Despite Important Advances in Therapy, Glycemic Control Is Not Optimal

New Approaches to Achieving Good Glycemic Control in Type 2 Diabetes: Part 1

Despite Important Advances in Therapy, Glycemic Control Is Not Optimal
Challenges and Solutions : Too many patients! – Prevention strategies can work Failure to attain and sustain optimal long-term glycemic control Hypoglycemia – major limitation to intensive therapy Inadequate postprandial glucose control Unpredictable glucose fluctuations Weight gain – new treatments lead to weight loss Excess cardiovascular disease and events Attempting normoglycemia led to increased mortality Not enough comparative effectiveness studies that are long term – UKPDS and ADOPT demonstrated differences between drugs in the long term Despite Important Advances in Therapy, Glycemic Control Is Not Optimal The clinician faces multiple challenges when dealing with type 2 diabetes. Recent advances have helped address some of these challenges. For example, prevention strategies have been shown to work. However, other problems remain. Most importantly, it is difficult, if not impossible, to achieve and maintain normoglycemia without side effects of treatment and possible increased risk of mortality.

Unmet Challenges Attaining standards of care
Identifying most effective sequence and combination of therapies Linking effective diabetes therapies with: Long-term (durable) glucose control Proven micro- and macrovascular protection No side effects such as weight gain and hypoglycemia Patient friendliness and not increasing burden Developing novel therapies based on pathophysiological defects Unmet Challenges Unmet challenges include attaining standards of care by identifying the most effective sequence and combination of therapies; linking effective diabetes therapies with long-term (durable) glucose control, proven micro- and macrovascular protection, and no side effects; and developing novel therapies based on pathophysiological defects.

Pathogenesis Concepts in Type 2 Diabetes
Insulin resistance occurs early, before glucose intolerance Genetic cause? Environmental: obesity, aging, lifestyle, etc. Healthy  cells compensate and remain euglycemic “Susceptible”  cells (in predisposed individuals) -cell dysfunction results in imperfect compensation Progress to prediabetes stage Onset of acquired abnormalities leads to worse hyperglycemia=glucotoxicity (a vicious cycle) Pathogenesis Concepts in Type 2 Diabetes Insulin resistance (the impaired effect of insulin to transport glucose into muscle and fat cells and to suppress glucose production in the liver) is a very early abnormality in diabetes. It is often familial, but the exact genetic cause is unknown. Obesity, physical inactivity, and aging are important acquired/environmental causes of insulin resistance. Despite insulin resistance, blood glucose can be kept normal by the increased production of insulin by a healthy pancreas. However, in some predisposed individuals, -cell function declines and then blood glucose declines. This process is further accelerated because glucose, in itself, is toxic to the -cell and worsens insulin resistance, a phenomenon called glucose toxicity. Fortunately, glucose toxicity may be reversible.

Impaired Insulin Secretion Decreased Glucose Uptake
Pathogenesis of Type 2 Diabetes Impaired Insulin Secretion Pancreas Hyperglycemia Increased Glucose Production Decreased Glucose Uptake Pathogenesis of Type 2 Diabetes The pathophysiology of hyperglycemia in type 2 diabetes involves several defects, the most important of which are Insulin deficiency due to insufficient pancreatic insulin release Insulin resistance (decreased glucose uptake) in peripheral tissues (including muscle and fat) and the liver in the fed (after feeding) state Excess hepatic glucose output Reference: DeFronzo RA. Lilly lecture The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37: Liver Muscle Liver Reprinted with permission from DeFronzo RA. Diabetes. 1988;37: Copyright © 1998 American Diabetes Association. All rights reserved.

Pancreatic Islet Dysfunction Leads to Insufficient Insulin and Elevated Glucagon in Type 2 Diabetes
CHO meal T2D Glucose mg/dL NGT NGT Insulin uU/mL T2D T2D Glucagon pg/mL Pancreatic Islet Dysfunction Leads to Insufficient Insulin and Elevated Glucagon in Type 2 Diabetes To determine how pancreatic islet hormone release is altered in type 2 diabetes, Müller and colleagues compared glucose, insulin, and glucagon levels in 11 subjects with normal glucose tolerance (NGT) (orange circles in top graph) and 12 patients with type 2 diabetes (orange triangles in top graph), before and after a high-carbohydrate (CHO) meal. In this study, fasting plasma levels of glucose, insulin, and glucagon were higher among patients with type 2 diabetes compared with subjects with NGT. The normal insulin response to a carbohydrate challenge (purple circles in middle graph) was a rapid and steep rise in plasma insulin. On the other hand, patients with type 2 diabetes (purple triangles in middle graph) had a blunted and delayed response. Plasma glucagon fell rapidly after the carbohydrate challenge in nondiabetic subjects (green circles in bottom graph). However, in patients with type 2 diabetes, glucagon levels were not suppressed (green triangles in bottom graph). In fact, they were inappropriately increased, suggesting a functional defect of -cell glucose sensing. Reference: Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med. 1970;283: NGT Time (min) 60 120 180 240 -60 CHO = high-carbohydrate; NGT = normal glucose tolerance; TD2 = type 2 diabetes Reprinted with permission from Müller WA et al. N Engl J Med. 1970;283: Copyright © 1970 Massachusetts Medical Society. All rights reserved.

Ominous Octet HYPERGLYCEMIA Decreased Incretin Effect
Decreased Insulin Secretion Increased Hepatic Glucose Production Islet– cell Increased Glucagon Secretion Decreased Glucose Uptake Increased Lipolysis Glucose Reabsorption HYPERGLYCEMIA Neurotransmitter Dysfunction Ominous Octet The pathogenesis of type 2 diabetes includes eight identified pathophysiological defects: Decreased insulin secretion Decreased incretin effect Decreased glucose uptake in the muscle Increased glucagon secretion Increased hepatic glucose production Increased lipolysis Increased glucose reabsorption Neurotransmitter dysfunction Reference: Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58: Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58: Copyright © 2009 American Diabetes Association. All rights reserved.

T2DM: Therapeutic Landscape (Noninsulin) 2012
Agent Examples Mechanism Action SUs glyburide, glipizide, glimepiride Closes KATP channels  Pancreatic insulin secretion ‘Glinides repaglinide, nateglinide Biguanides metformin Activates AMP-kinase  Hepatic glucose production TZDs rosiglitazone, pioglitazone Activates PPAR-  Peripheral insulin sensitivity -GIs acarbose, miglitol Blocks small bowel -glucosidase  Intestinal carbohydrate absorption GLP-1 R agonists exenatide, liraglutide Activates GLP-1 receptors  Pancreatic insulin secretion;  glucagon secretion; delays gastric emptying;  satiety Amylino-mimetics pramlintide Activates amylin receptors  Pancreatic glucagon secretion; delays gastric emptying;  satiety DPP-4 inhibitors sitagliptin, saxagliptin Inhibits DPP-4,  endogenous incretins  pancreatic glucagon secretion Bile acid sequestrants colesevelam Binds bile acid cholesterol ? D2 agonists bromocriptine Activates dopaminergic receptors ‘Resets hypothalamic circadian organization’;  insulin sensitivity T2DM: Therapeutic Landscape (Noninsulin) 2012 [I] A number of agents are available to treat type 2 diabetes mellitus and exert their effects through different mechanisms of action. Reference: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35: Inzucchi SE et al. Diabetes Care 2012;35:

T2DM: Therapeutic Landscape (Noninsulin) 2012
Agent A1c Advantages Disadvantages Cost SUs 1–2% Microvasc risk Hypo, wt gain, -cell exhaust $ ‘Glinides 1–1.5% PPG Hypo, wt gain, -cell exhaust, dose frequency $ $ $ Biguanides Wt loss, no hypo, CVD, ?  malignancy GI, lactic acidosis B12-deficiency TZDs No hypo; -cell preserv TG HDL BP ? CVD (pio) Wt gain, edema / HF Bone fxs, ? CVD (rosi) -GIs 0.5–1% PPG, ? CVD; GI, dose frequency $ $ GLP-1 R agonists 1% Wt loss,? -cell preserv, ? CV benefits GI; ? pancreatitis, injections Amylino-mimetics 0.5% Wt loss, PPG GI, dose frequency, injections DPP-4 inhibitors 0.6–0.8% No hypo Urticaria / Angioedema; ? pancreatitis Bile acid sequestrants No hypo; LDL-C GI; TGs D2 agonists Nausea; dizziness T2DM: Therapeutic Landscape (Noninsulin) 2012 [II] A number of agents are available to treat type 2 diabetes mellitus and have different advantage/disadvantage and cost profiles. Reference: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35: Inzucchi SE et al. Diabetes Care 2012;35:

Relative Risk Reduction
Prevention of Type 2 Diabetes Study Subjects Intervention Relative Risk Reduction Da Quing1 IGT Diet or Exercise or Both 42% / 49% / 34% Finnish DPS2 Lifestyle 58% DPP3 IGT /“IFG” Metformin 31% STOP-NIDDM4 Acarbose 25% EDIP5 IFG NS XENDOS6 Orlistat 45% TRIPOD7 Prior GDM Troglitazone 55% DREAM8,9 Rosiglitazone / Ramipril 62% / NS ACT NOW10 Pioglitazone 72% ORIGIN11 IGT / “IFG” Insulin Glargine / Omega-3  Behavior Prevention of Type 2 Diabetes Several studies have demonstrated that prevention of diabetes is possible. It is important to identify people who are at risk by screening for impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and then advising lifestyle change. For those unable to make the necessary lifestyle changes or for those in whom the disease progresses despite lifestyle changes, several pharmacological therapies have been shown to be effective; although, none of them are approved by the Federal Drug Administration (FDA) for the prevention of diabetes. References: Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet. 2008;371: Tuomilehto J, Lindström J, Eriksson JG, et al, for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med ;344: Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346: Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359: Kirkman MS, Shankar RR, Shankar S, et al. Treating postprandial hyperglycemia does not appear to delay progression of early type 2 diabetes: the Early Diabetes Intervention Program. Diabetes Care. 2006;29: Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27: Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51: DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368: DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355: DeFronzo RA, Tripathy D, Schwenke DC, et al, for the ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364: ORIGIN Trial Investigators. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J. 2008;155:26-32. Medication IFG: impaired fasting glucose IGT: impaired glucose tolerance GDM: gestational diabetes mellitus NS: not significant 1Li G et al. Lancet. 2008;371: | 2Tuomilehto J et al. N Engl J Med. 2001;344: | 3Diabetes Prevention Program Research Group. N Engl J Med. 2002;346: | 4Chiasson JL et al. Lancet. 2002;359: | 5Kirkman MS et al. Diabetes Care. 2006;29: | 6Torgerson JS et al. Diabetes Care. 2004;27: | 8DREAM Trial Investigators. Lancet. 2006;368; | 9DREAM Trial Investigators. N Engl J Med. 2006;355: | 10DeFronzo RA et al. N Engl J Med. 2011;364: | 11ORIGIN Trial Investigators. Am Heart J. 2008;155:26-32.

Screening and Diagnosis of Disorders of Glucose Metabolism
Screen for Diabetes: Fasting plasma glucose or 2-hour, 75-g oral glucose tolerance test IFG or IGT IFG and IGT + Other Features* Diabetes Lifestyle Intervention Lifestyle Intervention and / or Metformin Lifestyle Intervention + Metformin Screening and Diagnosis of Disorders of Glucose Metabolism This slide summarizes the American Diabetes Association (ADA) consensus recommendations on the treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). The statements allow for the off-label use of metformin in patients who are at particularly high risk of progression to overt diabetes. References: Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29: Nathan DM, Davidson MB, DeFronzo RA, et al, for the American Diabetes Association. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007;30: American Diabetes Association. Standards of medical care in diabetes—2008. Diabetes Care. 2008;31:S12-S54. IFG=impaired fasting glucose; IGT=impaired glucose tolerance IFG: fasting (8 hours) plasma glucose 100–125 mg/dL IGT: 2-hour value in 75-g OGTT 140–199 mg/dL Diabetes: FPG ≥ 126 mg/dL or 2-hour OGTT ≥ 200 mg/dL; should be confirmed on a separate day *<60 years of age, reduced HDL-C, BMI ≥35 kg/m2, hypertension, elevated triglycerides, A1C >6.0%, family history of diabetes in first-degree relative

The ABCs of Diabetes Care
A1C American Diabetes Association (ADA) recommends A1C <7.5% = average glucose of 150 mg/dL American Association of Clinical Endocrinologists (AACE) / International Diabetes Federation (IDF) recommend A1C <6.5% = average glucose of 135 mg/dL Blood pressure <130/80 mm Hg Cholesterol LDL-C: <100 mg/dL (<70 mg/dL in very high-risk patients) HDL-C: >40 mg/dL in men and >50 mg/dL in women Non-HDL-C: <130 mg/dL (100 mg/dL in high-risk patients) TG: <150 mg/dL Don’t forget aspirin! The ABCs of Diabetes Care This slide lists the ABCs of diabetes (A1C, blood pressure, and cholesterol), including the targets for each, as recommended by the (ADA) and other organizations. References: American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28:S4-S36. A desktop guide to Type 2 diabetes mellitus. European Diabetes Policy Group Diabet Med. 1999;16: American Diabetes Association. Diabetes Care. 2005;28:S4-S36 | International Diabetes Federation. Diabetic Med. 1999;16:

Main Findings from the ACCORD and ADVANCE Studies
10,251 participants Mean age: 62 years Median duration of diabetes mellitus: 10 years Mean A1C at entry: 8.3% Known heart disease or at least 2 risk factors 11,140 participants Mean age: 66 years Mean duration of diabetes mellitus: 8 years Mean A1C at entry: 7.48% History of major CV event or at least 1 risk factor Standard A1C 7.0%–7.9% Intensive A1C <6.0% Standard A1C usual care Intensive A1C ≤6.5% Main Findings from the ACCORD and ADVANCE Studies The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study concluded that intensive glucose lowering may cause harm in high-risk patients with type 2 diabetes and high A1C levels. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study concluded that intensive glucose lowering in high-risk patients reduced renal complications by 21%. Reference: Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) may cause harm in high-risk patients with type 2 diabetes (increased mortaltiy). CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) reduces renal complications in high-risk patients by 21% (95% CI, 7–34%) and did not increase mortality ACCORD Study Group. N Engl J Med. 2008;358: | ADVANCE Collaborative Group. N Engl J Med. 2008;358:

A1C <7.0% Is Appropriate for Most Patients with Diabetes
An A1C value of <7.0% is appropriate and well supported by clinical trial results: There are no data to support an A1C goal of <7.0% for reducing cardiovascular risk For individual patients, intensifying the regimen should be weighed by the potential risks and benefits: History of severe hypoglycemia Limited life expectancy Children Comorbid conditions Longstanding diabetes and minimal or stable microvascular complications A1C <7.0% Is Appropriate for Patients with High Cardiovascular Risk There are no data to support a goal of A1C <7.0% for reducing cardiovascular risk. For individual patients, intensifying the regimen should be weighed by the potential risks and benefits, including: a history of severe hypoglycemia, limited life expectancy, children, comorbid conditions, longstanding diabetes, and minimal or stable microvascular complications. References: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care .2012;35: American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2012;35(suppl.1):S11-63. Inzucchi SE et al. Diabetes Care 2012;35: | American Diabetes Association. Diabetes Care. 2008;31:S12-S54.

ACCORD, ADVANCE: Long-Term Glycemic Control in High-Risk T2DM
Glycemic control reduces microvascular events Intensive glucose lowering does not lower major cardiovascular events compared to standard glucose lowering Antihypertensive, lipid-lowering, and antiplatelet therapies remain standards of pharmacologic care to reduce cardiovascular events Lacking consensus for: Optimal glucose targets for long-term control Preferred regimen to maintain control ACCORD, ADVANCE: Long-term glycemic control in high-risk T2DM The ACCORD and ADVANCE studies demonstrated that good glycemic control does not significantly reduce the risk of cardiovascular disease events. However, the impact of glycemic control on microvascular events remains important. References: Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: T2DM = type 2 diabetes mellitus ACCORD Study Group. N Engl J Med. 2008;358: | ADVANCE Collaborative Group. N Engl J Med. 2008;358: [Insert Title Here].ppt

UKPDS Kaplan–Meier Curves for Prespecified Aggregate Clinical Outcome: Myocardial Infarction
Proportion with Event Conventional Therapy Sulfonylurea–insulin UKPDS Kaplan–Meier Curves for Prespecified Aggregate Clinical Outcome: Myocardial Infarction This slide summarizes long-term follow-up of patients in the United Kingdom Prospective Diabetes Study (UKPDS). Kaplan–Meier curves that demonstrate the proportions of patients in the UKPDS who had a myocardial infarction are shown for the sulfonylurea–insulin group versus the conventional-therapy group. Kaplan–Meier plots for cumulative incidence and log-rank P-values are shown at 5-year intervals during a 25-year period from the start of the interventional trial. Not shown are the curves for the 3 other prespecified aggregate clinical outcomes: The benefits seen for any diabetes-related endpoint or microvascular disease in the main trial remained significant at 25 years. In addition, all-cause mortality at 25 years was significantly lower for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group. It is important to note that randomization was not maintained at the completion of the main trial, and that there was no difference in glycemic control in the follow-up phase, which suggested a long-lasting "legacy" effect of good control at the time of diagnosis. Reference: Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: 10 15 20 25 5 Years Since Randomization No. at Risk Conventional Therapy Sulfonylurea–insulin 20 66 Reprinted from Holman RR et al. N Engl J Med. 2008;359: Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Years Since Randomization
UKPDS Kaplan-Meier Curves for a Prespecified Aggregate Clinical Outcome: Myocardial Infarction P=0.005 Conventional Therapy Proportion with Event Metformin UKPDS Kaplan–Meier Curves for Prespecified Aggregate Clinical Outcome: Myocardial Infarction This slide summarizes long-term follow-up of patients in the United Kingdom Prospective Diabetes Study (UKPDS). Kaplan–Meier curves that demonstrate the proportions of patients in the UKPDS who had a myocardial infarction are shown for metformin group versus the conventional-therapy group. Kaplan–Meier plots for cumulative incidence and log-rank P-values are shown at 5-year intervals during a 25-year period from the start of the interventional trial. Not shown are the curves for the 3 other prespecified aggregate clinical outcomes: The benefits seen for any diabetes-related endpoint or microvascular disease in the main trial remained significant at 25 years. In addition, all-cause mortality at 25 years was significantly lower for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group. It is important to note that randomization was not maintained at the completion of the main trial, and that there was no difference in glycemic control in the follow-up phase, which suggested a long-lasting "legacy" effect of good control at the time of diagnosis. Reference: Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: 10 15 20 25 5 Years Since Randomization No. at Risk Conventional Therapy Metformin 4 16 Reprinted from Holman RR et al. N Engl J Med. 2008;359: Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Individualizing A1C Targets in Type 2 Diabetes
Most Intensive Less Intensive Least Intensive 6.0% 7.0% 8.0% Psychosocioeconomic Considerations Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, Comprehensive Support Systems Less Motivated, Nonadherent, Limited Insight, Poor Self-Care Capacities, Weak Support Systems Hypoglycemia Risk Low Moderate High Patient Age 40 45 50 55 60 65 70 75 Disease Duration 5 10 15 20 Individualizing A1C Targets in Type 2 Diabetes Glycemic goals and treatment intensity for patients with type 2 diabetes should be individualized and include consideration of psychosocioeconomic factors, risk for hypoglycemia, age of the patient, duration of disease, other comorbid conditions, and vascular complications (microvascular and/or cardiovascular). Reference: Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154: Other Comorbidities None Few/Mild Multiple/Severe Established Vascular Complications None Early Microvascular Cardiovascular Advanced Microvascular Reprinted with permission from Ismail-Beigi F et al. Ann Intern Med 2011;154: Copyright © 2011 American College of Physicians. All rights reserved.

Alpha-glucosidase inhibitors
Therapy for Type 2 Diabetes: Sites of Action Secretagogues Simulate insulin secretion Alpha-glucosidase inhibitors Inhibit carbohydrate breakdown Incretins Insulin secretion  Glucagon secretion Incretins Slow gastric emptying Metformin Thiazolidinediones Glucose metabolism Thiazolidinediones Glucose intake  FFA output Therapy for Type 2 Diabetes: Sites of Action This slide shows therapeutic sites of action for type 2 diabetes. References: Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996;45: Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol. 2003;17: Metformin Thiazolidinediones Suppress glucose production Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661–1669 | Drucker DJ. Mol Endocrinol. 2003;17:161–171.

ADA/EASD Position Statement
Initial drug monotherapy Efficacy (A1C) Hypoglycemia Weight Side effects Costs Combination therapy: 2 drugs Efficacy (A1C) Hypoglycemia Weight Side effects Costs Combination therapy: 3 drugs ADA/EASD Position Statement The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus panel issued an updated position statement in Key points include: Individualization of glycemic targets and glucose-lowering therapies Diet, weight control, exercise, and education as foundation of therapy Metformin as first-line drug therapy unless contraindicated Combination therapy with 2 or 3 agents Insulin therapy alone or in combination with other agents Patient participation in all treatment decisions Comprehensive risk reduction Reference: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35: More-complex insulin strategies Reprinted with permission from Inzucchi SE et al. Diabetes Care. 2012;35: Copyright © 2012 American Diabetes Association. All rights reserved.

Fasting Plasma Glucose (mg/dl)
ADOPT: A Diabetes Outcome Progression Trial Rosiglitazone Sustained Fasting Plasma Glucose Over Time 160 150 140 130 120 Treatment Difference at 4 Years RSG VS MET -9.8 (-12.7 to -7.0), P<.001 RSG VS SU (-20.4 to -14.5), P<.001 SU MET Fasting Plasma Glucose (mg/dl) RSG ADOPT: A Diabetes Outcome Progression Trial The most important aspect of A Diabetes Outcome Progression Trial (ADOPT) is that it showed, for the first time, that the long-term efficacy of drugs for diabetes can be very different and vary over time. In the short term, sulfonylureas are very effective, but they fail over time perhaps because they have no effect on the natural history of diabetes and because decline in -cell function continues unchecked. This long term failure is perhaps less over 5 years with metformin perhaps because of its beneficial effect on body weight. In contrast, rosiglitazone treatment was associated with the best maintenance of glycemic control over 5 years, representing a change in the natural history of the disease. This may be because of its insulin-sensitizing effect which decreases beta cell load. However, it may also be related to a decrease in lipid accumulation in the pancreas-reducing “lipotoxicity.” Reference: Kahn SE, Haffner SM, Heise MA, et al, for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355: 1 2 3 4 5 Time (years) 3408 3054 2647 2242 840 Number of patients: 4118 Reprinted with permission from Kahn SE et al. N Engl J Med. 2006;355: Copyright © 2006 Massachusetts Medical Society. All rights reserved.

Expectations for New Agents and/or New Strategies
Modify disease progression and halting the decline in -cell function – better long-term control Reducing cardiovascular morbidity and mortality Lowering A1C to targets as close to normal as possible without unacceptable hypoglycemia in selected populations Lowering A1C with no weight gain or lowering A1C with weight loss (ideally) No unexpected side effects in the long term (eg rosiglitazone) Expectations for New Agents and/or New Strategies There are several drawbacks to the currently available treatments, including: failure to counteract progressive -cell dysfunction, concerns about weight gain and hypoglycemia, regimen complexity, and tolerability issues. Overcoming these shortcomings is important to improving diabetes therapy.

Incretin Hormones in Type 2 Diabetes

Incretins Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet  cells in a glucose-dependent fashion, and lower glucagon secretion from islet  cells Two predominant incretins: Glucagon-like peptide–1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP) (also known as gastric inhibitory peptide) Incretin effect is impaired in type 2 diabetes Known as GLP-1 deficiency Incretins Incretins are gut-derived hormones, which are secreted in response to nutrient ingestion, that potentiate insulin secretion from islet  cells in a glucose-dependent fashion and lower glucagon secretion from islet  cells. Two predominant incretins are glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (also known as gastric inhibitory peptide). GLP-1 deficiency impairs the incretin effect in type 2 diabetes. References: Holst JJ, Orskov C. The incretin approach for diabetes treatment: modulation of islet hormone release by GLP-1 agonism. Diabetes. 2004;53 Suppl 3:S197-S204. Meier JJ, Nauck MA. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev. 2005;21:

Effect diminished in diabetes
The Incretin Effect: Insulin Secretion Is Greater in Response to Oral vs IV Glucose 200 100 200 300 400 -30 30 60 90 120 150 180 210 Oral IV 150 Insulin (pmol/L) Glucose (mg/dL) 100 50 The Incretin Effect: Insulin Secretion Is Greater in Response to Oral vs IV Glucose It is well recognized that glucose given orally leads to a greater insulin secretory response than glucose given intravenously to induce the same level of hyperglycemia. This difference has been called the incretin effect and suggests the presence of gut factors or signals that stimulate insulin secretion. It is now known that gut hormones function as incretins. In addition to a diminished ability to secrete insulin, it has been demonstrated that the incretin effect is diminished in type 2 diabetes. Reference: Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63: -30 30 60 90 120 150 180 210 Time (min) Time (min) Effect diminished in diabetes Nauck M et al. J Clin Endocrinol Metab. 1986;63:

Release of gut hormones – Incretins
Role of Incretins in Glucose Homeostatis Ingestion of food Pancreas Glucose-dependent insulin from beta cells (GLP-1, GIP) Glucose uptake by muscles Release of gut hormones – Incretins Blood Glucose Beta cells Alpha cells Active GLP-1 & GIP Glucose dependent glucagon from alpha cells (GLP-1) GI tract DPP-4 enzyme Glucose production by liver Role of Incretins in Glucose Homeostasis This slide summarizes the effect of incretins in glucose regulation. Although glucagon-like peptide–1 (GLP-1) is a native hormone released by intestinal L cells in response to ingested food, its limitations in managing the progressively challenging glucose homeostasis of type 2 diabetes are related to its rapid and extensive inactivation. Deacon and colleagues found that GLP-1 was quickly cleaved at its N-terminus by dipeptidyl peptidase–4 (DPP-4), an enzyme that circulates freely in plasma and exists at the surface of endothelial cells. Under normal conditions, GLP-1 has a half-life of only 1 to 2 minutes. Therefore, to correct this system, one needs to either administer GLP-1 in a continuous manner or inhibit the DPP-4 enzyme. Reference: Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136: Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3: Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26: Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18: Inactive GLP-1 Inactive GIP DPP-4=dipeptidyl peptidase–4 GIP=glucose-dependent insulinotropic peptide GLP-1=glucagon-like peptide–1

Metabolism of Glucagon-Like Peptide–1 and Glucose-Dependent Insulinotropic Peptide
Capillary Active Hormones GLP-1 [7-36NH2] GIP [1-42] DPP-4 Inactive Metabolites GLP-1 [9-36NH2] GIP [3-42] Dipeptidyl peptidase–4 (DPP-4) Ubiquitous, specific protease Cleaves N-terminal dipeptide Inactivates >50% of GLP-1 ~1 min >50% of GIP in ~7 min Metabolism of Glucagon-Like Peptide–1 and Glucose-Dependent Insulinotropic Peptide This schematic describes the metabolism of glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Following release of the peptides into the circulation, the ubiquitous but specific serine protease, dipeptidyl peptidase-4 (DPP-4), cleaves the N-terminal two amino acids from active GIP and GLP-1. This process is rapid and the plasma half-lives of GLP-1 and GIP are 1 and 7 minutes, respectively. The degradation products, GLP-1 [9-36] amide and GIP [3-42], do not stimulate insulin secretion. GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1

Glucagon-Like Peptide–1 (GLP-1) Increases
-Cell Response and Decreases -Cell Workload  -Cell workload  -Cell response Promotes satiety and reduces appetite -Cells:  Postprandial glucose secretion -Cells: Enhance glucose-dependent insulin secretion Liver:  Glucagon reduces hepatic glucose output Glucagon-Like Peptide-1 (GLP-1) Increases -Cell Response and Decreases -Cell Workload Glucagon-like peptide-1 (GLP -1) has multiple effects. By decreasing -cell workload and improving -cell response, GLP-1 is an important regulator of glucose homeostasis. Upon food ingestion, GLP-1 is secreted into the circulation. GLP-1 increases -cell response by enhancing glucose-dependent insulin secretion. References: Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998;101: Larsson H, Holst JJ, Ahrén B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand. 1997;160: Nauck MA, Wollschläger D, Werner J, et al. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia. 1996;39: Drucker DJ. Glucagon-like peptides. Diabetes. 1998;47: GLP-1 secreted upon the ingestion of food Stomach: Helps regulate gastric emptying Larsson H et al. Acta Physiol Scand .1997;160: | Drucker DJ. Diabetes. 1998;47:

Glucagon-Like Peptide–1 Actions Are Glucose Dependent in Patients with Type 2 Diabetes
Glucagon-like peptide–1 (GLP-1; 7–36 amide) 1.2 pmol/kg/min or placebo was infused intravenously in 10 fasting patients with type 2 diabetes not controlled with diet and sulfonylurea therapy ± metformin or acarbose (mean A1C 11.6%, mean plasma glucose 13.1 mmol/l) With GLP-1 treatment Insulin and C-peptide increased significantly from baseline in all patients Glucagon decreased significantly Plasma glucose was reduced to normal fasting concentrations (mean 4.9 mmol/l) within 4 hours Once normalized, plasma glucose was not further reduced despite ongoing GLP-1 infusion Glucagon-Like Peptide–1 Actions Are Glucose-Dependent in Patients with Type 2 Diabetes The fact that glucagon-like peptide–1 (GLP-1) effects are glucose dependent is very important. Insulin is secreted only when plasma glucose concentrations are high and is not secreted when plasma glucose concentrations are low, thus avoiding hypoglycemia. This is very different from sulfonylureas which continue to stimulate insulin secretion even during hypoglycemia. Similarly, glucagon is suppressed when plasma glucose is high (as in the postprandial state) but not during hypoglycemia when it is needed. Reference: Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36: Nauck NA et al. Diabetologia. 1993;36:

Glucagon-Like Peptide–1 Normalizes Postprandial Hyperglycemia in Patients with Type 2 Diabetes
Healthy subjects T2DM patients 300 100 50 150 200 250 2 3 4 1 –1 Infusion GLP-1 [7-36 amide] 1.2 pmol/kg/min Placebo Liquid meal Infusion 300 100 50 150 200 250 2 3 4 1 –1 Liquid meal Placebo Plasma glucose (mg/dl) Plasma glucose (mg/dl) Glucagon-Like Peptide–1 Normalizes Postprandial Hyperglycemia in Patients with Type 2 Diabetes Glucagon-like peptide–1 infusions are particularly effective in normalizing postprandial glucose. Reference: Nauck MA. Glucagon-like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective. Acta Diabetol. 1998;35: GLP-1 [7-36 amide] 1.2 pmol/kg/min Time (h) Time (h) Nauck MA et al. Acta Diabetol. 1998;35:

Mean (SE) AUC for Visual Analogue Score (mm) vs Time (h)
Continuous Glucagon-Like Peptide–1 Infusion Reduces Appetite over 6 Weeks *Satiety Mean (SE) AUC for Visual Analogue Score (mm) vs Time (h) *Fullness Time (wk) *Prospective food intake *Hunger *p<.05 6 1 Continuous Glucagon-Like Peptide-1 Infusion Reduces Appetite over 6 Weeks This slide demonstrates an important effect of glucagon-like peptide–1 (GLP-1): decreased appetite and food intake, which results in weight loss. This is a desirable effect in type 2 diabetes, in which most patients are overweight or obese and other treatments lead to weight gain. Reference: Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359: Time (wk) All data for patients treated with glucagon-like peptide–1 (n = 10). No changes in these parameters were observed in the saline group. Zander M et al. Lancet. 2002;359:824–830.

Incretin-Based Therapies Approved or in Late-Stage Development
Dipeptidyl peptidase–4 inhibitors (incretin enhancers) Sitagliptin: Currently available Saxagliptin: Currently available Linagliptin: Currently available (no dose adjustment in renal insufficiency, unlike others in class) Vildagliptin: Approved by EMEA Additional trials requested by FDA Alogliptin: NDA filed Glucagon-like peptide–1 agonists (incretin mimetics) Exenatide: Currently available - bid Liraglutide: Currently available – once daily Exenatide LAR: Currently available- once weekly Albiglutide Taspoglutide Incretin-Based Therapies Approved or in Late-Stage Development Dipeptidyl peptidase–4 inhibitors are incretin enhancers, and include: sitagliptin, saxagliptin, linagliptin, vildagliptin, and alogliptin. Glucagon-like peptide–1 agonists are incretin mimetics, and include: exenatide, liraglutide, exenatide LAR, albiglutide, and taspoglutide.

Circulating GLP-1 Has Many Beneficial Effects
↑ Insulin secretion to maintain glucose homeostasis ↓ Glucagon secretion ↓ Postprandial glycemia ↓ Gastric emptying ↑ Satiety due to delayed gastric emptying ↓ Food ingestion due to effects on brain ↑ Β cell number and ↑ Β cell mass (animal studies) ↑ Β cell proliferation and ↑ islet neogenesis ↓ Apoptosis Circulating GLP-1 Has Many Beneficial Effects In addition to its beneficial effects on insulin secretion and therefore glucose concentration, glucagon-like peptide–1 (GLP-1) inhibits glucagon release, gastric emptying, and food intake, and increases pancreatic -cell mass and proliferation. Reference: Ranganath LR. Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. J Clin Pathol. 2008;61: Ranganath LR et al. J Clin Pathol. 2008;61:

Physiological Actions of GLP-1 and GIP
Neuroprotection Cardioprotection Cardiac output Appetite Gastric emptying GLP-1 Glucagon secretion Insulin secretion Insulin biosynthesis  cell proliferation  cell apoptosis GIP Physiological Actions of GLP-1 and GIP GLP-1 and GIP exert a number of physiological actions that may benefit patients with diabetes. Glucose production Glucose disposal Osteoblast Sodium excretion Lipogenesis

Comparison of Incretin Mimetics Available
Available agents: exenatide, exenatide long-acting release (LAR), liraglutide administered by subcutaneous injection not DDP-4 substrates Exenatide: half-life ~2–4 hours; twice-daily injections of 5–10 mg each Exenatide LAR: half-life >1 week; weekly injections of up to 2 mg Liraglutide: half-life ~12–14 hours; daily injections of up to 2 mg Comparison of Incretin Mimetics Available and in Development This slide summarizes the similarities and differences between 3 incretin mimetics. Reference: Nauck M, Schmidt W, Meier J. The incretin modulators–incretin mimetics (GLP-1 receptor agonists) and incretin enhancers (DPP-4 Inhibitors). In: Mogensen CE (ed). Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. New York: Springer; 2007: Nauck M et al. In: Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. 2007:

Exenatide + Oral Agents Summary of A1C Changes
Placebo Exenatide 5 µg Exenatide 10 µg “THE 3 AMIGOS TRIAL” 30-Week, Randomized, Placebo-Controlled 0.23% 0.12% 8.6% 0.08% 8.2% 8.5%  A1C (%) -0.40% * -0.46% * Exenatide + Oral Agents This slide summarizes the pivotal trials with exenatide that led to its approval. It is effective in significantly lowering A1C in combination with a variety of agents for the treatment of diabetes, including thiazolidinediones (not shown on the slide), as well as in monotherapy. References: Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27: DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28: Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28: -0.55% * -0.78% * -0.77% * -0.86% * Exenatide + Sulfonylurea + Metformin (n = 733) Exenatide + Sulfonylurea (n = 377) Exenatide + Metformin (n = 336) *p<0.01 vs. Placebo Buse JB et al. Diabetes Care. 2004;27: | Defronzo RA et al. Diabetes Care. 2005;28: | Kendall DM et al. Diabetes Care. 2005; 28:

Efficacy of Exenatide BID in Clinical Trials
Background Therapya Mean Disease Duration (y) ΔA1C (%) Exenatide BID Placebo Monotherapy1 2 ‒0.9 ‒0.2b MET2 5–6 ‒0.8 +0.1b SU3 6–7 TZD ± MET4,c 7–8 SU + MET5 9 +0.2b a 16–30 weeks, baseline A1C: 7.8–8.6% b p<0.001 for placebo vs 10 g exenatide BID c 79% of patients on both agents Efficacy of Exenatide BID in Clinical Trials This slide summarizes clinical trials of exenatide, alone or in combination with other agents. Compared with placebo, exenatide 10 g BID significantly reduced A1C. References: Moretto TJ, Milton DR, Ridge TD, Macconell LA, Okerson T, Wolka AM, Brodows RG. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30: DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28: Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27: Zinman B, Hoogwerf BJ, Durán García S, Milton DR, Giaconia JM, Kim DD, Trautmann ME, Brodows RG. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;146: Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28: Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Wintle ME, Maggs DG. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24: 1Moretto TJ et al. Clin Ther. 2008;30: | 2Defronzo RA et al. Diabetes Care. 2005;28: | 3Buse JB et al. Diabetes Care. 2004;27: | 4Zinman B et al. Ann Intern Med. 2007;146: | 5Kendall DM et al. Diabetes Care. 2005; 28: | 6Klonoff DC et al. Curr Med Res Opin. 2008;24:

Mean Disease Duration (y)
Efficacy of Liraglutide versus Oral Agents in Liraglutide Effect and Action in Diabetes (LEAD) Trial Series Background Therapya Mean Disease Duration (y) ΔA1C (%) Liraglutide Comparators Monotherapy1 5–6 1.2 mg: ‒0.8 1.8 mg: ‒1.1 Glim: ‒0.5b SU2 6–7 1.2 mg: ‒1.1 Placebo: +0.2b Rosi: ‒0.4b Met3 7–8 1.2 mg: ‒1.0 1.8 mg: ‒1.0 Placebo: +0.1b Glim: ‒1.0 Rosi ± Met4,c 9 1.2 mg: ‒1.5 1.8 mg: ‒1.5 Placebo: ‒0.5b Efficacy of Liraglutide versus Oral Agents in Liraglutide Effect and Action in Diabetes (LEAD) Trial Series This slide summarizes clinical trials of liraglutide, alone or in combination with other agents. Compared with placebo and rosiglitazone, liraglutide significantly reduced A1C. References: Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, Hale PM, Zdravkovic M, Bode B, for the LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373: Marre M, Shaw J, Brändle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, Le Thi TD, Colagiuri S, on behalf of the LEAD-1 SU Study Group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26: Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, Matthews DR, for the LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (Liraglutide Effect and Action in Diabetes)-2 Study. Diabetes Care. 2009;32:84-90. Zinman B, Hoogwerf BJ, Durán García S, Milton DR, Giaconia JM, Kim DD, Trautmann ME, Brodows RG. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;146: Garber A, Henry RR, Ratner R, Hale P, Chang CT, Bode B, on behalf of the LEAD-3 (Mono) Study Group. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13: a26 weeks (except 52 weeks for monotherapy), mean baseline A1C: 8.2–8.6% bp <0.005 vs liraglutide 1Garber A, et al. Lancet. 2009;373: | 2Marre M et al. Diabet Med. 2009;26: | 3Nauck M et al. Diabetes Care. 2009;32:84-90 | 4Zinman B et al. Ann Intern Med. 2007;146: | 5Garber A et al. Diabetes Obes Metab. 2011;13:

Mean Disease Duration (y)
Efficacy of Exenatide QW versus Oral Agents in the DURATION Trial Series Background Therapya Mean Disease Duration (y) ΔA1C (%) Exenatide QW Comparators Monotherapy1 3 ‒1.5 Met: ‒1.5 Pio: ‒1.6 Sita: ‒1.2b Met2 5–6 Pio: ‒1.2b Sita: ‒0.9b a 26 weeks, baseline A1C: 8.5–8.6% b p <0.05 vs exenatide QW Maintenance of glycemic control has been demonstrated over 3 years (ΔA1C = –1.6%)3 Efficacy of Exenatide QW versus Oral Agents in the DURATION Trial Series Weekly exenatide was compared with oral agents in the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once-Weekly (DURATION) trials. Glycemic control was shown to be maintained at 3-year follow-up. References: Russell-Jones D, Cuddihy RM, Hanefeld M, Kumar A, González JG, Chan M, Wolka AM, Boardman MK, on behalf of the DURATION-4 Study Group. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35: Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, Wilhelm K, Malone J, Porter LE, for the DURATION-2 Study Group. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;376: MacConell L, Walsh B, Li Y, Pencek R, Maggs D. Exenatide once weekly: sustained improvement in glycemic control and weight loss through 3 years (abstract 969-P). Presented at American Diabetes Association 71st Scientific Sessions, San Diego, California, June 2011. DURATION = Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once-Weekly 1Russell-Jones D et al. Diabetes Care. 2012;35: | 2Bergenstal RM et al. Lancet. 2010; 376: | 3MacConell L et al. Presented at 71st ADA Scientific Sessions (abstract 969-P), San Diego, CA, June 2011.

Glycemic Control with GLP-1 Receptor Agonists in Head-to-Head Clinical Trials
Size (N): Study length (weeks): LEAD-61 464 26 DURATION-12 303 30 DURATION-53 254 24 DURATION-64 912 26 EXN BID LIRA EXN QW * Glycemic Control with GLP-1 Receptor Agonists in Head-to-Head Clinical Trials This slide summarizes A1C results from the Liraglutide Effect and Action in Diabetes (LEAD)–6 trial and Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once-Weekly (DURATION)–1, DURATION-5, and DURATION-6 trials. References: Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L, for the LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39-47. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L, for the DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372: Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, Trautmann M, Porter L. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96: Buse JB, Nauck, MA, Forst T, Sheu WHH, Hoogwerf BJ, Shenouda SK, Heilmann CR, Boardman MK, Fineman M, Porter L, Schernthaner G. Efficacy and safety of exenatide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6): a randomised, open-label -study (abstract 75). Presented at 47th EASD Annual Meeting, Lisbon, Portugal, 14 September 2011. * * *Significant difference vs comparator GLP-1 receptor agonist 1Buse JB et al. Lancet. 2009;374:39-47 | 2Drucker DJ et al. Lancet. 2008;372: | 3Blevins T, et al. J Clin Endocrinol Metab. 2011;96: | 4Buse JB et al. Presented at 47th EASD Annual Meeting, Lisbon, Portugal, 14 September 2011.

Exenatide + Oral Agents Summary of Weight Changes
Placebo Exenatide 5 µg Exenatide 10 µg “THE 3 AMIGOS TRIAL” 30-Week, Randomized, Placebo-Controlled -0.3 -0.6 -0.9 -0.9 -1.6 * -1.6 * -1.6 * -1.6 *  Weight (kg) Exenatide + Oral Agents An important feature of exenatide treatment is its effect on body weight. Consistent weight loss has been seen in several clinical trials either as monotherapy or in combination with other agents. Although some studies describe weight loss in combination with insulin, exenatide is not approved in combination with insulin. Reference: Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27: DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28: Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28: -2.8 * Exenatide + Sulfonylurea + Metformin (n = 733) Exenatide + Sulfonylurea (n = 377) Exenatide + Metformin (n = 336) *p<0.01 vs. placebo Buse JB et al. Diabetes Care. 2004;27: | Defronzo RA et al. Diabetes Care. 2005;28: | Kendall DM et al. Diabetes Care. 2005; 28:

Changes in Body Weight with Exenatide versus Insulin
Insulin glargine group (n = 260) Change in Body Weight (kg) * * Exenatide group (n = 275) * * * Changes in Body Weight with Exenatide versus Insulin This study demonstrated a clear (and not surprising effect) when comparing exenatide to insulin in patients who failed on oral agents. Both treatments improved glycemic control, but exenatide led to weight loss, whereas insulin led to weight gain. Reference: Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG, for the GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143: * 2 4 8 12 18 26 Weeks *P< compared with insulin glargine measure at the same time point. Reprinted with permission from Heine R et al. Ann Intern Med. 2005;143:559–569. Copyright © 2005 American College of Physicians. All rights reserved.

Distribution of Weight Loss and A1C Change with Exenatide BID and Exenatide QW
Once a week (73%) Twice a day (74 %) Once a week (1%) Twice a day (5%) Once a week (3%) Once a week (23%) Twice a day (16%) 10 -10 Weight Change (kg) -20 -30 Distribution of Weight Loss and A1C Change with Exenatide BID and Exenatide QW In the first Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once-Weekly trial (DURATION-1), exenatide administered either twice daily or once weekly significantly reduced A1C, regardless of concomitant weight loss, which occurred in >75% of both treatment groups. In most patients, both A1C and bodyweight were reduced. Reference: Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L, for the DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372: -40 -6 -5 -4 -3 -2 -1 1 2 3 A1C Change (%) Reprinted with permission from Drucker DJ et al. Lancet. 2008;372: Copyright © 2008 Elsevier. All rights reserved.

Comparison of Incretin Modulators
GLP-1 Analogues DPP-4 Inhibitors Administration route Injection Oral  GLP-1 Sustained Meal-related Effect on A1C  Effects on body weight   Side effects Nausea, Rare: pancreatitis (Well tolerated) Nasopharyngitis, skin rashes, Stevens-Johnson syndrome -cell function  Comparison of Incretin Modulators This slide compares glucagon-like peptide–1 (GLP-1) analogs and dipeptidyl peptidase–4 (DPP-4) inhibitors. GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase–4

Cardiovascular Effects of GLP-1 Analogs
Beneficial BP effects Rapid Probably not due to weight loss May be direct vascular effects or natriuretic effects Weight loss may contribute to sustained reductions Beneficial effects on lipids, other CVD risk factors Largely mediated through weight loss May have direct cardioprotective effects Cardiovascular Effects of GLP-1 Analogs Glucagon-like peptide–1 (GLP-1) analogs have a number of beneficial cardiovascular effects, including on blood pressure and lipids.

Complementary actions
Combination of Basal Insulin with a GLP-1 Agonist Has a Scientific Logic Basal insulin analogs Simple to initiate Control nocturnal and FPG Lower hypoglycaemia risk vs NPH Modest weight increase (1–3 kg) Achieve A1C targets in ~50–60% GLP-1 agonists Simple to initiate Pronounced PPG control No increase in hypoglycaemia Weight lowering/neutral effects Achieve A1C targets in ~40–60% Complementary actions Combination of Basal Insulin with a GLP-1 Agonist Has a Scientific Logic The scientific rationale for combining basal insulin with glucagon-like peptide–1 (GLP-1) agonists includes both complementary actions and additive effects. Additive effects

Exenatide BID Combined with Basal Insulin
EXN BID + GLAR vs PBO + GLAR1 30-Week Trial (N = 259) More patients discontinued EXN BID (9%) vs PBO (1%) due to adverse events (p <0.01)1 Significant A1C reduction regardless of intensification order2 EXN BID + insulin glargine Insulin glargine + EXN BID Exenatide BID Combined with Basal Insulin In a randomized trial of exenatide BID vs placebo in patients receiving insulin glargine, combination therapy with exenatide significantly reduced A1C compared with placebo, although exenatide was also associated with significantly more discontinuations due to adverse events. In a retrospective chart review, combination therapy with glargine and exenatide for up to 2 years reduced A1C without significantly increasing body weight or hypoglycemia risk, regardless of the order in which agents were initiated. References: Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, Hoogwerf BJ, Rosenstock J. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154: Levin PA, Mersey JH, Zhou S, Bromberger LA. Clinical outcomes using long-term combination therapy with insulin glargine and exenatide in patients with type 2 diabetes mellitus. Endocr Pract. 2012;18:17-25. p <0.001 1Buse JB et al. Ann Intern Med. 2011;154: | 2Levin PA, et al. Endocr Pract. 2012;18:17-25.

Managing Nausea Associated with GLP-1 Receptor Agonists
Discuss expectations Nausea is likely to be mild and resolve in a few weeks Nausea may actually be “fullness” Suggest decreased portion sizes Suggest reduced fat content of meals Keep a log of foods that cause nausea Be aware of severe persistent abdominal pain, which could indicate pancreatitis Titrate more slowly – maintain at lower dose for a longer period Be aware of severe GI disease GLP-1 receptor agonists slow gastric emptying and are associated with GI adverse events GLP-1 receptor agonists have not been studied in patients with severe GI disease Avoid exenatide in patients with history of gastroparesis Managing Nausea Associated with GLP-1 Receptor Agonists Because nausea may be associated with glucagon-like peptide–1 (GLP-1) receptor agonist treatment, patient education and monitoring are recommended to minimize complications. References: Kruger DF, Bode B, Spollett GR. Understanding GLP-1 analogs and enhancing patients success. Diabetes Educ Jul-Aug;36(suppl 3):44S-72S. Amylin Pharmaceuticals, Byetta prescribing information, revised December 2011. Amylin Pharmaceuticals, Bydureon prescribing information, revised January 2012. Novo Nordisk, Victoza prescribing information, revised April 2012. Kruger DF et al. Diabetes Educ. 2010;36(suppl 3):44S-72S | Amylin Pharmaceuticals, Byetta prescribing information, December 2011 | Amylin Pharmaceuticals, Bydureon prescribing information, January 2012 | Novo Nordisk, Victoza prescribing information, April 2012.

Absolute and Relative Risk of Acute Pancreatitis with Antidiabetic Agents in Human Subjects
Exenatide-Met/Gly Sitagliptin-Met/Gly 0.0 0.5 1.0 1.5 2.0 Relative Risk of Acute Pancreatitis (±95% CI) Absolute and Relative Risk of Acute Pancreatitis with Antidiabetic Agents in Human Subjects In a review of insurance claim records for hospitalizations with a primary diagnosis of acute pancreatitis, relative and absolute risks for acute pancreatitis in patients who initiated therapy with exenatide or sitagliptin were similar to those in propensity score–matched patients who initiated therapy with either metformin or glyburide (grouped together in this analysis). Reference: Dore DD, Seeger JD, Chan KA. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin. 2009;25: The absolute risk of acute pancreatitis was comparable among initiators of exenatide and sitagliptin Drug Pair 1: Exenatide 0.13% (N = 27,996); Met/Gly 0.13% (N = 27,983) Drug Pair 2: Sitagliptin 0.12% (N = 16,267); Met/Gly 0.12% (N = 16,281) Dore DD et al. Curr Med Res Opin. 2009;25(4):1019–1027.

Incretin-Based Therapies: Reports of Pancreatitis
Patients with diabetes should be counseled about the symptoms of pancreatitis Symptoms include persistent abdominal pain that can radiate to the back and may or may not be accompanied by nausea and vomiting Exenatide and liraglutide should be stopped if signs of pancreatitis develop and should be used with caution in patients who have a history of the disease Incretin-Based Therapies: Reports of Pancreatitis Because of reports of pancreatitis with the use of glucagon-like peptide–1 (GLP-1) receptor agonists, patients should be instructed on the symptoms of pancreatitis, and exenatide and liraglutide should be discontinued if these symptoms occur. In patients with a history of pancreatitis, GLP-1 receptor agonists should be used with caution.

Liraglutide and Exenatide ER: Boxed Warning
Warning: risk of thyroid C-cell tumors [Liraglutide/Exenatide extended-release] causes thyroid C-cell tumors at clinically relevant exposures in rodents Unknown whether [Victoza/Bydureon] causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies Contraindicated in patients with: Personal or family history of MTC Multiple endocrine neoplasia syndrome type 2 (MEN 2) Liraglutide and Exenatide ER: Boxed Warning Long-acting glucagon-like peptide–1 agonists cause dose-dependent and treatment duration–dependent increases in incidence of thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice, as reflected in the boxed warning in the prescribing information for exenatide extended-release and liraglutide. References: Amylin Pharmaceuticals, Bydureon prescribing information, revised January 2012. Novo Nordisk, Victoza prescribing information, revised April 2012. Amylin Pharmaceuticals, Bydureon prescribing information, January 2012 | Novo Nordisk, Victoza prescribing information, April 2012.

DPP-4 Inhibitors vs. GLP-1 Agonists
GLP-1 and GIP enhanced Physiological fluctuations in hormone levels Limited by endogenous secretion Comparable to TZD, SU Superior tolerability Weight neutral Oral, once daily GLP-1 agonists Pure GLP-1 effect Sustained effect that may be prolonged Not limited by endogenous secretion Superior to SU, TZD Nausea, vomiting Weight loss Injection DPP-4 Inhibitors vs. GLP-1 Agonists Characteristics, advantages, and disadvantages of dipeptidyl peptidase–4 (DPP-4) inhibitors and glucagon-like peptide–1 (GLP-1) agonists are compared on this slide.

Comparison of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors
Sitagliptin Linagliptin Saxagliptin Vildagliptin Usual phase 3 dose 100 mg QD 5 mg QD 50 mg BD Half-life (t1/2), h 12.4 12.5–21.1 2.2–3.8 1.3–2.4 DPP-4 inhibition at 24 h ~80% ~80% (25 mg) ~55% (5 mg) 50% (100 mg) Elimination Kidney (mostly unchanged) Bile but not kidney Liver and kidney Active metabolite Kidney>>Liver Inactive metabolite Renal dose adjustments required Yes No None for mild impairment; not recommended for moderate or severe impairment Selectivity for DPP-4 >2600-fold vs DPP-8 >10,000-fold vs DPP-9 >10,000-fold vs DPP-8/9 >400-fold vs DPP-8 >100-fold vs DPP-9 >90-fold vs DPP-8 Potential for drug–drug interaction Low Strong CYP3A4/5 inhibitors Food effect Comparison of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors Dipeptidyl peptidase–4 (DPP-4) inhibitors available in the US are sitagliptin, linagliptin, saxagliptin, and vildagliptin.

Properties of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors
Oral administration GLP-1/GLP-1 receptor agonist concentration elevated 3–6 hours after meals when secretion from endogenous sources is stimulated GLP-1 concentration close to physiological concentration (~ x 2–3) Action through GLP-1 receptors and possibly GIP receptors and/or other receptors GLP-1 action probably through nerves more than circulation A1C reduction −0.5% to −1.1% Weight change ±0 kg -Cell mass effects probable in animals, no human data Properties of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors This slide summarizes the properties of dipeptidyl peptidase–4 (DPP-4) inhibitors. Reference: Nauck M, Schmidt W, Meier J. The incretin modulators–incretin mimetics (GLP-1 receptor agonists) and incretin enhancers (DPP-4 inhibitors). In: Mogensen CE, ed. Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. New York: Springer; 2007: Nauck M et al. In: Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. 2007:

Vildagliptin: A1C Changes
Monotherapy Add-on Combination Therapy vs Placebo vs RSG vs Met Met ≥1500 mg/d Pio mg qd Pio* mg qd Insulin >30 U/d -2.0 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 –0.5 Mean Change from Baseline in A1C (%) –0.8 –0.8 –0.9 –0.9 –1.0 –1.1 *Initial combination therapy All statistically significant Vildagliptin: A1C Changes In a review of clinical trials of dipeptidyl peptidase–4 (DPP-4) inhibitors, vildagliptin monotherapy or combination therapy provided statistically significant reductions in A1C. References: Rosenstock J, Zinman B. Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2007;14: Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drug-naïve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Horm Metab Res. 2007;39: Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;76: Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30: Schweizer A, Couturier A, Foley JE, Dejager S. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with type 2 diabetes. Diabet Med. 2007;24: Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30: –1.9 Study duration (wks) 24 52 N (ITT population) 380 340 697 780 416 398 592 256 Baseline A1C (%) 8.4 8.3 8.7 8.8 8.5 Reprinted with permission from Rosenstock J et al. Curr Opin Endocrinol Diabetes Obes. 2007;14: Copyright © 2007 Wolters Kluwer Health. All rights reserved.

Mean change from baseline in HbA1c (%)
Sitagliptin: A1C Changes Monotherapy Add-on Combination Therapy Met ≥1500 mg/d Met* 2000 mg/d Pio –45 mg/d vs Placebo vs Placebo vs Glipizide -2.0 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 -0.5 -0.5 -0.6 Mean change from baseline in HbA1c (%) -0.7 -0.85 Sitagliptin: A1C Changes In a review of clinical trials of dipeptidyl peptidase–4 (DPP-4) inhibitors, sitagliptin monotherapy or combination therapy provided statistically significant reductions in A1C. References: Rosenstock J, Zinman B. Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2007;14: Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, for the Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29: Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49: Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29: Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE, for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30: Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9: Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, for the Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28: *Initial combination therapy All statistically significant -1.9 Study duration (wks) 24 18 52 N (ITT population) 711 495 677 1135 1056 337 Baseline A1C (%) 8.0 8.1 7.7 8.8 Reprinted with permission from Rosenstock J et al. Curr Opin Endocrinol Diabetes Obes. 2007;14: Copyright © 2007 Wolters Kluwer Health. All rights reserved.

Efficacy of Add-on Sitagliptin
1 2 Efficacy of Add-on Sitagliptin The addition of sitagliptin to either metformin or pioglitazone significantly reduced A1C compared with metformin or piogliazone monotherapy in patients with diabetes. References: Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29: Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, for the Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28: LSM  = least- squares mean change –0.65% (P<0.001) –0.70% (P<0.001) 1Charbonnel B et al. Diabetes Care 2006;29: | 2Rosenstock J et al. Clin Ther 2006;28:

Similar Glycemic Control with Sitagliptin vs Glipizide Added to Metformin
8.4 Sitagliptin 100 mg qd (n=382) Glipizide (n=411) 8.2 8.0 7.8 7.6 Mean change from baseline (for both groups)*: –0.67% 7.4 *Per protocol analysis; –0.51% and –0.56% for sitagliptin and glipizide, respectively, in last observation carried forward (LOCF) analysis Mean change in A1C 7.2 7.0 6.8 6.6 Similar Glycemic Control with Sitagliptin vs Glipizide Added to Metformin Combination therapy with metformin and sitagliptin or metformin and glipizide provided similar improvements on A1C in diabetic patients with elevated A1C on metformin monotherapy. Reference: Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9: 6.4 6.2 6.0 12 24 38 52 Time (weeks) Reprinted with permission from Nauck MA et al. Diabetes Obes Metab. 2007; 9: Copyright © 2007 John Wiley and Sons. All rights reserved.

Saxagliptin Monotherapy in Treatment-Naïve Patients with Type 2 Diabetes
2.5 5 10 PBO 100 103 95 92 7.9 8.0 Dose n = SAXA (mg) Baseline mean A1C (%) BL 4 6 8 12 16 20 24 Weeks Mean ± SE change in A1C from baseline (%) PBO SAXA 5 mg SAXA 2.5 mg SAXA 10 mg 2.5 5 10 7.9 8.0 Dose Baseline mean A1C (%) SAXA (mg) 0.19 Adjusted mean ± SE change in A1C (%) Saxagliptin Monotherapy in Treatment-Naïve Patients with Type 2 Diabetes In 401 patients with A1C ≥7% and ≤10% randomized to oral saxagliptin 2.5, 5, or 10 mg once daily or placebo for 24 weeks, A1C was significantly reduced from baseline to week 24 in all saxagliptin treatment groups compared with placebo. The treatment effect was apparent at week 4, the earliest follow-up assessment of A1C. Reference: Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R, for the CV Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25: –0.43* –0.45* –0.54* *P< vs PBO Reprinted with permission from Rosenstock J et al. Curr Med Res Opin. 2009; 25: Copyright © 2009 Informa Healthcare. All rights reserved.

Saxagliptin Add-on to Metformin: Reduction in A1C in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone PBO + MET A1C, Mean ± SE Change from Baseline (%) SAXA 10 mg + MET SAXA 2.5 mg + MET Saxagliptin Add-on to Metformin: Reduction in A1C in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone Saxagliptin added on to metformin significantly reduced A1C in patients whose diabetes was inadequately controlled with metformin monotherapy. Reference: DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, Chen RS, for the Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32: SAXA 5 mg + MET BL 6 Reprinted with permission from DeFronzo RA et al. Diabetes Care. 2009;32: Copyright © 2009 American Diabetes Association. All rights reserved.

Efficacy of Saxagliptin Monotherapy Therapy over 24 Weeks Compared with Placebo
SAXA Dose (Main treatment cohort) A1C Change (%)* FPG Change (mg/dL)* PPG-AUC Change (mg + min/dL)* 2.5 mg once daily −0.62† −21† −6221 5.0 mg once daily −0.64† −15† −6249† 10.0 mg once daily −0.73† −23† −7437† Efficacy of Saxagliptin Monotherapy Therapy over 24 Weeks Compared with Placebo Saxagliptin monotherapy was given once daily for 24 weeks in drug-naïve patients. The study was multicentered, randomized, parallel-group, double-blind, and placebo-controlled. Baseline A1C was ≥7.0% to ≤10% in the main treatment cohort and >10% to ≤12% in the open-label cohort. There were no cases of confirmed hypoglycemia, and saxagliptin treatment was weight neutral. Most common (≥5%) adverse effects included: upper respiratory tract infection, headache, urinary tract infection, nasopharyngitis, and sinusitis. Adverse event frequency similar for all treatment groups in the main treatment cohort. Reference: Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R, for the CV Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25: SAXA = saxagliptin FPG = fasting plasma glucose PPG-AUC = postprandial glucose area under the curve * Placebo-subtracted difference † Statistically significant decrease from baseline Rosenstock J et al. Curr Med Res Opin. 2009;25:

p<0.001 for difference between treatment groups
Prandial Glucagon after up to 2 Years Add-on Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Vildagliptin Glimepiride Glucagon (pmol.hr/L) 1 2 3 4 5 -1 -2 -3 -4 -5 p<0.001 for difference between treatment groups Prandial Glucagon after up to 2 Years Add-on Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin At up to 2-year follow-up in patients whose diabetes was inadequately controlled with metformin monotherapy, vildagliptin added to metformin significantly reduced prandial glucagon compared with glimepiride added to metformin. Reference: Ahrén B, Foley JE, Ferrannini E, Matthews DR, Zinman B, Dejager S, Fonseca VA. Changes in prandial glucagon levels after a 2-year treatment with vildagliptin or glimepiride in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care. 2010;33: Reprinted with permission from Ahrén B et al. Diabetes Care. 2010;33: Copyright © 2010 American Diabetes Association. All rights reserved.

Insulin Secretory Rate Relative to Glucose after up to 2 Years Add-on Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin 3.0 4.0 5.0 0.5 1.5 2.5 3.5 4.5 2.0 1.0 Insulin Secretory Rate Relative to Glucose (pmol/min/m2/mmol/L) Vildagliptin Glimepiride Insulin Secretory Rate Relative to Glucose after up to 2 Years Add-on Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin At up to 2-year follow-up in patients whose diabetes was inadequately controlled with metformin monotherapy, vildagliptin or glimepiride added to metformin increased insulin secretion relative to glucose, with a significantly greater increase in the group receiving glimepiride compared with the group receiving vildagliptin. Reference: Ahrén B, Foley JE, Ferrannini E, Matthews DR, Zinman B, Dejager S, Fonseca VA. Changes in prandial glucagon levels after a 2-year treatment with vildagliptin or glimepiride in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care. 2010;33: p=0.022 for difference between treatment groups Ahrén B et al. Diabetes Care. 2010;33:

Risk Ratio DPP-4 vs. Control Mean % Experiencing Outcome
Adverse Events with Dipeptidyl Peptidase–4 (DPP-4) Inhibitors Adverse Events No. of Studies Risk Ratio DPP-4 vs. Control Mean % Experiencing Outcome DPP-4 Control Hypoglycemia 20 0.97 1.6% 1.4% Nausea 10 0.89 2.7% 3.1% Vomiting 6 0.69 1.3% 1.5% Diarrhea 7 0.80 3.8% 4.0% Abdominal pain 5 0.73 2.4% 3.2% Cough 1.07 2.9% Influenza 0.87 4.1% 4.7% Nasopharyngitis 12 1.17 6.4% 6.1% Upper respiratory tract infection 9 0.99 6.3% Sinusitis 3 0.61 2.0% 3.4% Urinary tract infection 1.52 Headache 13 1.38 5.1% 3.9% Adverse Events with Dipeptidyl Peptidase–4 (DPP-4) Inhibitors This slide summarizes the adverse effects of dipeptidyl peptidase–4 inhibitors in a meta-analysis of clinical trials. Reference: Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298: Amori RE et al. JAMA. 2007;298:

Despite Important Advances in Therapy, Glycemic Control Is Not Optimal

Similar presentations

Presentation on theme: "Despite Important Advances in Therapy, Glycemic Control Is Not Optimal"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Despite Important Advances in Therapy, Glycemic Control Is Not Optimal

Similar presentations

Presentation on theme: "Despite Important Advances in Therapy, Glycemic Control Is Not Optimal"— Presentation transcript:

Similar presentations

About project

Feedback