GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics

GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics
Shannon I. Brow, RN, CDE, FNP-C Medical Science Liaison Amylin Pharmaceuticals, Inc

Faculty Disclosures: Shannon I. Brow, RN, CDE, FNP-C
Employee of Amylin Pharmaceuticals, Inc Stockholder: Amylin Pharmaceuticals, Inc

Learning Objectives Discuss the progressive nature of diabetes
Discuss the new ADA diagnostic criteria for diabetes published Jan 2010 Review incretin physiology in healthy individuals and in patients with type 2 diabetes Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists Identify where incretin therapies can be used in the treatment of type 2 diabetes

Progressive Nature of Type 2 Diabetes
Glucose (mg/dL) Diabetes diagnosis 50 100 150 200 250 300 350 Fasting glucose Prediabetes (Obesity, IFG, IGT) Postmeal Glucose -15 -10 -5 5 10 15 20 25 30 Years Relative Amount -10 -5 5 10 15 20 25 30 Insulin resistance Insulin level 50 100 150 200 250 -15 Incretin effect b-cell function β-cell failure Years Onset diabetes Microvascular changes Macrovascular changes Clinical features IFG, impaired fasting glucose; IGT, impaired glucose tolerance. Kendall DM, et al. Am J Med 2009;122:S37-S50. Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.

Postprandial Glucose Contribution to A1C
FPG (Fasting Plasma Glucose) PPG (Postprandial Plasma Glucose) 100 <7.3 30% 70% 50% 55% 45% 60% 40% >10.2 70% 30% 80 Slide Index PH0031-OL L: A,B,C DISCUSSION POINTS: When examining the relative contribution of fasting plasma glucose (FPG) and postprandial glucose (PPG) to overall hyperglycemia, the trend is for a proportionately increasing contribution of postprandial glycemia to A1C, as A1C decreases toward the normal range, with an opposite trend as A1C increases. In the commonly-observed ranges of A1C (7.3 to 10.2%), in patients with type 2 diabetes, each of fasting and postprandial glycemia contribute significantly to A1C. On the graph, the teal bars indicate PPG is of greater relative importance (contribution) as A1C decreases toward <7.3% A1C. Reversely, PPG contribution lessens while FPG contribution increases (lavender bars) as A1C increases toward >10.2% A1C). Therefore, in order to reach standard glycemic goals, PPG must be addressed and controlled. SLIDE BACKGROUND: This study analyzed the diurnal glycemic profiles of 290 patients with type 2 diabetes who exhibited different levels of glycemic control, as measured by A1C. The patients were treated with diet alone, or with a stable dose of metformin (1700 mg/day), glyburide (5-15 mg/day), or both for at least 3 months prior to this study. Plasma glucose (PG) concentrations were determined at fasting (8:00 A.M.) and during postprandial and post-absorptive periods (at 11:00 A.M., 2:00 P.M., and 5:00 P.M.). The areas under the curve above fasting PG concentrations (AUC1) and 6.1 mmol/l (AUC2 ) were calculated for further evaluation of the relative contributions of postprandial (AUC1/AUC2, %) and fasting [(AUC2 - AUC1 )/AUC2 , %] PG increments to the overall diurnal hyperglycemia. The data were then compared over quintiles of A1C. 60 % Contribution 40 20 A1C Range (%) Data from Monnier L, et al. Diabetes Care 2003; 26:

Plasma Glucose Is Normally Maintained in a Narrow Range
Healthy Subjects Type 2 Diabetes 400 300 SLIDE BACKGROUND: This slide illustrates that in healthy individuals, changes in glucose after meals are modest and kept within a very narrow range. Therefore, the natural defense against hyperglycemia is very aggressive. In patients with type 2 diabetes who have established fasting hyperglycemia, increases in postprandial glucose concentrations are further exaggerated. Plasma Glucose (mg/dL) 200 100 Breakfast Lunch Dinner 06.00 10.00 14.00 18.00 22.00 02.00 08.00 Time of Day (h) N = 30; Mean (SE) Data from Polonsky KS, et al. N Engl J Med. 1988;318:

A1C Goals Unmet in Majority of Patients With Diabetes
20.2% have A1C >9% 12.4% have A1C >10%1 10.0 9.5 9.0 Slide Index CC0009-OL L: A,B,C DISCUSSION POINTS: Although we have better tools to more aggressively treat diabetes, recent population data show that A1C levels are often in excess of 8% or 9%. This is far above the current AACE/ACE-recommended target goal (A1C <6.5%) and the ADA-recommended target goal (A1C <7%). Click 1: Percent of patients 9% and 10% arrows appear. Approximately 33% of patients fall well within the “red” range where patients show very poor glycemic control (A1C 9%). Click 2: Percent of patients >8% arrow appears. Recent publications based on data collected in the late 1990s through 2000 found approximately 60% to over 70% of patients with diabetes have an A1C 8%. Click 3: Percent of patients with type 2 diabetes 7% arrow appears. NHANES found that only 36% of patients with type 2 diabetes obtain glycemic control <7% A1C. Therefore, 64% of patients with type 2 diabetes with an A1C 7% have not achieved the ADA-recommended target. SLIDE BACKGROUND: Data from 2 US population-based cross-sectional surveys (NHANES and BRFSS): NHANES III: National Health and Nutrition Examination Survey, 1988 to 1994 (total people surveyed = 16,705 [n = 1026 participants with self-reported diagnosis of diabetes]). BRFSS: Behavioral Risk Factors Surveillance System, 1995 (total people surveyed = 103,929 [n = 3059 participants with self-reported diagnosis of diabetes]). Saaddine et al (Ann Intern Med 2002; 136: ) analyzed data from these 2 surveys. Subjects: age 18 to 75 y with a self-reported diabetes diagnosis (median A1C = 7.5%). Harmel et al (Endocr Pract 2002; 8: ) study was a noncomparative, multicenter, epidemiologic survey of type 2 patients from 9 community care clinics in the western US ( ). Subjects: age 35 to 70 y, using oral antidiabetic medications or insulin or both (n = 588; 67% received oral antidiabetic medication; 33% received insulin; mean A1C = 8.2%). A1C (%) 8.5 37.2% have A1C >8% 8.0 7.5 64.2% of patients with type 2 diabetes have A1C 7%2 7.0 ADA recommended target (<7%)3 6.5 ACE recommended target (<6.5%)4 6.0 Upper limit of normal range (6%) 5.5 1. Data from Saydah SH, et al. JAMA 2004; 291: 2. Calculated from Koro CE, et al. Diabetes Care 2004; 27:17-20. 3. Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S50. 4. Data from ACE. Endocrine Practice 2002.

Criteria for the Diagnosis of Diabetes
1. A1c ≥ 6.5%. This test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* OR 2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* 3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. This test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l). * In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing American Diabetes Association. Diabetes Care 2010;33(suppl 1):S62-S69.

Increased Beta-Cell Workload
The Pathogenesis of Type 2 Diabetes A New Perspective of the Core Defects Paradigm Increased Beta-Cell Workload (Insulin Resistance) Diminished Beta-Cell Response (Insulin Deficiency) Insulin Resistance Insulin Deficiency DISCUSSION POINTS: Insulin deficiency and insulin resistance, the two core defects of type 2 diabetes, lead to the development of hyperglycemia and type 2 diabetes. The beta-cell response and beta-cell workload concepts provide another way to understand the core defects paradigm. Insulin deficiency is an inadequate beta-cell response to the “demands” for insulin (carbohydrate ingestion, hepatic glucose production, insulin resistance). Contributors to increased glucose, thus increased beta-cell workload and insulin demand include: insulin resistance (perhaps the most prominent) paradoxical elevated postprandial glucagon secretion that stimulates the hepatic glucose production increased food intake and weight gain dysregulated gastric emptying that increases the absorption rate of meal-derived nutrients into the circulation The result is imbalanced beta-cell workload (increased) and beta-cell response (decreased) that contribute to the subsequent development of hyperglycemia and type 2 diabetes. SLIDE BACKGROUND: Contributors to insulin resistance include genetics, age, exercise/physical fitness, dietary nutrients, medications, obesity, and body fat distribution. Hyperglycemia Adapted from ©2005 International Diabetes Center, Minneapolis, MN All rights reserved

Decreased Beta-Cell Response Increased Beta-Cell Workload
The Pathogenesis of Type 2 Diabetes An Imbalance of Beta-Cell Workload and Beta-Cell Response  Insulin resistance Obesity  Food intake  Gastric Emptying –  Rate of nutrient absorption  Glucagon secretion  Hepatic glucose output Decreased Beta-Cell Response DISCUSSION POINTS: In type 2 diabetes, the ability to regulate many key physiological processes is impaired, manifesting as an increase in beta-cell workload and reduced beta-cell secretion as a result of reduced beta-cell capacity to secrete insulin and the increase in beta-cell workload. Beta cells secrete less and less insulin in response to elevated glucose, and first-phase insulin response progressively worsens. Several factors contribute to beta-cell workload and are known to contribute significantly to the pathophysiology of type 2 diabetes. The imbalance between beta-cell workload (demand) and beta-cell response gives rise to hyperglycemia. SLIDE BACKGROUND: Contributors to insulin resistance (in addition to obesity) include genetics, age, exercise/physical fitness, dietary nutrients, medications, and body fat distribution. Increased Beta-Cell Workload  Insulin secretion in response to elevated glucose  First-phase insulin response Hyperglycemia

The Pathophysiology of Type 2 Diabetes
Incretin “Defect” Insulin Resistance Relative Insulin Deficiency DISCUSSION: Classic understanding of the pathogenesis of type 2 diabetes consists or progressive insulin resistance coupled with gradual deterioration of beta cell function The literature makes it clear there is another fundamental defect in the pathogenesis of type 2 diabetes: dysregulation of incretin hormones The acute effects of incretin hormones play a major role in insulin secretion from the beta cell Hyperglycemia Type 2 Diabetes

Clinical Challenges With Type 2 Diabetes
A1C Weight Diet and Exercise MET SFU Insulin Diet and Exercise MET SFU Insulin 9 10 DISCUSSION POINTS Glucose control and weight management remain 2 of the most important clinical challenges with type 2 diabetes The data in this slide represent United Kingdom Prospective Diabetes Study (UKPDS) publication number 34 and describes the glycosylated hemoglobin A1c (A1C) and weight data from 1704 overweight (>120% ideal body weight) patients, a subset population of the 4075 patients in the entire UKPDS The study demonstrated that controlling weight while improving glycemia is difficult, especially in obese patients, regardless of the therapeutic agent used SLIDE BACKGROUND The lower A1C at baseline reflects a more recent onset of diabetes Reference Data from UKPDS Group (34). Lancet. 1998;352: 8 5 Median A1C (%)  Weight (kg) 7 6 6.2% A1C Upper limit of normal -5 2 4 6 2 4 6 Time From Randomization (y) Time From Randomization (y) n = 1704; A1C indicates glycosylated hemoglobin A1c; MET, metformin; SFU, sulfonylurea Data from UKPDS Group (34). Lancet 1998;352:

Blood Glucose Concentrations Are Largely Determined by Beta-Cell Function
Insulin synthesis Insulin secretion Beta-Cell Functional Capacity Beta-cell mass (cell turnover and neogenesis) First-phase/second-phase insulin release Insulin processing (proinsulin to insulin) Glucose sensitivity Beta-Cell Functional Demand Glucose absorption (diet, gastric emptying) Hepatic glucose production (glycolysis, gluconeogenesis) Peripheral glucose uptake (insulin sensitivity, exercise) DISCUSSION POINTS: Glucose concentrations are determined by beta-cell functional capacity (insulin activity) and beta-cell functional demand (glucose load), each of which is determined by multiple factors.

Multihormonal Regulation of Glucose Appearance and Disappearance
Mixed Meal (With ~85 g Dextrose) 0.6 Regulated by hormones: GLP-1, amylin, CCK, etc. 0.4 0.2 Meal-Derived Glucose DISCUSSION POINTS: Different hormones are responsible for mediating the different glucose fluxes that occur postprandially: Meal-derived glucose appearance is modulated by a number of hormones that regulate the rate of gastric emptying. Increase in glucose disappearance is insulin dependent. Suppression of hepatic glucose production is regulated by the opposing effects of insulin and glucagon. SLIDE BACKGROUND: Subjects received a 2-h primed, continuous infusion of tritiated glucose before the liquid meal (45% dextrose enriched with deuterated glucose, 35% fat, and 20% mixture of amino acids). The labeled glucose was utilized to determine total glucose production (tritiated glucose) and the contribution of meal-related glucose (deuterated glucose). Hepatic Glucose Production Balance of insulin suppression and glucagon stimulation Grams of Glucose (flux/min) Total Glucose Uptake -0.2 Insulin-mediated glucose uptake -0.4 -0.6 -30 120 240 360 480 Time (min) N = 5; Mean (SE) Data from Pehling G, et al. J Clin Invest 1984;74:

The Incretin Effect in Healthy Subjects
Oral Glucose Intravenous (IV) Glucose * 200 2.0 1.5 Incretin Effect DISCUSSION POINTS: The increasing plasma glucose resulting from ingestion of 50 g oral glucose (white line in left-side graph) results in an increase of C-peptide (a measure of insulin secretion) (white line in right-side graph). An isoglycemic intravenous glucose infusion designed to mimic the plasma glucose excursion achieved by the oral glucose load was later administered to the same study patients (orange line in left-side graph). The resulting beta-cell response, measured as C-peptide, is shown on the right-side graph. Despite the same plasma glucose profiles, there are significant differences in the beta-cell response, as measured by C-peptide. This difference prompted study into the role of incretins – factors secreted from the intestinal tract, upon the ingestion of food, that enhance the secretion of insulin – that would account for the greater insulin response to oral glucose. This incretin effect suggested that incretins, and not merely the direct actions of plasma glucose, affect the insulin secretory response. SLIDE BACKGROUND: Young, healthy subjects (n = 6), given 50 g oral glucose load or isoglycemic intravenous glucose infusion. Food elicits dynamic changes in insulin secretion, beginning with the cephalic phase, in which anticipation of a meal results in CNS-mediated release of insulin. An early prandial phase, mediated by gut-derived incretin hormones (e.g., GLP-1 and GIP), occurs after food intake but before the ingested nutrients appear in the circulation (or reach the intestinal L cells that secrete GLP-1). Cleavage of proinsulin generates both insulin and the C-peptide, which are stored together and cosecreted. Therefore, C-peptide serves as a marker for insulin secretion. 100 Plasma Glucose (mg/dL) C-Peptide (nmol/L) 1.0 0.5 0.0 60 120 180 60 120 180 Time (min) Time (min) N = 6; Mean (SE); *P0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:

GIP 42-amino acid peptide GLP-1 30-amino acid peptide
Incretins Gut-derived factors that potentiate insulin secretion following meal ingestion 2 principal incretins identified to date: GIP amino acid peptide GLP amino acid peptide DISCUSSION POINTS: Incretins, peptide hormones released by the intestine following a meal, enhance insulin secretion. Two principal incretins have been identified, glucose-dependent insulinotropic peptide (or gastric inhibitory peptide) and glucagon-like peptide 1 (GLP-1). Adapted from Holst JJ, et al. Am J Physiol Endocrinol Metab 2004; 287:E199-E206. Drucker DJ. Diabetes Care 2003; 26:

Comparison of the Incretins
Site of Production GLP-1 L-cells (Ileum and Colon) GIP K-cells (Duodenum and Jejunum) Decreases secretion in T2DM Yes No Inhibits glucagon secretion postprandially Yes No DISCUSSION POINTS: The gastrointestinal (GI) peptides, glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) and glucagon-like peptide-1 (GLP-1) are secreted in response to food ingestion. The evidence from antagonist and knockout models suggest that GIP and GLP-1 represent the dominant peptides responsible for the majority of nutrient-stimulated insulin secretion. In type 2 diabetes: GIP secretion is normal, but there is a defective beta-cell response to exogenously administered GIP. GLP-1 secretion is diminished, but glucoregulatory responses to exogenously administered GLP-1 are preserved. Reduces food intake Yes No Slows gastric emptying Yes No Stimulates beta-cell mass/growth Yes Yes Promotes insulin biosynthesis Yes Yes Knockout mice (result in IGT) Yes Yes Adapted from Mayo KE, et al. Pharmacol Rev 2003;55: Adapted from Drucker DJ. Diabetes Care 2003;26: Adapted from Nauck M, et al. Diabetologia 1986;29:46-52.

The Incretin Effect Is Reduced in Type 2 Diabetes
Oral Glucose Intravenous (IV) Glucose Healthy Subjects Type 2 Diabetes * 80 80 Incretin Effect Incretin Effect DISCUSSION POINTS: The additional insulin response observed with oral vs. IV glucose administration (i.e., the incretin effect) is reduced in subjects with type 2 diabetes compared to healthy subjects. SLIDE BACKGROUND: Insulin responses to a 50 g oral glucose load and intravenous glucose infusion designed to mimic glucose concentration profiles after a 50 g oral glucose load were measured in patients with type 2 diabetes (N = 14) and healthy controls (N = 8). The contribution of incretin factors to total insulin responses (with 100% = response to oral load) was 73% in control subjects and 36% in subjects with type 2 diabetes (P0.05). The greater beta-cell response observed in subjects with type 2 diabetes during intravenous glucose administration is due to the higher glucose stimulus in subjects with diabetes. 60 60 * Insulin (mU/L) 40 Insulin (mU/L) 40 20 20 60 120 180 60 120 180 Time (min) Time (min) N = 22; Mean (SE); *P0.05 Data from Nauck M, et al. Diabetologia 1986;29:46-52.

Glucagon-Like Peptide-1 (GLP-1) is an Important Incretin Hormone
The “incretin effect” started the search Incretins Gut hormones that enhance insulin secretion in response to food Glucose-dependent insulin secretion GLP-1 Secreted from L cells of the intestines Most well-characterized incretin Diminished in type 2 diabetes Glucagon Secreted from pancreatic alpha cells Counterregulatory hormone to insulin Elevated in type 2 diabetes DISCUSSION POINTS: The observation of the “incretin effect” started the search for “incretins” – factors secreted from the intestines that enhance the secretion of insulin in response to the ingestion of food. Glucose-dependent insulin secretion means enhanced insulin secretion is dependent on elevated blood glucose concentrations, and that when blood glucose concentrations return toward normal, enhanced insulin secretion subsides – hence, the glucose-dependent property. One of the incretins, glucagon-like peptide-1 (GLP-1) is of special interest, as besides enhancing glucose-dependent insulin secretion (beta-cell response), GLP-1 has other glucoregulatory effects that decrease beta-cell workload. Upon ingestion of food, GLP-1 is secreted into the circulation by the L cells of the small intestine. This occurs in advance of food directly stimulating the L cells, suggesting that a neural and/or hormonal communication pathway triggers the release of GLP-1 to prepare the body in advance of the absorption of carbohydrates from the meal. The similarity of GLP-1’s full name with glucagon is only because their amino acid chains are products of the same gene – not because they have similar sites of secretion, actions, or sites of action. NOTE: Speakers can highlight the differences that are included on the slide itself. Adapted from Aronoff SL, et al. Diabetes Spectrum 2004;17:

Postprandial GLP-1 Concentrations Are Lower in Subjects With IGT and Type 2 Diabetes
Healthy Subjects Impaired Glucose Tolerance Type 2 Diabetes Meal 20 * * * * * * 15 * DISCUSSION POINTS: These data show that postprandial GLP-1 concentrations are reduced in subjects with type 2 diabetes and impaired glucose tolerance (IGT). The top line represents GLP-1 concentrations in subjects with normal glucose tolerance (NGT). GLP-1 concentrations are statistically significantly reduced in patients with type 2 diabetes compared to NGT subjects from t = 60 min to 150 min. SLIDE BACKGROUND: Fifty-four subjects with type 2 diabetes (BMI 30.2 kg/m2, age 56 y, A1C 8.4%), 15 IGT (BMI 35.0 kg/m2, age 55 y, A1C 6.1%), and 33 NGT (BMI 29.6 kg/m2, age 56 y, A1C 5.9%). All antidiabetic medications were discontinued 3 days prior to study, during which time subjects were fed a mixed meal (t = 0) and blood samples were taken for 6 subsequent hours. Plasma concentration of GLP-1 were measured by means of RIA specific for C-terminus of GLP-1 which does not distinguish between GLP-1 (7-36) amide and its metabolite GLP-1 (9-36) amide. GLP-1 (pmol/L) 10 * 5 60 120 180 240 Time (min) N = 102; Mean (SE); *P<0.05 between type 2 diabetes and healthy subjects Data from Toft-Nielsen MB, et al. J Clin Endocrinol Metab 2001;86:

Insulin and Glucagon Responses Are Altered in Type 2 Diabetes
Healthy Subjects Type 2 Diabetes Carbohydrate Meal Carbohydrate Meal 120 Insulin (µU/mL) 60 140 Glucagon (pg/mL) DISCUSSION POINTS: This study also examined insulin secretion (beta-cell response) and glucagon secretion (alpha-cell response) to the same carbohydrate meal when ingested by patients with type 2 diabetes. In patients with type 2 diabetes (n = 12), compared to those without diabetes (n = 14), there is: less insulin secretion (less beta-cell response) paradoxically increased glucagon secretion – resulting in greater hepatic glucose output, and hence increased beta-cell workload. Other studies have shown that exogenous insulin does NOT adequately suppress the rise in glucagon. hyperglycemia as a result of decreased beta-cell response and greater beta-cell workload. SLIDE BACKGROUND: The carbohydrate meal consisted of 140 g spaghetti, 256 g corn, 252 g rice, 2 medium-sized potatoes (244 g), all of which were boiled, and 2 slides of white bread (26 g). Together, they contained approximately 200 g of carbohydrate. Mealtime hyperglucagonemia has been observed in individuals with IGT and patients with type 2 diabetes. Only 5 of the 12 subjects with type 2 diabetes are represented in the insulin graph (7 of 12 patients had insulin antibodies, thus precluding insulin assay). 120 100 Meal 360 300 Glucose (mg/dL) 240 140 80 -60 60 120 180 240 Time (min) N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med 1970;283:

GLP-1 Modulates Numerous Functions in Humans
GLP-1: Secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells:  Glucose-dependent postprandial glucagon secretion DISCUSSION POINTS: Upon food ingestion, GLP-1 is secreted into the circulation from L cells of small intestine. GLP-1 increases beta-cell response by enhancing glucose-dependent insulin secretion. GLP-1 decreases beta-cell workload and hence the demand for insulin secretion by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (beta-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on beta-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake By decreasing beta-cell workload and improving beta-cell response, GLP-1 is an important regulator of glucose homeostasis. SLIDE BACKGROUND: Effect on Beta Cell: Drucker DJ. Diabetes. 1998; 47: Effect on Alpha Cell: Larsson H, et al. Acta Physiol Scand. 1997; 160: Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997; 160: Effects on Stomach: Nauck MA, et al. Diabetologia. 1996; 39: Effects on CNS: Flint A, et al. J Clin Invest. 1998; 101: Liver:  Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest 1998;101: Data from Larsson H, et al. Acta Physiol Scand 1997;160: Data from Nauck MA, et al. Diabetologia 1996;39: Data from Drucker DJ. Diabetes 1998;47:

GLP-1 Effects Are Glucose Dependent in Type 2 Diabetes
Placebo GLP-1 PBO PBO PBO GLP-1 GLP-1 GLP-1 270 300 20 DISCUSSION POINTS: A continuous infusion of GLP-1 resulted in significant decrease in plasma glucose over a 4-h period, compared to placebo. GLP-1 initially enhanced insulin secretion, but as plasma glucose approached normal concentrations, insulin secretion subsided despite the continuing GLP-1 infusion – demonstrating glucose-dependent insulin secretion, compared to placebo. GLP-1 suppresses glucagon concentrations in the presence of hyperglycemia. However, glucagon concentrations return to baseline as plasma glucose approaches normal, despite continued infusion of GLP-1 – demonstrating that GLP-1 does not suppress glucagon during euglycemia or hypoglycemia. Glucose dependency is demonstrated by a return of plasma insulin and glucagon to pretreatment concentrations as plasma glucose approaches the normal range. SLIDE BACKGROUND: Subjects with type 2 diabetes (n = 10) – all on diet/SFU and some on metformin or acarbose. All antidiabetic medications were withheld at the start of the study. IV GLP-1 (7-36 amide) was infused for 4 h at 1.2 pmol/kg/min. * * 180 200 * Glucose (mg/dL) Insulin (pmol/L) Glucagon (pmol/L) 10 90 100 -30 60 120 180 240 -30 60 120 180 240 -30 60 120 180 240 Time (min) Time (min) Time (min) N = 10; Mean (SE); *P<0.05 Data from Nauck MA, et al. Diabetologia 1993;36:

GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV)
His Ala Glu Gly Thr Phe Ser Asp Lys Gln Leu Tyr Ile Trp Val Arg DPP-IV 7 37 9 DISCUSSION POINTS: GLP-1 is inactivated by DPP-IV by N-terminal degradation of the peptide at position 2 alanine. GLP-1 half-life in man is in the order of 1-2 min with a high clearance of 4-10 L/min. Adapted from Mentlein R. Eur. J. Biochem 1993;214:

Leveraging the Therapeutic Potential of GLP-1
Short half-life (2 minutes) Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) DPP-IV inhibition Extends endogenous GLP-1 half-life Approved in US: Sitagliptin (Merck) Saxaglitpin (BMS and AZ) In development, e.g., Alogliptin (Takeda) Denagliptin (Glaxo) Melogliptin (Glenmark) Vildagliptin – LAF 237 (Novartis) DISCUSSION POINTS: The half-life of GLP-1 is less than 2 min – meaning a continuous infusion of exogenous GLP-1 would be necessary to overcome the enzymatic degradation of GLP-1 by DPP-IV. Inhibition of DPP-IV, which would extend the half-life of endogenous GLP-1, is one avenue of research. Incretin mimetics are compounds that mimic GLP-1’s glucoregulatory effects, but are resistant to DPP-IV degradation. Examples are: Analogs of the natural GLP-1 molecule. Exenatide, a naturally occurring incretin mimetic that mimics multiple glucoregulatory effects of GLP-1 and is resistant to DPP-IV enzymatic degradation, is the first FDA-approved incretin mimetic.

Leveraging the Therapeutic Potential of GLP-1
GLP-1 receptor agonists Mimic many of the glucoregulatory effects of GLP-1 Resistant to DPP-IV Approved in US: Exenatide (Amylin and Lilly) Liraglutide (Novo Nordisk) In development, e.g., Albiglutide (Glaxo Smith Kline) CJC (ConjuChem) Exenatide once weekly (Amylin, Lilly, Alkermes) Lixisenatide (Sanofi- Aventis) Taspoglutide (Roche)

DPP-4 Inhibitor and GLP-1 Receptor Agonist Discussion
The slides that follow include data from the first FDA approved agent in each class Concepts are broad, yet representative of drugs that are FDA approved in each class There is no intent to claim superiority of the drug discussed compared to the other same class agent

Continuously Infused GLP-1 Improved the Defects of T2D
T2D Defects1 Continuously Infused GLP-11,2 Insulin production First-phase insulin response Glucagon; glucose output Gastric emptying Food intake HL Refs Aronoff_Diabetes_Spectrum_2004_p184,185,186,187,188.pdf Nielsen_Regul_Pept_2004_p77.pdf DISCUSSION Continuously infused GLP-1 has the following effects1,2 It enhances glucose-dependent insulin production It restores first-phase insulin response It decreases postprandial glucagon production, thus decreasing glucagon-stimulated hepatic glucose output It regulates gastric emptying, decreasing the rate of peak nutrient absorption from meals It decreases food intake REFERENCES 1. Aronoff SL, et al. Diabetes Spectrum. 2004;17: 2. Nielsen LL, et al. Regul Pept. 2004;117:77-78 1. Aronoff SL, et al. Diabetes Spectrum 2004;17: Nielsen LL, et al. Regul Pep. 2004;117:77-88. 32

Effects of GLP-1 on the b cell in Healthy Subjects
DISCUSSION One of the effects of GLP-1 is to directly stimulate glucose-dependent insulin secretion by binding to receptors on islet β cells GLP-1 receptor activation leads to insulin release via stimulation of exocytotic pathways and recruits signaling mechanisms that lead to promotion of cell proliferation and survival REFERENCE Drucker DJ. Cell Metab. 2006;3: 33

GLP-1 in T2D DISCUSSION The magnitude of nutrient-stimulated insulin secretion is diminished in patients with type 2 diabetes Meal-stimulated plasma levels of GLP-1 are modestly but significantly diminished in patients with impaired glucose tolerance and in patients with type 2 diabetes REFERENCE Baggio LL, et al. Gastroenterology. 2007;132: 34

GLP-1 Is Cleaved and Inactivated by DPP-4
DISCUSSION DPP-4 is a serine protease that preferentially cleaves peptide hormones containing a position 2 alanine or proline GLP-1 is an endogenous physiological substrate for DPP-4 DPP-4 cleaves and inactivates GLP-1 DPP-4 is a principal determinant of the circulating half-life of intact bioactive GLP-1 REFERENCE Drucker DJ. Diabetes Care. 2007;30: 35

Mechanism of Action: DPP-4 Inhibitors
Sitagliptin example

Sitagliptin Decreased A1C From Baseline Over 24 wks
Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009

Sitagliptin Decreased A1C Over 52 wks
Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009

DPP-4 Inhibitors Prevent the Inactivation of GLP-1
DISCUSSION DPP-4 is a serine protease that preferentially cleaves peptide hormones containing a position 2 alanine or proline1 GLP-1 is an endogenous physiological substrate for DPP-4 DPP-4 cleaves and inactivates GLP-1 DPP-4 is a principal determinant of the circulating t1/2 of intact bioactive GLP-1 DPP-4 inhibitors block DPP-4 enzyme activity, stabilizing active levels of GLP-12 REFERENCES 1. Drucker DJ. Diabetes Care. 2007;30: 2. Herman GA, et al. J Clin Endocrinol Metab.; 2006;91: 39

The Beginning Exenatide
Synthetic version of salivary protein found in the Gila monster More than 50% amino acid sequence identity with human GLP-1 Binds to known human GLP-1 receptors on beta cells (in vitro) Resistant to DPP-IV inactivation DISCUSSION POINTS: Exenatide, which was discovered in the salivary secretions of the Gila monster, has 53% amino acid sequence identity with mammalian GLP-1. Exenatide binds in vitro to the known human GLP-1 receptors on beta cells and mimics multiple glucoregulatory effects of GLP-1. The amino acid at position 2, the site of DPP-IV inactivation on the GLP-1 molecule, is different in exenatide – making exenatide resistant to DPP-IV enzymatic degradation. After a single SC injection, exenatide can be measured in the plasma for up to 10 h. SLIDE BACKGROUND: Following exenatide SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean terminal half-life of exenatide is 2.4 h. Pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose. Site of DPP-IV Inactivation Following injection, exenatide is measurable in plasma for up to 10 hours Adapted from Nielsen LL, et al. Regul Pept 2004;117: Adapted from Kolterman OG, et al. Am J Health-Syst Pharm 2005;62:

Exenatide Restored First-Phase Insulin Response
Healthy Controls Type 2 Diabetes Placebo Exenatide 30 30 Exenatide DISCUSSION POINTS: In individuals without type 2 diabetes (n = 13): the first-phase insulin response (the initial insulin secretion in the first 10 min after an IV glucose infusion) is extremely robust the second-phase insulin response (the more modest but sustained insulin secretion that continues from 10 to 120 min) is maintained to restore plasma glucose to normal concentrations Patients with type 2 diabetes have blunted first-phase and second-phase insulin responses (beta-cell response) compared to healthy controls. In patients with type 2 diabetes, after an IV glucose infusion, exenatide: elicited a 4-fold increase in first-phase insulin release (AUC0-10 min) (P< vs placebo) resulted in a significantly increased second-phase insulin release (AUC min) (P< vs. placebo) and was greater than that observed in the healthy control subjects (n = 12) (P<0.005) The increased insulin secretion seen with exenatide was appropriate for the insulin resistance in these patients with type 2 diabetes and resulted in glucose clearance rate that was comparable to the healthy controls. SLIDE BACKGROUND: IV infusion is not an approved route of administration for exenatide. Phase 2, randomized, single-blind, single-center crossover study of effects of exenatide on first- and second-phase insulin responses. Subjects with type 2 diabetes received both exenatide and placebo. 13 patients with type 2 diabetes (A1C 6.6%, BMI 32 kg/m2, 4-y history of disease); treatment: metformin, 2 acarbose, 1 diet/exercise. 12 age-, BMI-, and gender-matched healthy controls (A1C 5.5%, BMI 32 kg/m2) 20 20 Insulin (pM/kg/min) Insulin (pM/kg/min) 10 10 Placebo -180 -90 30 60 90 120 -180 -90 30 60 90 120 IV Glucose IV Glucose Time (min) Time (min) Evaluable; N = 25; Mean (SE) Fehse F, et al. J Clin Endocrinol Metab 2005;90(11):

Exenatide Suppressed Postprandial Glucose and Glucagon in Type 2 Diabetes
Placebo 0.10 µg/kg Exenatide 360 200 DISCUSSION POINTS: When a single dose of subcutaneous exenatide or placebo was administered to patients with type 2 diabetes 15 min prior to a standard meal test (liquid meal), exenatide: Eliminated the abnormal rise postprandial plasma glucose Suppressed postprandial glucagon concentrations, an important contributor to postprandial glucose surge SLIDE BACKGROUND: In a crossover study, subjects with type 2 diabetes (n = 20) were injected with single SC exenatide dose or placebo. 270 150 Plasma Glucose (mg/dL) Plasma Glucagon (pg/mL) 180 100 90 50 60 120 180 240 300 60 120 180 Standardized Breakfast Standardized Breakfast Exenatide or Placebo Exenatide or Placebo Time (min) Time (min) N = 20; Mean (SE) Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:

Plasma Glucose (mg/dL) Serum Insulin (pmol/L)
Exenatide Acutely Reduced Glucose Through Enhanced Glucose-Dependent Insulin Secretion Placebo µg/kg Exenatide µg/kg Exenatide 225 250 DISCUSSION POINTS: When a single subcutaneous dose of exenatide (0.05 µg/kg [n = 11] or 0.10 µg/kg [n = 12]) or placebo (n = 11) was given to hyperglycemic, fasting patients with type 2 diabetes: Plasma glucose concentrations were significantly lowered compared with placebo Plasma insulin concentrations were significantly increased compared with placebo As plasma glucose concentrations approached euglycemia (normal levels) for the exenatide treatment groups (~3 h), insulin secretion subsided to near-basal level, which demonstrated the glucose-dependent property of exenatide. SLIDE BACKGROUND: In a crossover study, subjects with type 2 diabetes were injected with single SC exenatide dose or placebo after an overnight fast (subjects remained fasting during the subsequent 8 h). 200 180 Plasma Glucose (mg/dL) Serum Insulin (pmol/L) 150 135 100 90 50 2 4 6 8 2 4 6 8 SC Injection SC Injection Time (h) Time (h) Type 2 Diabetes; N = 34; Mean (SE) Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:

Exenatide Is Not Inactivated by DPP-4
DISCUSSION Exenatide is not inactivated by DPP-4 and has a much longer plasma half-life than GLP-11,2 Exenatide is the synthetic version of exendin-41 Exendin-4 and GLP-1 have equivalent binding affinities for the GLP-1 receptor in in vitro assays, and both peptides stimulate the receptor equipotently1 REFERENCES 1. Nielsen LL, et al. Regul Pept. 2004;117:77-88 2. Baggio LL, et al. Gastroenterology. 2007;132: 44

Exenatide vs Sitagliptin MOA Study: Study Design
Primary endpoint: comparison of the effects of exenatide and sitagliptin on 2-hour PPG concentrations in patients with T2D Study Termination Randomization Crossover Treatment Period 1 Treatment Period 2 Exenatide 5 µg BID Exenatide 10 µg BID Exenatide 5 µg BID Exenatide 10 µg BID Sequence A Placebo Lead-in Sequence B HL Ref DeFronzo_Curr_Med_Res_Opin_2008_p7,9,15,27_ms.doc DISCUSSION This Phase 4, double-blind, randomized, double-dummy, crossover, multicenter study was composed of a 1-week placebo lead-in period followed by two 2-week treatment periods in patients with type 2 diabetes treated with a stable regimen of MET This crossover study is the first head-to-head clinical study to directly compare the mechanistic differences between the GLP-1 receptor agonist exenatide and the DPP-4 inhibitor sitagliptin Secondary/additional endpoints compared the effects of exenatide and sitagliptin on active GLP-1 concentration, FPG concentrations, insulinogenic index of insulin secretion, glucagon concentration, gastric emptying rate, caloric intake, body weight, and safety Within 2 weeks of screening, eligible patients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequences Exenatide treatment consisted of 5-µg SC doses BID for the first week, followed by 10-µg SC doses BID for the second week Sitagliptin treatment consisted of 100-mg doses taken orally every morning (QAM) for 2 weeks Standard meal tests were administered at the end of each treatment period After patients underwent an overnight fast of at least 10 hours, exenatide or sitagliptin was administered 15 minutes or 30 minutes (respectively) before the standard meal Meal size was calculated individually at screening to provide 20% of a patient’s total daily caloric intake requirements based on body weight; meals had a macronutrient composition of 55% carbohydrate, 15% protein, and 30% fat SLIDE BACKGROUND This study was designed to test the mechanistic effects of exenatide and sitagliptin on endpoints measured as part of the standard meal test Therefore, the primary analyses were performed on the evaluable population (n = 61), which was defined as ITT patients (N = 95) who completed standard meal procedures in both treatment periods, who received treatment per assigned sequence, and who had at least one quantifiable postdose plasma exenatide measurement and one sitagliptin measurement within the first 2 hours after a standard meal Patients were also required to meet the following criteria Age, 18 to 70 years A1C, 7.0% to 11.0% FPG concentration, <280 mg/dL BMI, 25 to 45 kg/m2 REFERENCE DeFronzo RA, et al. Curr Med Res Opin. In press Sitagliptin 100 mg Qam Sitagliptin 100 mg Qam 1 week 2 weeks 2 weeks Standard Meal Test Standard Meal Test Standard Meal Test MET background; MOA indicates mechanism of action; QAM, once per day in the morning DeFronzo RA, et al. Curr Med Res Opin 2008;24; 45

2-h Postprandial Plasma GLP-1 (pM) 2-h Plasma Exenatide (pM)
Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1 Baseline Exenatide Sitagliptin 75 75 63.8 50 50 2-h Postprandial Plasma GLP-1 (pM) 2-h Plasma Exenatide (pM) 25 25 HL Refs DeFronzo_Curr_Med_Res_Opin_2008_p11,18,25,28_ms.doc Herman_Clin_Pharmacol_Ther_2005_p682.pdf Kolterman_Am_J_Health Syst_Pharm_2005_p177,180,181.pdf Parkes_Drug_Dev_Res_2001_p Göke_J_Biol_Chem_1993_p19654.pdf DISCUSSION The left panel shows 2‑hour postprandial active plasma GLP‑1 concentrations during a standard meal test at baseline and after 2 weeks of treatment with exenatide or sitagliptin1 The mean 2‑hour plasma concentration of exenatide is shown in the right panel After treatment with exenatide or sitagliptin, plasma exenatide and sitagliptin concentrations were at known therapeutic levels2,3 Mean ± SE 2‑hour plasma exenatide concentration was 63.8 ± 6.7 pM, and the mean ± SE 2‑hour plasma sitagliptin concentration was ± 28.4 nM1 Consistent with the therapeutic concentrations of sitagliptin achieved in the present study, 2‑hour postprandial active GLP‑1 concentrations with sitagliptin treatment (15.1 ± 1.0 pM) were approximately 2 times as high as concentrations at baseline (7.2 ± 0.7 pM) and with exenatide treatment (7.9 ± 2.3 pM)1 (mean ± SE) SLIDE BACKGROUND The mean 2‑hour plasma exenatide concentration (63.8 pM) was approximately 4 times as great as the mean 2‑hour postprandial plasma GLP‑1 concentration observed with sitagliptin (15.1 pM)1 On a picomolar basis, the degree of activation of the GLP‑1 receptor by exenatide is at least equivalent to,4 if not greater than, the degree of activation by native GLP-1, according to in vitro studies5 REFERENCES 1. DeFronzo RA, et al. Curr Med Res Opin. In press 2. Herman GA, et al. Clin Pharmacol Ther. 2005;78: 3. Kolterman OG, et al. Am J Health Syst Pharm. 2005;62: 4. Parkes D, et al. Drug Dev Res. 2001;53: 5. Göke R, et al. J Biol Chem. 1993;268: 15.1 7.2 7.9 Plasma GLP-1 Plasma Exenatide Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE 2-wk posttreatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008;24: 46

Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin
Primary Endpoint Baseline Exenatide Sitagliptin HL Refs DeFronzo_Curr_Med_Res_Opin_2008_p7,9,12,25,29_ms.doc Amylin_BCA403_SDS_ _p42,43,44.pdf Amylin_BCA403_SDS_2.2.3_p53,54,55.pdf Amylin_BCA403_SDS_2.1.8_p41.pdf ADA_Diabetes_Care_2008_pS18.pdf DISCUSSION Compared to PPG concentrations at baseline, reductions in PPG concentrations over time were greater with exenatide treatment than with sitagliptin treatment1 The 2-hour PPG concentration (LS mean ± SE) for the ITT population was significantly lower with exenatide than with sitagliptin (166 ± 7 mg/dL vs 210 ± 7 mg/dL; P <0.0001) The change in 2‑hour PPG concentration from baseline (LS mean ± SE) for the ITT population was ‑91 ± 7 mg/dL for exenatide vs ‑47 ± 7 mg/dL for sitagliptin (P <0.0001)2 The 2-hour PPG concentration (LS mean ± SE) for the evaluable population was significantly lower with exenatide than with sitagliptin (133 ± 6 mg/dL vs 208 ± 6 mg/dL; P <0.0001) The change in 2‑hour PPG concentration from baseline (LS mean ± SE) for the evaluable population was ‑112 ± 6 mg/dL for exenatide vs ‑37 ± 6 mg/dL for sitagliptin (P <0.0001)2 All PPG parameters (area under the curve [AUC], average concentration [Cave], and maximum concentration [Cmax]) were significantly lower with exenatide treatment than with sitagliptin treatment (P <0.0001)1 Exenatide decreased PPG AUC0-240 min (mg • min/dL) by 26% vs sitagliptin (0.74 ± 0.02; geometric LS mean ratio ± SE)2 Exenatide decreased PPG Cave0-240 min (mg/mL) by 26% vs sitagliptin (0.74 ± 0.02; geometric LS mean ratio ± SE)2 The Cave is equal to the corresponding AUC divided by the time period Exenatide decreased Cmax (mg/dL) by 19% vs sitagliptin (0.81 ± 0.03; geometric LS mean ratio ± SE)2 The current ADA peak PPG goal3 for patients with type 2 diabetes is <180 mg/dL SLIDE BACKGROUND1 This was a Phase 4, double-blind, randomized, double-dummy, crossover, multicenter study composed of a 1-week placebo lead-in period followed by two 2-week treatment periods in patients with type 2 diabetes treated with a stable regimen of MET Patients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequences Exenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second week Sitagliptin doses were 100 mg PO QAM for 2 weeks The primary endpoint (comparison of the effects of exenatide and sitagliptin on 2-hour PPG concentrations) was analyzed using a mixed-effect model with treatment, treatment sequence, and period as fixed effects, patient-within-sequence as a random effect, and study baseline 2-hour PPG concentration (on Day -1) as a covariate REFERENCES 1. DeFronzo RA, et al. Curr Med Res Opin. In press 2. Data on file, Amylin Pharmaceuticals, Inc. 3. ADA. Diabetes Care. 2008;31;(Suppl 1):S12-S54 PPG (mg/dL) Standard Meal Time (min) Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P<0.0001 DeFronzo RA, et al. Curr Med Res Opin 2008;24: 47

Reductions in 2-Hour PPG Were Greater With Exenatide Than With Sitagliptin
Baseline End of Period 1 End of Period 2 Exenatide Sitagliptin HL Refs Amylin_BCA403_SDS_ _p31.pdf DeFronzo_Curr_Med_Res_Opin_2008_p7,9,12,25,29_ms.doc ADA_Diabetes_Care_2008_pS18.pdf DISCUSSION For patients treated with exenatide-sitagliptin (n = 29), the baseline 2-hour PPG concentration was 232 ± 13 mg/dL (all data given as mean ± SE)1 Exenatide treatment (period 1) reduced the 2-hour PPG concentration2 to 133 ± 10 mg/dL Subsequent sitagliptin treatment (period 2) increased the 2-hour PPG concentration2 to 205 ± 12 mg/dL For patients treated with sitagliptin-exenatide (n = 32), the baseline 2-hour PPG concentration1 was 257 ± 11 mg/dL Sitagliptin treatment (period 1) reduced the 2-hour PPG concentration2 to 209 ± 11 mg/dL Subsequent exenatide treatment (period 2) further reduced the 2-hour PPG concentration2 to 133 ± 9 mg/dL The current ADA peak PPG goal3 for patients with type 2 diabetes is <180 mg/dL SLIDE BACKGROUND1 This was a Phase 4, double-blind, randomized, double-dummy, crossover, multicenter study composed of a 1-week placebo lead-in period followed by two 2-week treatment periods in patients with type 2 diabetes treated with a stable regimen of MET Patients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequences Exenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second week Sitagliptin doses were 100 mg PO QAM for 2 weeks The primary endpoint (comparison of the effects of exenatide and sitagliptin on 2-hour PPG concentrations) was analyzed using a mixed-effect model with treatment, treatment sequence, and period as fixed effects, patient-within-sequence as a random effect, and study baseline 2-hour PPG concentration (on Day -1) as a covariate REFERENCES 1. Data on file, Amylin Pharmaceuticals, Inc. 2. DeFronzo RA, et al. Curr Med Res Opin. In press 3. ADA. Diabetes Care. 2008;31;(Suppl 1):S12-S54 2-hr PPG (mg/dL) After Period 1, patients were switched to the other therapy Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32 Mean ± SE; DeFronzo RA, et al. Curr Med Res Opin 2008;24: 48

Improvement in Insulinogenic Index Was Greater With Exenatide Than With Sitagliptin
Geometric Mean Baseline Insulinogenic Index2: 0.4 P = 0.02 1.0 0.9 0.8 0.82 0.82 HL Refs DeFronzo_Curr_Med_Res_Opin_2008_p7,9,10,12,13,25,30_ms.doc Hovorka_Comput_Methods_Programs_Biomed_1996_p253.pdf Amylin_BCA403_SDS_2.17.2_p172.pdf DISCUSSION1 Acute β-cell function, as assessed with the insulinogenic index and insulin secretion rate (ISR), was greatly improved with exenatide treatment compared with sitagliptin treatment The insulinogenic index was significantly greater with exenatide treatment than it was with sitagliptin treatment (insulinogenic index [µIU/10‑2L per mg] geometric LS mean ratio ± SE of exenatide to sitagliptin: 1.50 ± 0.26; P = ) The acute insulin response, as determined by the ISR from 0 to 30 minutes (AUC ISR/AUC glucose [pmol • dL]/[kg • mg • min]) was significantly greater for exenatide (0.040 ± 0.003) than for sitagliptin (0.030 ± 0.002; P = ) (mean ± SE) SLIDE BACKGROUND1 This was a Phase 4, double-blind, randomized, double-dummy, crossover, multicenter study composed of a week placebo lead-in period followed by two 2-week treatment periods in patients with type 2 diabetes treated with a stable regimen of MET Patients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequences Exenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second week Sitagliptin doses were 100 mg PO QAM for 2 weeks ISR was estimated from plasma C‑peptide levels using the Insulin SECretion computer program, which employs a regularized method of deconvolution constrained to nonnegative values to carry out the calculations2 An index of the acute phase insulin response to the meal was calculated as the ratio of the ISR AUC to the plasma glucose AUC levels for 0 to 30 minutes after the meal, and the indexes were compared between treatments using the mixed‑effect model The insulinogenic index at peak glucose was calculated as: [insulin (uIU/mL) at peak glucose - insulin at mealtime]/ [glucose (mg/dL) at peak - glucose at mealtime] REFERENCES 1. DeFronzo RA, et al. Curr Med Res Opin. In press 2. Hovorka R, et al. Comput Methods Programs Biomed. 1996;50: Insulinogenic Index1 0.7 0.6 0.55 0.55 0.5 0.4 Exenatide Sitagliptin Patients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean ± SE Standard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24: Data on file, Amylin Pharmaceuticals, Inc. 49

Plasma Glucagon (pg/mL)
Exenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than Sitagliptin Baseline Exenatide Sitagliptin Plasma Glucagon (pg/mL) HL Refs DeFronzo_Curr_Med_Res_Opin_2008_p7,13,25,30_ms.doc Amylin_BCA403_SDS_ _2.6.3_p80,81,82,87.pdf DISCUSSION1 Compared to levels at baseline, reductions in postprandial glucagon levels over time were greater with exenatide treatment than with sitagliptin treatment Exenatide decreased glucagon AUC0-240 min [(pg • min)/mL] by 12% vs sitagliptin (0.88 ± 0.03; geometric LS mean ratio ± SE; P = )2 SLIDE BACKGROUND1 This was a Phase 4, double-blind, randomized, double-dummy, crossover, multicenter study composed of a 1-week placebo lead-in period followed by two 2-week treatment periods in patients with type 2 diabetes treated with a stable regimen of MET Patients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequences Exenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second week Sitagliptin doses were 100 mg PO QAM for 2 weeks REFERENCES 1. DeFronzo RA, et al. Curr Med Res Opin. In press 2. Data on file, Amylin Pharmaceuticals, Inc. Standard Meal Time (min) Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE DeFronzo RA, et al. Curr Med Res Opin 2008;24: 50

Exenatide Slowed Gastric Emptying Compared to Sitagliptin
Baseline Exenatide Sitagliptin HL Refs DeFronzo_Curr_Med_Res_Opin_2008_p7,8,13,17,25,31_ms.doc Amylin_BCA403_SDS_ _2.9.3_p107,108,109,116.pdf DISCUSSION1 Exenatide treatment reduced the rate of gastric emptying compared with rates at baseline and with sitagliptin treatment Exenatide decreased acetaminophen AUC0-240 min (mg • min/dL) by 44% vs sitagliptin (0.56 ± 0.05; geometric LS mean ratio ± SE; P<0.0001)2 Sitagliptin had no effect on gastric emptying SLIDE BACKGROUND1 This was a Phase 4, double-blind, randomized, double-dummy, crossover, multicenter study composed of a 1-week placebo lead-in period followed by two 2-week treatment periods in patients with type 2 diabetes treated with a stable regimen of MET Patients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequences Exenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second week Sitagliptin doses were 100 mg PO QAM for 2 weeks Gastric emptying rate was assessed at baseline and at the end of each treatment period by determining plasma acetaminophen concentrations during the 4-hour period after a single oral dose of acetaminophen (1,000 mg of liquid) that was administered immediately before the standard meal REFERENCES 1. DeFronzo RA, et al. Curr Med Res Opin. In press 2. Data on file, Amylin Pharmaceuticals, Inc. Plasma Acetaminophen (µg/mL) Standard Meal Time (min) Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophen was administered immediately before the standard meal; DeFronzo RA, et al. Curr Med Res Opin 2008;24: 51

GLP-1 Receptor Agonists1,2
Actions of Incretin-Based Therapies for T2D: GLP-1 Receptor Agonists and DPP-4 Inhibitors Action GLP-1 Receptor Agonists1,2 DPP-4 Inhibitors1,2 Insulin production +++ ++ First-phase insulin response Glucagon; glucose output + Gastric emptying Delayed No effect Food intake Decreased HL Ref DeFronzo_Curr_Med_Res_Opin_2008_p12,13,14_ms.doc DISCUSSION1,2 GLP-1 agonists and DPP-4 inhibitors have some overlapping actions that are beneficial in the treatment of type 2 diabetes Both suppress glucagon secretion, leading to a reduction in glucose output Both enhance glucose-dependent insulin secretion GLP-1 agonists have additional therapeutic actions for which DPP-4 inhibitors exhibit marginal or no obvious effects GLP-1 agonists suppress appetite/induce satiety GLP-1 agonists decelerate gastric emptying REFERENCES 1. Drucker DJ and Nauck MA. Lancet. 2006;368: 2. DeFronzo RA, et al. Curr Med Res Opin. In press 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24: Drucker DJ and Nauck MA. Lancet 2006;368: 52

Algorithm for Type 2 Diabetes
Tier 1: well-validated core therapies Lifestyle + Metformin + Intensive insulin Lifestyle + Metformin + Basal insulin Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylurea Step 1 Step 2 Step 3 Tier 2: less well-validated core therapies Lifestyle + Metformin + Pioglitazone Sulfonylurea Lifestyle + Metformin + Pioglitazone (no hypoglycemia /edema (CHF)/ bone loss) Sources: p. 8, Fig 2, including legend aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide bInsufficient clinical use to be confident regarding safety Algorithm for the metabolic management of type 2 diabetes Reinforce lifestyle interventions at every visit, check A1C every 3 months until A1C is <7% and then at least every 6 months The interventions should be changed if A1C is ≥7% For Tier 2, if hypoglycemia is especially undesirable and if weight loss is a major consideration, exenatide is an option (p. 8, 3rd column, Tier 2) Lifestyle + Metformin + GLP-1 agonist (no hypoglycemia/weight loss /nausea/vomiting ) Lifestyle + Metformin + Basal insulin Validation based on clinical trials & clinical judgment Nathan DM, et al. Diabetes Care 2008;31(12):1-11.

AACE/ACE Glycemic Control Algorithm: T2 Diabetes
Increase therapy every 2-3 months if glycemic goal is not achieved 6.5% 7.5% 7.6% 9.0% >9.0 Lifestyle Modification (to be considered throughout treatment) Monotherapy Can include: MET DPP4 GLP-1 TZD AGI Dual Therapy MET+GLP-1, DPP4,or TZD TZD+GLP-1 or DPP4 MET+Colsevelam or AGI Triple Therapy MET+GLP-1 or DPP4 with TZD or SFU After Orals Insulin ± other agents Dual Therapy MET+GLP-1, DPP4, or TZD MET+SFU or Glinide Triple Therapy MET+GLP-1 or DPP4 + TZD or SFU MET + TZD + SFU The goal of therapy should: Achieve an A1C less than or equal to 6.5% 6.5% may not be appropriate for all patients – need to individualize treatment goals For patients with diabetes and A1C>6.5%, pharmacologic Rx may be considered MET is the preferred initial agent Minimize hypoglycemia Minimize weight gain Get to the desired goals quickly Address FPG and PPG Always include lifestyle modifications Understand that combination therapy is often necessary Safety/efficacy trump cost Other considerations: Use a DPP4-inh. if ↑ PPG and FPG or use GLP-1 R-ag. if ↑↑ PPG Use a TZD in pts with metabolic syndrome or NAFLD For secretagogues: Use Glinide if ↑ PPG or SFU if ↑ FPG Low-dose is recommended Discontinue secretagogue with multidose insulin Decrease secretagogue by 50% when added to GLP-1 R-ag. or DPP4-inh. Can use pramlintide with prandial insulin regimens If A1C<8.5%, combination Rx with agents that cause hypoglycemia should be used with caution If A1C>8.5%, in pts on Dual Therapy, insulin should be considered Symptoms Insulin ± other agents No Symptoms MET+GLP-1 or DPP4 + TZD or SFU MET + TZD + SFU Insulin ± other agents Adapted from AACE Glycemic Control Algorithm, Rodbard HW, et al. Endocr Pract Reproductions can be found at

AACE/ACE Algorithm Summary
The algorithm is intended for use in conjunction with more detailed and comprehensive information (e.g., prescribing information, ACE/AACE Road Maps, etc) The algorithm is intended to provide guidance A1C goal of ≤ 6.5% or less Needs to be individualized to minimize risks of hypoglycemia Therapeutic pathways stratified based on current A1C values 8 major classes of medications Prioritized by safety, efficacy, risk of hypo, simplicity, patient adherence and cost of medication Combination medications that have complimentary mechanisms of action This algorithm is intended for use in conjunction with more detailed and comprehensive guidelines, such as the AACE Diabetes Guidelines and the ACE/AACE Road Maps to Achieve Glycemic Control, and with comprehensive sets of prescribing information and a compendium of drug-drug interactions. This algorithm provides a foundation that can be modified in the future as new medications and data becomes available. The algorithm is intended to provide guidance. It may be modified to incorporate the experience and preferences of the individual physician, clinic or institution, the nature of their patient populations and other considerations such as availability of medications in their local formulary and costs. Rodbard HW, et al. Endocr Pract 2009;15(6):

GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics

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