Insight Into Incretin Mimetics for Type 2 Diabetes

Insight Into Incretin Mimetics for Type 2 Diabetes A CME/CE Program Sponsored by PRIME

Learning Objectives Describe current barriers in targeting physiologic defects causing Type 2 diabetes Compare and contrast the therapeutic potential of incretin hormones with existing diabetes therapies Discuss the impact and potential outcomes of incretin mimetics in managed care

Diabetes: 20.8 Million and Climbing Estimated 14.6 million diagnosed + 6.2 million undiagnosed Type 2 diabetes accounts for 90-95% of cases Over 4,100 new cases are diagnosed each day Diagnosed Cases (Millions) 25 20 15 10 5 0 1980 1990 2000 2005 Data from the Centers for Disease Control and Prevention. Number of Persons with Diagnosed Diabetes, by Age, United States, 1980-2005. Accessed at: http://www.cdc.gov/diabetes/pubs/factsheet05.htm on 12/13/05.

Etiology of Type 2 Diabetes: Insulin Resistance and Diminished Insulin Secretion Genes Insulin Resistance Lifestyle and Diet Normal β-cell function Abnormal β-cell function Hyperinsulinemia Normoglycemia Felig P, et al. Endocrinology and Metabolism. 3rd ed. McGraw-Hill Inc; 1995. Adapted from: Dailey G. Relating Pathophysiology to Glucose Control. 2000 Relative insulin deficiency Hyperglycemia Type 2 diabetes

Economic Impact of Diabetes Total expenditures attributable to diabetes in 2002 = $132 billion Direct medical expenditures = $91.8 billion The largest source of direct medical expenditures is inpatient care, nursing home care, and office visits Indirect medical expenditures = $39.8 billion American Diabetes Association. Diabetes Care. 2003;26(3):917-932.

Economic Impact of Diabetes Median annual direct costs per patient with diet-controlled Type 2 Diabetes, BMI = 30 kg/m 2, and no end organ complications = $1,700 for white men and $2,100 for white women African-American patients generally incur lower costs, indicating they may receive less care Increase in BMI by 10 kg/m 2, use of prescription antihyperglycemic or antihypertensive drugs, CKD, CVA, or PVD may increase costs by up to 30% Requirement for insulin use or presence of CAD (angina and/or MI) may increase costs by 60-90% Requirement for dialysis increases costs 11-fold Brandle M, et al. Diabetes Care. 2003;26(8):2300-2304.

Excess U.S. Health Care Cost Attributable to Diabetes in 2002 Cost of Outpatient Care and Medications $ Millions 12,000 10,000 8,000 6,000 4,000 $10,033 million $3,930 million <45 45-64 65 or older $5,009 million $6,991 million $5,516 million 2,000 0 Physician Home Visits $146 million Ambulance OAD Insulin Other Medication American Diabetes Association. Diabetes Care. 2003;26:917-932. OAD = Oral Antidiabetic Drug

DCCT and UKPDS: Rising A1C Associated With Rising Complication Risk Continuous relationship between A1C and complication risk Lower A1C associated with lower complication risk No glycemic threshold down to normal range Rate/100 Patient Years 16 12 8 4 0 DCCT (Type 1) Retinopathy 5 6 7 8 9 10 11 12 Incidence/100 Patient Years 8 6 4 2 0 UKPDS (Type 2) Microvascular 5 6 7 8 9 10 11 A1C (%) A1C (%) DCCT Research Group. Diabetes 1996; 45:1289-1298. Adapted from Stratton IM, et al. BMJ 2000; 321:405-412.

HbA1C Goals For Clinical Practice 10.5 10.0 9.5 >9.5 41.3% of MCO population NCQA 2002 HEDIS: poor control HbA1C (%) 8.5 8.0 7.5 7.0 6.5 6.0 >8.0 <7.0 <6.5 6.0 ADA: recommended target AACE/ACE: recommended target Upper limit of normal range 5.5 ADA. Diabetes Care. 2002; 25(s1): S33-S49. ACE Consensus Conference on Guidelines for Glycemic Control. Endocrine Practice 2001 HEDIS 2000. Washington: National Committee for Quality Assurance, 1999. State of Managed Care Quality. National Committee for Quality Assurance, 2000.

Reduction in A1C Reduces Complications A1C Retinopathy Nephropathy DCCT 8.7 vs. 7% 54-76% 34-43% UKPDS 7.9 vs. 7% 21% 34% DCCT Research Group. N Engl J Med.1993; 329:977-986. UKPDS Group. Lancet.1998; 352: 837-853.

Cumulative Incidence of New Clinical Albuminuria > 300 mg/24 h During EDIC Cumulative Incidence (%) 12 10 8 6 4 2 0 83% risk reduction p <.0001 1-2 3-4 5-6 7-8 EDIC Year DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569

Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type I Diabetes Cumulative Incidence of Any Predefined Cardiovascular Outcome 0.12 0.10 0.08 0.06 0.04 0.02 0.00 Conventional Treatment Intensive Treatment 0 2 4 6 8 10 12 14 16 18 20 No. at Risk: Years Since Entry Intensive treatment 705 683 629 113 Conventional treatment 714 688 618 92 Cumulative Incidence of Nonfatal Myocardial Infarction, Stroke, or Death from Cardiovascular Disease 0.12 0.10 0.08 0.06 0.04 0.02 0.00 Conventional Treatment Intensive Treatment 0 2 4 6 8 10 12 14 16 18 20 No. at Risk: Years Since Entry Intensive treatment 705 686 640 118 Conventional treatment 721 694 637 96 Nathan D. et al. New Engl J Med. 2005;353:2643-2653.

Lower A1C Values Related to Lower Costs Retrospective database analysis designed to determine whether Type 2 diabetic patients treated in a managed care organization with Hb A1C 7.0% [at target level ] have lower diabetes-related costs than those > 7.0% [above target level ] 46% identified patients at target level with total 1 year costs of $1,171 54% identified patients above target level with total 1 year costs of $1,540, an excess of 32% (p < 0.001) Shetty S, et al. J Manag Care Pharm. 2005;11(7):559-564.

Targets for Glycemic Control A1C (%) Normal: 4%-6% Fasting or Preprandial (mg/dl) Postprandial (mg/dl) ADA < 7.0% 90-130 < 180* ACE 6.5% < 110 < 140 *peak postprandial 2-hour postprandial American Diabetes Association. Diabetes Care. 2005;28(suppl 1):S10. American Association of Clinical Endocrinologists. Endocr Pract. 2002;8(Suppl 1):5-11.

Currently Available Therapies for Type 2 Diabetes Oral insulin secretagogues Sulfonylureas (e.g., glyburide) Repaglinide Nateglinide Biguanides Thiazolidinediones Alpha-Glucosidase Inhibitors Human insulin and analogues Pramlintide Exenatide

Some Limitations of Therapy for Type 2 Diabetes Risk of hypoglycemia Inadequate postprandial glucose control Unpredictable glucose fluctuations Weight gain Progressive β-cell failure Over time, most patients will fail to maintain goal glycemia with oral therapy for Type 2 diabetes because of progressive β-cell failure

Novel Therapeutic Approach Restoring the Loss of Incretin Effect in Diabetes

Incretin Effect Plasma Insulin Responses to Oral and Intravenous Glucose Normal Weight: Non-Diabetic Subjects Normal Weight: Diabetic Subjects Plasma Insulin (µu/ml) 90 60 30 Oral Glucose Intravenous Glucose Plasma Insulin (µu/ml) 90 60 30 Oral Glucose Intravenous Glucose 0 0 30 60 90 120 150 180 0 0 30 60 90 120 150 180 Time (min) Non-Diabetic Subjects (glucose range 3.9-6.7 mmol/l) Diabetic Subjects (glucose range 4.7-12.2 mmol/l) Data from: Perley M, et al. J Clin Invest. 1967; 46:1954-1962. Time (min) = The Incretin Effect

The Incretin Hormones Peptide hormones secreted by the neuroendocrine cells of the gastrointestinal tract in response to nutrient ingestion Help to modulate pancreatic islet cell secretions Major incretins that affect glucose metabolism: GLP-1: glucagon-like peptide-1 GIP: glucose-dependent insulinotropic polypeptide Drucker DJ. Gastroenterology. 2002;122(2):531-544.

Glucagon-Like Peptide-1 (GLP-1) Product of the proglucagon gene secreted by intestinal L-cells Released rapidly in response to meals Has a very short half-life in vivo and is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) into inactive metabolites which are renally excreted Patients with impaired glucose tolerance and Type 2 diabetes have lower plasma levels of GLP-1 compared to healthy individuals Toft-Neilsen M, et al. J Clin Endocrinol Metab. 2001;86:3717-3723. Deacon CF, et al. Diabetes 1995;44:1126-1131.

Effects of GLP-1 on β-cells Acute: Enhances glucose-dependent insulin secretion Subacute: Stimulates transcription of proinsulin and biosynthesis of insulin Increases expression of Glut-2 and glucokinase Chronic: Stimulates proliferation and neogenesis of β-cells from precursor ductal cells and inhibits β-cell apoptosis Drucker DJ. Mol Endocrinol 2003; 17:161-171. Farilla L, et al. Endocrinology 2002;143(11):4397-4408.

GLP-1 Modes of Action in Humans Upon ingestion of food Stimulates glucose-dependent insulin secretion Suppresses glucagon secretion GLP-1 is secreted from the L-cells in the intestine Slows gastric emptying Reduces food intake This in turn Drucker DJ. Curr Pharm Des. 2001; 7:1399-1412. Drucker DJ. Mol Endocrinol. 2003; 17:161-171. Long term effects demonstrated in animals Increases β-cell mass and maintains β-cell efficiency

Enhancing the Effects of GLP-1 in Patients with Type 2 Diabetes Continuous infusion of native GLP-1 May be impractical outside the research setting Extending the activation of GLP-1 receptors Naturally occurring exendin-4 (Heloderma suspectum) Synthetic version = exenatide Long-acting GLP-1 analogues Blocking the degradation of GLP-1 DPP-IV inhibitors

Effect of 6-Week Course of GLP-1 Infusion in Type 2 Diabetes GLP-1 as a continuous subcutaneous infusion for 6 weeks resulted in: Lowered fasting plasma glucose by 77 mg/dl and mean plasma glucose by 100 mg/dl Decreased A1C levels by 1.3% Decreased body weight by 2-3 kg Increased insulin sensitivity by 77% Zander M, et al. Lancet. 2000;359:824-830.

Exendin-4 and GLP-1 Amino Acid Sequences: Exenatide (synthetic exendin-4) has an amino acid sequence that overlaps with native GLP-1 In clinical studies, exenatide exhibited actions that are similar to those of GLP-1: Glucose dependent stimulation of insulin secretion Glucose dependent suppression of postprandial glucagon secretion Slowing of gastric emptying Exenatide was recently approved by the FDA for the treatment of Type 2 Diabetes Eng J, et al. J Biol Chem 1992; 267:7402-7405; Keating GM. Drugs 2005;65(12):1681-1692.

Effect of Exenatide on Postprandial Glucose and Glucagon in Type 2 Diabetes Placebo Exenatide 0.1 µg/kg Placebo Exenatide 0.1 µg/kg Plasma Glucagon (pg/ml) 250 200 150 100 Exenatide or Placebo Standardized Breakfast Plasma Glucose (mmol/l) 20 15 10 5 Exenatide or Placebo Standardized Breakfast 50 0 30 60 90 120 150 180 0 0 60 120 180 240 300 Time (min) Time (min) Data adapted from Kolterman OG, et al. J Clin Endocrinol Metab. 2003; 88:3082-3089.

Effect of Exenatide on Fasting Plasma Glucose and Insulin in Type 2 Diabetes Serum Insulin (pmol/l) 300 250 200 150 100 50 Placebo 0.05 µg/kg exenatide 0.1 µg/kg exenatide 0.2 µg/kg exenatide 0-1 0 1 2 3 4 5 6 7 8 Plasma Glucose (mmol/l) 15 12.5 10 7.5 5 Placebo 0.05 µg/kg exenatide 0.1 µg/kg exenatide 0.2 µg/kg exenatide -1 0 1 2 3 4 5 6 7 8 Time (h) Time (h) Data adapted from: Kolterman OG, et al. J Clin Endocrinol Metab. 2003; 88:3082-3089.

Effect of 4 Weeks of Exenatide Treatment on A1C in Type 2 Diabetes Patients Mean (SE) Change in AIC (%) 0-0.2-0.4-0.6-0.8-1 -1.2 Placebo Exanatide (Breafast/Dinner) Exenatide (Breakfast/Bedtime) P < 0.006 compared to placebo. Exenatide (TID) Fineman MS, et al. Diabetes Care. 2003; 26:2370-2377.

Exenatide Large Phase 3 Clinical Studies (ITT) 0.5 0.1 0.1 0.2 Δ A1C (%) 0-0.5-1 -0.4 * Baseline -0.8-0.4* MET 1 n 113 110 113 8.2 8.3 8.2-0.8* Placebo BID Exenatide 5 mcg BID Exenatide 10 mcg BID -0.5* 123 125 129 8.7 8.5 8.6 SFU 2 MET + SFU 3-0.9* -0.6* 247 245 241 8.5 8.5 8.5-0.8* Mean (SE): *P < 0.005 1. DeFronzo. Diabetes Care. 2005;28:1092. 2. Buse. Diabetes Care. 2004;27:2628. 3. Kendall. Diabetes Care. 2005;28:1083.

Large Exenatide Phase 3 Clinical Studies Patients Achieving A1C 7% (ITT) % Achieving A1C 7% 60 40 MET (n = 243) 1 * 32 * 46 Placebo BID Exenatide 5 mcg BID Exenatide 10 mcg BID SFU (n = 237) 2 * 33 * 41 MET + SFU (n = 554) 3 * 27 * 34 20 13 9 9 0 Evaluable patients at 30 weeks with baseline A1C > 7%; *P < 0.01 1. DeFronzo. Diabetes Care. 2005;28:1092. 2. Buse. Diabetes Care. 2004;27:2628. 3. Kendall. Diabetes Care. 2005;28:1083.

Weight Changes: Exenatide + Oral Agent Therapy 30-Week, Randomized, Placebo-Controlled Trials Change in Weight (kg) 0.0-0.5-1.0-1.5-2.0-2.5-3.0 Placebo Exenatide 5 mcg Exenatide 10 mcg -0.6-0.9-1.6* Exenatide + SU 1 (n=377) 1. Buse. Diabetes Care. 2004;27:2628. 2. DeFronzo. Diabetes Care. 2005;28:1092. 3. Kendall. Diabetes Care. 2005;28:1083. -0.3-0.9-1.6* -1.6* -1.6* -2.8* Exenatide + Met 2 (n=336) Exenatide + SU + Met 3 (n=733) *P < 0.05 vs placebo

Major Adverse Events Associated with Exenatide Across All Studies Adverse Event Nausea Severe Nausea Hypoglycemia Dizziness Vomiting Diarrhea Headache Placebo 7-23% 2% 3-13% 6-7% 2-5% 4-8% 5-7% Exenatide 36-45% 3-5% 25% 4-15% 11-15% 10-17% 7-11% Buse JB, et al for the Exenatide-113 Clinical Study Group. Diabetes Care. 2004;27:2628-2635. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100. Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

Exenatide vs. Glargine Insulin in Patients Failing Oral Agent Therapy 8.5 2 Hemoglobin A 1c Level (%) 8.0 7.5 7.0 6.5 Exenatide group (n = 275) Insuline glargine group (n = 260) 0 12 26 Weeks Exenatide Group, n 275 244 229 Insulin Glargine Group, n 260 249 243 Heine, R J, et al. Ann Intern Med. 2005;143:559-569. Change in Body Weight (kg) 1 0-1 -2-3 * * * * Exenatide group (n = 275) Insulin glargine group (n = 260) 0 2 4 8 12 18 26 Weeks Exenatide Group, n 281 277 275 261 245 235 231 Insulin Glargine Group, n 267 266 261 253 251 246 244 *P < 0.0001 * *

Liraglutide (NN2211) His Ala Glu Gly Thr Phe Thr Ser Asp Val C-16 fatty acid (palmitoyl) Glu Glu Lys Ala Ala Gln Gly Glu Leu Tyr Ser Ser Phe Ile Ala Trp Leu Val Lys Arg Gly Arg Gly Liraglutide is a long-acting GLP-1 analogue currently in clinical trials* Acylation of GLP-1 improves pharmacokinetics by slowing absorption, reducing renal clearance, and slowing degradation by DPP-IV *Novo Nordisk expects to communicate full results from the phase 2b study at a scientific meeting in 2006. Knudsen LB, et al. J Med Chem 2000;43:1664-1669. Available at: http://www.glucagon.com/liraglutide.htm. Accessed on December 19, 2005.

Liraglutide (NN2211) Has a prolonged half-life (11-15 hours) when compared to native GLP-1 In early clinical trials*, has shown the ability to: Increase insulin secretion Suppress post-prandial glucagon secretion Delay gastric emptying Decrease A1C Decrease fasting blood sugar Improved glycemic control without weight gain *Novo Nordisk expects to communicate full results from the phase 2b study at a scientific meeting in 2006. Diabetes Care. 2004 Aug;27(8):1915-21. Diabet Med. 2005 Aug;22(8):1016-23.

Effects of Liraglutide on A1C after 12 weeks treatment 0,8 Change A1C (%) vs pbo, mean (95%CI) 0,4 0-0,4-0,8-1,2 Liraglutide 0.045 mg 0.225 mg 0.45 mg 0.60 mg 0.75 mg Matthews D, et al. Diabetes. 2002;51(Suppl 2):A84. Glimepiride

DPP-IV Inhibitors GLP-1 Secretion and Metabolism Mixed Meal Intestinal GLP-1 Release Plasma GLP-1(7-36) Active GLP-1 Actions DPP-IV XRapid Inactivation (> 80% of Pool) GLP-1(9-36) Inactive Renal Clearance Since DPP-IV rapidly breaks down GLP-1, inhibitors of this enzyme will result in a prolongation in the physiologic actions of GLP-1 Vildagliptin (DPP-IV inhibitor) manufactured by Novartis is currently in phase III trials which are expected to end 2005. Available at: http://www.glucagon.com/dpp-iv_inhibitors_and_treatment_of_human_diabetes.htm. Accessed 12/20/05.

Effects of the DPP-IV Inhibitor Vildagliptin on Glycemic Control Hemoglobin A1C (%) 8.00 7.75 7.50 7.25 7.00 6.75 6.50 Studies to date show that DPP-IV inhibitors significantly decrease Hb A1C and other measures of glycemic control. Placebo NVP DPP728 150 mg 2 NVP DPP728 100 mg 3-4 -2 0 2 4 Time (weeks) Ahrén B, et al. Diabetes Care. 2002;25:869-875.

Effects of the DPP-IV Inhibitor Vildagliptin on Glycemic Control Hemoglobin A1C (%) 8.4 8.0 7.6 7.2 6.8 LAF/MET (Core, ITT n = 56) PBOMET (Core, ITT n = 51) LAF/MET (Extension, ITT n = 42) PBO/MET (Extension, ITT n = 29) -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) Ahrén B, et al. Diabetes Care. 2004;27:2874-2880. Studies to date show that DPP-IV inhibitors significantly decrease Hb A1C and other measures of glycemic control.

Current Status of Incretin Related Therapies Exenatide received FDA approval in 2005 as therapy for type 2 patients who have not achieved adequate glycemic control despite treatment with metformin and/or a sulfonylurea agents Both long-acting GLP-1 analogues and oral DPP-IV inhibitors are currently in development

Managed Care Issues Cost of medication therapy vs. cost of diabetes and its complications Formulary Status When is prior authorization appropriate Impact of medication tiers and co-pays Medication costs related to other costs including physician and ER visits and hospitalizations Costs and mechanisms of medication acquisition including distribution through specialty pharmacy companies Impact of medication administration: oral vs. injection Need for patient education about disease and treatments Gleeson JM, et al. J Managed Care Pharm. 2005;11(Suppl 7):S2-S13.

Conclusions Incretin-related therapies offer great potential for the treatment of people with Type 2 diabetes These therapies have a unique mechanism of action that addresses glucose appearance as well as glucose disappearance As more agents in this class are developed and approved, their appropriate place in the treatment algorithm for Type 2 diabetes will need to be determined