Presentation on theme: "GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics"— Presentation transcript:
1 GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics Shannon I. Brow, RN, CDE, FNP-CMedical Science LiaisonAmylin Pharmaceuticals, Inc
2 Faculty Disclosures: Shannon I. Brow, RN, CDE, FNP-C Employee of Amylin Pharmaceuticals, IncStockholder: Amylin Pharmaceuticals, Inc
3 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010Review incretin physiology in healthy individuals and in patients with type 2 diabetesDiscuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonistsIdentify where incretin therapies can be used in the treatment of type 2 diabetes
4 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010Review incretin physiology in healthy individuals and in patients with type 2 diabetesDiscuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonistsIdentify where incretin therapies can be used in the treatment of type 2 diabetes
5 Progressive Nature of Type 2 Diabetes Glucose (mg/dL)Diabetesdiagnosis50100150200250300350Fasting glucosePrediabetes(Obesity, IFG, IGT)Postmeal Glucose-15-10-551015202530YearsRelative Amount-10-551015202530Insulin resistanceInsulin level50100150200250-15Incretin effectb-cell functionβ-cell failureYearsOnsetdiabetesMicrovascular changesMacrovascular changesClinicalfeaturesIFG, 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.
6 Postprandial Glucose Contribution to A1C FPG (Fasting Plasma Glucose)PPG (Postprandial Plasma Glucose)100<7.330%70%50%55%45%60%40%>10.270%30%80Slide Index PH0031-OLL: A,B,CDISCUSSION 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% Contribution4020A1C Range (%)Data from Monnier L, et al. Diabetes Care 2003; 26:
7 Plasma Glucose Is Normally Maintained in a Narrow Range Healthy SubjectsType 2 Diabetes400300SLIDE 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)200100BreakfastLunchDinner06.0010.0014.0018.0022.0002.0008.00Time of Day (h)N = 30; Mean (SE)Data from Polonsky KS, et al. N Engl J Med. 1988;318:
8 A1C Goals Unmet in Majority of Patients With Diabetes 20.2% have A1C >9%12.4% have A1C >10%110.09.59.0Slide Index CC0009-OLL: A,B,CDISCUSSION 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 (%)8.537.2% have A1C >8%8.07.564.2% of patients with type 2 diabetes have A1C 7%27.0ADA recommended target (<7%)36.5ACE recommended target (<6.5%)46.0Upper limit of normal range (6%)5.51. 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.
9 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010Review incretin physiology in healthy individuals and in patients with type 2 diabetesDiscuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonistsIdentify where incretin therapies can be used in the treatment of type 2 diabetes
10 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.*OR2. 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 testingAmerican Diabetes Association. Diabetes Care 2010;33(suppl 1):S62-S69.
12 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 resistanceObesity Food intake Gastric Emptying – Rate of nutrient absorption Glucagon secretion Hepatic glucose outputDecreased Beta-Cell ResponseDISCUSSION 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 responseHyperglycemia
13 The Pathophysiology of Type 2 Diabetes Incretin “Defect”Insulin ResistanceRelative Insulin DeficiencyDISCUSSION:Classic understanding of the pathogenesis of type 2 diabetes consists or progressive insulin resistance coupled with gradual deterioration of beta cell functionThe literature makes it clear there is another fundamental defect in the pathogenesis of type 2 diabetes: dysregulation of incretin hormonesThe acute effects of incretin hormones play a major role in insulin secretion from the beta cellHyperglycemia Type 2 Diabetes
14 Clinical Challenges With Type 2 Diabetes A1CWeightDiet and Exercise MET SFU InsulinDiet and Exercise MET SFU Insulin910DISCUSSION POINTSGlucose control and weight management remain 2 of the most important clinical challenges with type 2 diabetesThe 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 UKPDSThe study demonstrated that controlling weight while improving glycemia is difficult, especially in obese patients, regardless of the therapeutic agent usedSLIDE BACKGROUNDThe lower A1C at baseline reflects a more recent onset of diabetesReferenceData from UKPDS Group (34). Lancet. 1998;352:85Median A1C (%) Weight (kg)766.2% A1C Upper limit of normal-5246246Time 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:
15 Blood Glucose Concentrations Are Largely Determined by Beta-Cell Function Insulin synthesisInsulin secretionBeta-Cell Functional CapacityBeta-cell mass (cell turnover and neogenesis)First-phase/second-phase insulin releaseInsulin processing (proinsulin to insulin)Glucose sensitivityBeta-Cell Functional DemandGlucose 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.
16 Multihormonal Regulation of Glucose Appearance and Disappearance Mixed Meal (With ~85 g Dextrose)0.6Regulated by hormones: GLP-1, amylin, CCK, etc.0.40.2Meal-Derived GlucoseDISCUSSION 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 ProductionBalance ofinsulin suppression and glucagon stimulationGrams of Glucose (flux/min)Total Glucose Uptake-0.2Insulin-mediatedglucose uptake-0.4-0.6-30120240360480Time (min)N = 5; Mean (SE) Data from Pehling G, et al. J Clin Invest 1984;74:
17 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010Review incretin physiology in healthy individuals and in patients with type 2 diabetesDiscuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonistsIdentify where incretin therapies can be used in the treatment of type 2 diabetes
18 The Incretin Effect in Healthy Subjects Oral GlucoseIntravenous (IV) Glucose*2002.01.5Incretin EffectDISCUSSION 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.100Plasma Glucose (mg/dL)C-Peptide (nmol/L)1.00.50.06012018060120180Time (min)Time (min)N = 6; Mean (SE); *P0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:
19 GIP 42-amino acid peptide GLP-1 30-amino acid peptide IncretinsGut-derived factors that potentiate insulin secretion following meal ingestion2 principal incretins identified to date:GIP amino acid peptideGLP amino acid peptideDISCUSSION 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:
20 Comparison of the Incretins Site of ProductionGLP-1L-cells (Ileum and Colon)GIPK-cells (Duodenum and Jejunum)Decreases secretion in T2DMYesNoInhibits glucagon secretion postprandiallyYesNoDISCUSSION 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 intakeYesNoSlows gastric emptyingYesNoStimulates beta-cell mass/growthYesYesPromotes insulin biosynthesisYesYesKnockout mice (result in IGT)YesYesAdapted 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.
21 The Incretin Effect Is Reduced in Type 2 Diabetes Oral GlucoseIntravenous (IV) GlucoseHealthy SubjectsType 2 Diabetes*8080Incretin EffectIncretin EffectDISCUSSION 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 (P0.05).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.6060*Insulin (mU/L)40Insulin (mU/L)4020206012018060120180Time (min)Time (min)N = 22; Mean (SE); *P0.05 Data from Nauck M, et al. Diabetologia 1986;29:46-52.
22 Glucagon-Like Peptide-1 (GLP-1) is an Important Incretin Hormone The “incretin effect” started the searchIncretinsGut hormones that enhance insulin secretion in response to foodGlucose-dependent insulin secretionGLP-1Secreted from L cells of the intestinesMost well-characterized incretinDiminished in type 2 diabetesGlucagonSecreted from pancreatic alpha cellsCounterregulatory hormone to insulinElevated in type 2 diabetesDISCUSSION 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:
23 Postprandial GLP-1 Concentrations Are Lower in Subjects With IGT and Type 2 Diabetes Healthy SubjectsImpaired Glucose ToleranceType 2 DiabetesMeal20******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*560120180240Time (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:
24 Insulin and Glucagon Responses Are Altered in Type 2 Diabetes Healthy SubjectsType 2 DiabetesCarbohydrate MealCarbohydrate Meal120Insulin (µU/mL)60140Glucagon (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).120100Meal360300Glucose (mg/dL)24014080-6060120180240Time (min)N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med 1970;283:
25 GLP-1 Modulates Numerous Functions in Humans GLP-1: Secreted upon the ingestion of foodPromotes satiety and reduces appetiteAlpha cells: Glucose-dependent postprandial glucagon secretionDISCUSSION 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 glucagonReducing postprandial glucagon secretion, GLP-1 has an indirect benefit on beta-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose outputHaving effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intakeBy 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 outputBeta cells: Enhances glucose-dependent insulin secretionStomach: Helps regulate gastric emptyingData 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:
26 GLP-1 Effects Are Glucose Dependent in Type 2 Diabetes PlaceboGLP-1PBOPBOPBOGLP-1GLP-1GLP-127030020DISCUSSION 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.**180200*Glucose (mg/dL)Insulin (pmol/L)Glucagon (pmol/L)1090100-3060120180240-3060120180240-3060120180240Time (min)Time (min)Time (min)N = 10; Mean (SE); *P<0.05 Data from Nauck MA, et al. Diabetologia 1993;36:
27 GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV) HisAlaGluGlyThrPheSerAspLysGlnLeuTyrIleTrpValArgDPP-IV7379DISCUSSION 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:
28 Leveraging the Therapeutic Potential of GLP-1 Short half-life (2 minutes)Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV)DPP-IV inhibitionExtends endogenous GLP-1 half-lifeApproved 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.
29 Leveraging the Therapeutic Potential of GLP-1 GLP-1 receptor agonistsMimic many of the glucoregulatory effects of GLP-1Resistant to DPP-IVApproved 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)
30 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010Review incretin physiology in healthy individuals and in patients with type 2 diabetesDiscuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonistsIdentify where incretin therapies can be used in the treatment of type 2 diabetes
31 DPP-4 Inhibitor and GLP-1 Receptor Agonist Discussion The slides that follow include data from the first FDA approved agent in each classConcepts are broad, yet representative of drugs that are FDA approved in each classThere is no intent to claim superiority of the drug discussed compared to the other same class agent
32 Continuously Infused GLP-1 Improved the Defects of T2D T2D Defects1Continuously Infused GLP-11,2Insulin productionFirst-phase insulin responseGlucagon; glucose outputGastric emptyingFood intakeHL RefsAronoff_Diabetes_Spectrum_2004_p184,185,186,187,188.pdfNielsen_Regul_Pept_2004_p77.pdfDISCUSSIONContinuously infused GLP-1 has the following effects1,2It enhances glucose-dependent insulin productionIt restores first-phase insulin responseIt decreases postprandial glucagon production, thus decreasing glucagon-stimulated hepatic glucose outputIt regulates gastric emptying, decreasing the rate of peak nutrient absorption from mealsIt decreases food intakeREFERENCES1. Aronoff SL, et al. Diabetes Spectrum. 2004;17:2. Nielsen LL, et al. Regul Pept. 2004;117:77-781. Aronoff SL, et al. Diabetes Spectrum 2004;17: Nielsen LL, et al. Regul Pep. 2004;117:77-88.32
33 Effects of GLP-1 on the b cell in Healthy Subjects DISCUSSIONOne of the effects of GLP-1 is to directly stimulate glucose-dependent insulin secretion by binding to receptors on islet β cellsGLP-1 receptor activation leads to insulin release via stimulation of exocytotic pathways and recruits signaling mechanisms that lead to promotion of cell proliferation and survivalREFERENCEDrucker DJ. Cell Metab. 2006;3:33
34 GLP-1 in T2DDISCUSSIONThe magnitude of nutrient-stimulated insulin secretion is diminished in patients with type 2 diabetesMeal-stimulated plasma levels of GLP-1 are modestly but significantly diminished in patients with impaired glucose tolerance and in patients with type 2 diabetesREFERENCEBaggio LL, et al. Gastroenterology. 2007;132:34
35 GLP-1 Is Cleaved and Inactivated by DPP-4 DISCUSSIONDPP-4 is a serine protease that preferentially cleaves peptide hormones containing a position 2 alanine or prolineGLP-1 is an endogenous physiological substrate for DPP-4DPP-4 cleaves and inactivates GLP-1DPP-4 is a principal determinant of the circulating half-life of intact bioactive GLP-1REFERENCEDrucker DJ. Diabetes Care. 2007;30:35
36 Mechanism of Action: DPP-4 Inhibitors Sitagliptin example
37 Sitagliptin Decreased A1C From Baseline Over 24 wks Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009
38 Sitagliptin Decreased A1C Over 52 wks Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009
39 DPP-4 Inhibitors Prevent the Inactivation of GLP-1 DISCUSSIONDPP-4 is a serine protease that preferentially cleaves peptide hormones containing a position 2 alanine or proline1GLP-1 is an endogenous physiological substrate for DPP-4DPP-4 cleaves and inactivates GLP-1DPP-4 is a principal determinant of the circulating t1/2 of intact bioactive GLP-1DPP-4 inhibitors block DPP-4 enzyme activity, stabilizing active levels of GLP-12REFERENCES1. Drucker DJ. Diabetes Care. 2007;30:2. Herman GA, et al. J Clin Endocrinol Metab.; 2006;91:39
40 The Beginning Exenatide Synthetic version of salivary protein found in the Gila monsterMore than 50% amino acid sequence identity with human GLP-1Binds to known human GLP-1 receptors on beta cells (in vitro)Resistant to DPP-IV inactivationDISCUSSION 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 InactivationFollowing injection, exenatide is measurable in plasma for up to 10 hoursAdapted from Nielsen LL, et al. Regul Pept 2004;117: Adapted from Kolterman OG, et al. Am J Health-Syst Pharm 2005;62:
41 Exenatide Restored First-Phase Insulin Response Healthy ControlsType 2 DiabetesPlaceboExenatide3030ExenatideDISCUSSION 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 robustthe 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 concentrationsPatients 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)2020Insulin (pM/kg/min)Insulin (pM/kg/min)1010Placebo-180-90306090120-180-90306090120IV GlucoseIV GlucoseTime (min)Time (min)Evaluable; N = 25; Mean (SE) Fehse F, et al. J Clin Endocrinol Metab 2005;90(11):
42 Exenatide Suppressed Postprandial Glucose and Glucagon in Type 2 Diabetes Placebo 0.10 µg/kg Exenatide360200DISCUSSION 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 glucoseSuppressed postprandial glucagon concentrations, an important contributor to postprandial glucose surgeSLIDE BACKGROUND:In a crossover study, subjects with type 2 diabetes (n = 20) were injected with single SC exenatide dose or placebo.270150Plasma Glucose (mg/dL)Plasma Glucagon (pg/mL)18010090506012018024030060120180Standardized BreakfastStandardized BreakfastExenatide or PlaceboExenatide or PlaceboTime (min)Time (min)N = 20; Mean (SE) Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:
43 Plasma Glucose (mg/dL) Serum Insulin (pmol/L) Exenatide Acutely Reduced Glucose Through Enhanced Glucose-Dependent Insulin SecretionPlacebo µg/kg Exenatide µg/kg Exenatide225250DISCUSSION 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 placeboPlasma insulin concentrations were significantly increased compared with placeboAs 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).200180Plasma Glucose (mg/dL)Serum Insulin (pmol/L)150135100905024682468SC InjectionSC InjectionTime (h)Time (h)Type 2 Diabetes; N = 34; Mean (SE) Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:
44 Exenatide Is Not Inactivated by DPP-4 DISCUSSIONExenatide is not inactivated by DPP-4 and has a much longer plasma half-life than GLP-11,2Exenatide is the synthetic version of exendin-41Exendin-4 and GLP-1 have equivalent binding affinities for the GLP-1 receptor in in vitro assays, and both peptides stimulate the receptor equipotently1REFERENCES1. Nielsen LL, et al. Regul Pept. 2004;117:77-882. Baggio LL, et al. Gastroenterology. 2007;132:44
45 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 T2DStudyTerminationRandomizationCrossoverTreatment Period 1Treatment Period 2Exenatide 5 µg BIDExenatide 10 µg BIDExenatide 5 µg BIDExenatide 10 µg BIDSequence APlacebo Lead-inSequence BHL RefDeFronzo_Curr_Med_Res_Opin_2008_p7,9,15,27_ms.docDISCUSSIONThis 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 METThis 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 sitagliptinSecondary/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 safetyWithin 2 weeks of screening, eligible patients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequencesExenatide treatment consisted of 5-µg SC doses BID for the first week, followed by 10-µg SC doses BID for the second weekSitagliptin treatment consisted of 100-mg doses taken orally every morning (QAM) for 2 weeksStandard meal tests were administered at the end of each treatment periodAfter patients underwent an overnight fast of at least 10 hours, exenatide or sitagliptin was administered 15 minutes or 30 minutes (respectively) before the standard mealMeal 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% fatSLIDE BACKGROUNDThis study was designed to test the mechanistic effects of exenatide and sitagliptin on endpoints measured as part of the standard meal testTherefore, 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 mealPatients were also required to meet the following criteriaAge, 18 to 70 yearsA1C, 7.0% to 11.0%FPG concentration, <280 mg/dLBMI, 25 to 45 kg/m2REFERENCEDeFronzo RA, et al. Curr Med Res Opin. In pressSitagliptin 100 mg QamSitagliptin 100 mg Qam1 week2 weeks2 weeksStandardMeal TestStandardMeal TestStandardMeal TestMET background; MOA indicates mechanism of action; QAM, once per day in the morningDeFronzo RA, et al. Curr Med Res Opin 2008;24;45
46 2-h Postprandial Plasma GLP-1 (pM) 2-h Plasma Exenatide (pM) Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1BaselineExenatideSitagliptin757563.850502-h Postprandial Plasma GLP-1 (pM)2-h Plasma Exenatide (pM)2525HL RefsDeFronzo_Curr_Med_Res_Opin_2008_p11,18,25,28_ms.docHerman_Clin_Pharmacol_Ther_2005_p682.pdfKolterman_Am_J_Health Syst_Pharm_2005_p177,180,181.pdfParkes_Drug_Dev_Res_2001_pGöke_J_Biol_Chem_1993_p19654.pdfDISCUSSIONThe 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 sitagliptin1The mean 2‑hour plasma concentration of exenatide is shown in the right panelAfter treatment with exenatide or sitagliptin, plasma exenatide and sitagliptin concentrations were at known therapeutic levels2,3Mean ± SE 2‑hour plasma exenatide concentration was 63.8 ± 6.7 pM, and the mean ± SE 2‑hour plasma sitagliptin concentration was ± 28.4 nM1Consistent 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 BACKGROUNDThe 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)1On 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 studies5REFERENCES1. DeFronzo RA, et al. Curr Med Res Opin. In press2. 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;268:22.214.171.124Plasma GLP-1Plasma ExenatidePatients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE2-wk posttreatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008;24:46
47 Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin Primary EndpointBaselineExenatideSitagliptinHL RefsDeFronzo_Curr_Med_Res_Opin_2008_p7,9,12,25,29_ms.docAmylin_BCA403_SDS_ _p42,43,44.pdfAmylin_BCA403_SDS_2.2.3_p53,54,55.pdfAmylin_BCA403_SDS_2.1.8_p41.pdfADA_Diabetes_Care_2008_pS18.pdfDISCUSSIONCompared to PPG concentrations at baseline, reductions in PPG concentrations over time were greater with exenatide treatment than with sitagliptin treatment1The 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)2The 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)2All 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)1Exenatide decreased PPG AUC0-240 min (mg • min/dL) by 26% vs sitagliptin (0.74 ± 0.02; geometric LS mean ratio ± SE)2Exenatide decreased PPG Cave0-240 min (mg/mL) by 26% vs sitagliptin (0.74 ± 0.02; geometric LS mean ratio ± SE)2The Cave is equal to the corresponding AUC divided by the time periodExenatide decreased Cmax (mg/dL) by 19% vs sitagliptin (0.81 ± 0.03; geometric LS mean ratio ± SE)2The current ADA peak PPG goal3 for patients with type 2 diabetes is <180 mg/dLSLIDE BACKGROUND1This 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 METPatients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequencesExenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second weekSitagliptin doses were 100 mg PO QAM for 2 weeksThe 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 covariateREFERENCES1. DeFronzo RA, et al. Curr Med Res Opin. In press2. Data on file, Amylin Pharmaceuticals, Inc.3. ADA. Diabetes Care. 2008;31;(Suppl 1):S12-S54PPG (mg/dL)Standard MealTime (min)Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P<0.0001DeFronzo RA, et al. Curr Med Res Opin 2008;24:47
48 Reductions in 2-Hour PPG Were Greater With Exenatide Than With Sitagliptin BaselineEnd of Period 1End of Period 2ExenatideSitagliptinHL RefsAmylin_BCA403_SDS_ _p31.pdfDeFronzo_Curr_Med_Res_Opin_2008_p7,9,12,25,29_ms.docADA_Diabetes_Care_2008_pS18.pdfDISCUSSIONFor patients treated with exenatide-sitagliptin (n = 29), the baseline 2-hour PPG concentration was 232 ± 13 mg/dL (all data given as mean ± SE)1Exenatide treatment (period 1) reduced the 2-hour PPG concentration2 to 133 ± 10 mg/dLSubsequent sitagliptin treatment (period 2) increased the 2-hour PPG concentration2 to 205 ± 12 mg/dLFor patients treated with sitagliptin-exenatide (n = 32), the baseline 2-hour PPG concentration1 was 257 ± 11 mg/dLSitagliptin treatment (period 1) reduced the 2-hour PPG concentration2 to 209 ± 11 mg/dLSubsequent exenatide treatment (period 2) further reduced the 2-hour PPG concentration2 to 133 ± 9 mg/dLThe current ADA peak PPG goal3 for patients with type 2 diabetes is <180 mg/dLSLIDE BACKGROUND1This 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 METPatients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequencesExenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second weekSitagliptin doses were 100 mg PO QAM for 2 weeksThe 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 covariateREFERENCES1. Data on file, Amylin Pharmaceuticals, Inc.2. DeFronzo RA, et al. Curr Med Res Opin. In press3. ADA. Diabetes Care. 2008;31;(Suppl 1):S12-S542-hr PPG (mg/dL)After Period 1, patients were switched to the other therapyPatients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32Mean ± SE; DeFronzo RA, et al. Curr Med Res Opin 2008;24:48
49 Improvement in Insulinogenic Index Was Greater With Exenatide Than With Sitagliptin Geometric Mean BaselineInsulinogenic Index2: 0.4P = 0.021.00.90.80.820.82HL RefsDeFronzo_Curr_Med_Res_Opin_2008_p7,9,10,12,13,25,30_ms.docHovorka_Comput_Methods_Programs_Biomed_1996_p253.pdfAmylin_BCA403_SDS_2.17.2_p172.pdfDISCUSSION1Acute β-cell function, as assessed with the insulinogenic index and insulin secretion rate (ISR), was greatly improved with exenatide treatment compared with sitagliptin treatmentThe 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 BACKGROUND1This 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 METPatients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequencesExenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second weekSitagliptin doses were 100 mg PO QAM for 2 weeksISR 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 calculations2An 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 modelThe 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]REFERENCES1. DeFronzo RA, et al. Curr Med Res Opin. In press2. Hovorka R, et al. Comput Methods Programs Biomed. 1996;50:Insulinogenic Index10.70.60.550.550.50.4ExenatideSitagliptinPatients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean ± SEStandard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24: Data on file, Amylin Pharmaceuticals, Inc.49
50 Plasma Glucagon (pg/mL) Exenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than SitagliptinBaselineExenatideSitagliptinPlasma Glucagon (pg/mL)HL RefsDeFronzo_Curr_Med_Res_Opin_2008_p7,13,25,30_ms.docAmylin_BCA403_SDS_ _2.6.3_p80,81,82,87.pdfDISCUSSION1Compared to levels at baseline, reductions in postprandial glucagon levels over time were greater with exenatide treatment than with sitagliptin treatmentExenatide decreased glucagon AUC0-240 min [(pg • min)/mL] by 12% vs sitagliptin (0.88 ± 0.03; geometric LS mean ratio ± SE; P = )2SLIDE BACKGROUND1This 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 METPatients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequencesExenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second weekSitagliptin doses were 100 mg PO QAM for 2 weeksREFERENCES1. DeFronzo RA, et al. Curr Med Res Opin. In press2. Data on file, Amylin Pharmaceuticals, Inc.Standard MealTime (min)Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SEDeFronzo RA, et al. Curr Med Res Opin 2008;24:50
51 Exenatide Slowed Gastric Emptying Compared to Sitagliptin BaselineExenatideSitagliptinHL RefsDeFronzo_Curr_Med_Res_Opin_2008_p7,8,13,17,25,31_ms.docAmylin_BCA403_SDS_ _2.9.3_p107,108,109,116.pdfDISCUSSION1Exenatide treatment reduced the rate of gastric emptying compared with rates at baseline and with sitagliptin treatmentExenatide decreased acetaminophen AUC0-240 min (mg • min/dL) by 44% vs sitagliptin (0.56 ± 0.05; geometric LS mean ratio ± SE; P<0.0001)2Sitagliptin had no effect on gastric emptyingSLIDE BACKGROUND1This 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 METPatients were randomly assigned to exenatide-sitagliptin or sitagliptin-exenatide treatment sequencesExenatide doses were 5 µg SC BID for the first week, followed by exenatide 10 µg SC BID for the second weekSitagliptin doses were 100 mg PO QAM for 2 weeksGastric 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 mealREFERENCES1. DeFronzo RA, et al. Curr Med Res Opin. In press2. Data on file, Amylin Pharmaceuticals, Inc.Plasma Acetaminophen (µg/mL)Standard MealTime (min)Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophenwas administered immediately before the standard meal; DeFronzo RA, et al. Curr Med Res Opin 2008;24:51
52 GLP-1 Receptor Agonists1,2 Actions of Incretin-Based Therapies for T2D: GLP-1 Receptor Agonists and DPP-4 InhibitorsActionGLP-1 Receptor Agonists1,2DPP-4 Inhibitors1,2Insulinproduction+++++First-phase insulin responseGlucagon; glucose output+Gastric emptyingDelayedNo effectFood intakeDecreasedHL RefDeFronzo_Curr_Med_Res_Opin_2008_p12,13,14_ms.docDISCUSSION1,2GLP-1 agonists and DPP-4 inhibitors have some overlapping actions that are beneficial in the treatment of type 2 diabetesBoth suppress glucagon secretion, leading to a reduction in glucose outputBoth enhance glucose-dependent insulin secretionGLP-1 agonists have additional therapeutic actions for which DPP-4 inhibitors exhibit marginal or no obvious effectsGLP-1 agonists suppress appetite/induce satietyGLP-1 agonists decelerate gastric emptyingREFERENCES1. Drucker DJ and Nauck MA. Lancet. 2006;368:2. DeFronzo RA, et al. Curr Med Res Opin. In press1. DeFronzo RA, et al. Curr Med Res Opin 2008;24: Drucker DJ and Nauck MA. Lancet 2006;368:52
53 Learning Objectives Discuss the progressive nature of diabetes Discuss the new ADA diagnostic criteria for diabetes published Jan 2010Review incretin physiology in healthy individuals and in patients with type 2 diabetesDiscuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonistsIdentify where incretin therapies can be used in the treatment of type 2 diabetes
54 Algorithm for Type 2 Diabetes Tier 1: well-validated core therapiesLifestyle + Metformin+Intensive insulinLifestyle + Metformin+Basal insulinDiagnosis:Lifestyle+MetforminLifestyle + Metformin+SulfonylureaStep 1Step 2Step 3Tier 2: less well-validated core therapiesLifestyle + Metformin+PioglitazoneSulfonylureaLifestyle + Metformin+Pioglitazone(no hypoglycemia /edema (CHF)/ bone loss)Sources: p. 8, Fig 2, including legendaSulfonylureas other than glybenclamide (glyburide) or chlorpropamidebInsufficient clinical use to be confident regarding safetyAlgorithm for the metabolic management of type 2 diabetesReinforce lifestyle interventions at every visit, check A1C every 3 months until A1C is <7% and then at least every 6 monthsThe 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 insulinValidation based on clinical trials & clinical judgmentNathan DM, et al. Diabetes Care 2008;31(12):1-11.
55 AACE/ACE Glycemic Control Algorithm: T2 Diabetes Increase therapy every 2-3 months if glycemic goal is not achieved6.5%7.5%7.6%9.0%>9.0Lifestyle Modification (to be considered throughout treatment)MonotherapyCan include:METDPP4GLP-1TZDAGIDual TherapyMET+GLP-1, DPP4,or TZDTZD+GLP-1 or DPP4MET+Colsevelam or AGITriple TherapyMET+GLP-1 or DPP4 with TZD or SFUAfter OralsInsulin ± other agentsDual TherapyMET+GLP-1, DPP4, or TZDMET+SFU or GlinideTriple TherapyMET+GLP-1 or DPP4 + TZD or SFUMET + TZD + SFUThe 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 goalsFor patients with diabetes and A1C>6.5%, pharmacologic Rx may be consideredMET is the preferred initial agentMinimize hypoglycemiaMinimize weight gainGet to the desired goals quicklyAddress FPG and PPGAlways include lifestyle modificationsUnderstand that combination therapy is often necessarySafety/efficacy trump costOther considerations:Use a DPP4-inh. if ↑ PPG and FPG or use GLP-1 R-ag. if ↑↑ PPGUse a TZD in pts with metabolic syndrome or NAFLDFor secretagogues:Use Glinide if ↑ PPG or SFU if ↑ FPGLow-dose is recommendedDiscontinue secretagogue with multidose insulinDecrease secretagogue by 50% when added to GLP-1 R-ag. or DPP4-inh.Can use pramlintide with prandial insulin regimensIf A1C<8.5%, combination Rx with agents that cause hypoglycemia should be used with cautionIf A1C>8.5%, in pts on Dual Therapy, insulin should be consideredSymptomsInsulin ± other agentsNo SymptomsMET+GLP-1 or DPP4 + TZD or SFUMET + TZD + SFUInsulin ± other agentsAdapted from AACE Glycemic Control Algorithm, Rodbard HW, et al. Endocr Pract Reproductions can be found at
56 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 guidanceA1C goal of ≤ 6.5% or lessNeeds to be individualized to minimize risks of hypoglycemiaTherapeutic pathways stratified based on current A1C values8 major classes of medicationsPrioritized by safety, efficacy, risk of hypo, simplicity, patient adherence and cost of medicationCombination medications that have complimentary mechanisms of actionThis 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):