 Treatment (wk) Baseline Weight: 99 kg N = 217; Mean ± SE Klonoff DC, et al. Curr Med Res Opin 2008; 24:275-286

Exenatide vs Glargine Over 1 Year Impact on C-peptide Secretion During Hyperglycaemic Clamp 10 4 P< 0.0001 AIR arg C-peptide (nmol/l) 9 8 7 6 5 4 3 Ratio to baseline 3 2 1 0 3.19 1.31 2 1 0 Glucose 15 mm 165 180 190 210 240 260 270 290 Time (min) Mean (SE) Exenatide Glucose Bolus Arginine Bolus Bunck M. Diabetologia. EASD 2007/2008

The Temporal Pattern of Weight Loss with Exenatide Therapy Weight HbA1c Kendall DM et al. Diabetes 2008. ADA Annual Scientific Sessions

Impact of DPP-4 Inhibitor on Glycemic Control and Beta Cell Function 0.0 1400 Placebo LS Mean Change in A1C (%) 0.3 0.6 0.9 1.2 Sitagliptin 100 mg Glipizide Insulin Secretion (pmol/min) 1200 1000 800 600 400 Sitagliptin 100 mg Baseline (dashed) End-treatment period 1.5 Baseline A1C 7.7% 0 6 12 18 24 30 38 46 52 200 Pooled monotherapy studies 160 180 200 220 240 260 Week Glucose concentration (mg/dl) Nauck M. Diabetes Obes Metab, 2007; 9:195-205 Xu L, et al. Diabetes Obes Metab. 2008;10:1212-20

Impact of Type 2 Diabetes Therapy on Disease Progression: A Checklist Therapy Improved Insulin Secretion Increased β cell mass Diabetes Prevention Disease Modification Lifestyle (MNT) Metformin Sulfonylurea Insulin AGI TZD Incretin based Rx??

A Glimpse of the Future: Implications for Clinical Care Early intervention and diabetes treatment response Achieve and sustain glucose control Legacy effect on risk of complications Therapeutic Options Disease modification targeting pathophysiologic defects Sustain beta-cell responsiveness Early combination therapy Limit factors that negatively impact treatment response? Hypoglycemia? Weight gain? Treatment tolerability and concordance

Clinical Implications of Disease Progression: The Natural History of Type 2 Diabetes 9.5 Early 9.0 deterioration in glycemic control 8.5 Drives the risk for complications A1C (%) 8.0 7.5 7.0 6.5 May limit later efforts at intensive glucose control? 6.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 TIME (yrs since diagnosis) Adapted from Prof. Stefano del Prato. EASD Commentary, Rome ITALY, 2008. With permission