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Slide Source: Lipids Online Slide Library www.lipidsonline.org New Approaches to Achieving Good Glycemic Control in Type 2 Diabetes: Part 1.

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Presentation on theme: "Slide Source: Lipids Online Slide Library www.lipidsonline.org New Approaches to Achieving Good Glycemic Control in Type 2 Diabetes: Part 1."— Presentation transcript:

1 Slide Source: Lipids Online Slide Library New Approaches to Achieving Good Glycemic Control in Type 2 Diabetes: Part 1

2 Slide Source: Lipids Online Slide Library 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

3 Slide Source: Lipids Online Slide Library 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

4 Slide Source: Lipids Online Slide Library 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)

5 Slide Source: Lipids Online Slide Library Pathogenesis of Type 2 Diabetes HyperglycemiaHyperglycemia Liver Increased Glucose Production Reprinted with permission from DeFronzo RA. Diabetes. 1988;37: Copyright © 1998 American Diabetes Association. All rights reserved. Impaired Insulin Secretion Pancreas Liver Decreased Glucose Uptake Muscle

6 Slide Source: Lipids Online Slide Library Pancreatic Islet Dysfunction Leads to Insufficient Insulin and Elevated Glucagon in 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. pg/mL CHO = high-carbohydrate; NGT = normal glucose tolerance; TD2 = type 2 diabetes Time (min) Glucagon uU/mL Insulin Glucose T2D NGT T2D NGT CHO meal mg/dL T2D NGT

7 Slide Source: Lipids Online Slide Library Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58: Copyright © 2009 American Diabetes Association. All rights reserved. Ominous Octet Decreased Incretin Effect Decreased Insulin Secretion Increased Hepatic Glucose Production Islet–  cell Increased Glucagon Secretion Decreased Glucose Uptake Increased Lipolysis IncreasedGlucoseReabsorption HYPERGLYCEMIA Neurotransmitter Dysfunction

8 Slide Source: Lipids Online Slide Library AgentExamples MechanismAction SUsglyburide, glipizide, glimepiride Closes K ATP channels  Pancreatic insulin secretion ‘Glinides repaglinide, nateglinide Closes K ATP channels  Pancreatic insulin secretion BiguanidesmetforminActivates AMP-kinase  Hepatic glucose production TZDsrosiglitazone, pioglitazone Activates PPAR- Peripheral insulin sensitivity -GIs acarbose, miglitolBlocks 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 pramlintideActivates amylin receptors  Pancreatic glucagon secretion; delays gastric emptying;  satiety DPP-4 inhibitors sitagliptin, saxagliptin Inhibits DPP-4,  endogenous incretins  Pancreatic insulin secretion;  pancreatic glucagon secretion Bile acid sequestrants colesevelamBinds bile acid cholesterol ? D2 agonists bromocriptineActivates dopaminergic receptors ‘Resets hypothalamic circadian organization’;  insulin sensitivity T2DM: Therapeutic Landscape (Noninsulin) 2012 Inzucchi SE et al. Diabetes Care 2012;35:

9 Slide Source: Lipids Online Slide Library Agent A1c AdvantagesDisadvantagesCost SUs1–2% Microvasc risk Hypo, wt gain, -cell exhaust $ ‘Glinides 1–1.5% PPGHypo, wt gain, -cell exhaust, dose frequency $ $ $ Biguanides1–2%Wt loss, no hypo, CVD, ?  malignancy GI, lactic acidosis B12-deficiency $ TZDs1–1.5% 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 hypoUrticaria / Angioedema; ? pancreatitis $ $ $ Bile acid sequestrants 0.5% No hypo; LDL-CGI; TGs $ $ $ D2 agonists 0.5%No hypoNausea; dizziness$ $ $ T2DM: Therapeutic Landscape (Noninsulin) 2012 Inzucchi SE et al. Diabetes Care 2012;35:

10 Slide Source: Lipids Online Slide Library Prevention of Type 2 Diabetes StudySubjectsInterventionRelative Risk Reduction Da Quing 1 IGTDiet or Exercise or Both42% / 49% / 34% Finnish DPS 2 IGTLifestyle58% DPP 3 IGTLifestyle58% DPP 3 IGT /“IFG”Metformin31% STOP-NIDDM 4 IGTAcarbose25% EDIP 5 IFGAcarboseNS XENDOS 6 IGTOrlistat45% TRIPOD 7 Prior GDMTroglitazone55% DREAM 8,9 IFGRosiglitazone / Ramipril62% / NS ACT NOW 10 IGTPioglitazone72% ORIGIN 11 IGT / “IFG”Insulin Glargine / Omega-3  1 Li G et al. Lancet. 2008;371: | 2 Tuomilehto J et al. N Engl J Med. 2001;344: | 3 Diabetes Prevention Program Research Group. N Engl J Med. 2002;346: | 4 Chiasson JL et al. Lancet. 2002;359: | 5 Kirkman MS et al. Diabetes Care. 2006;29: | 6 Torgerson JS et al. Diabetes Care. 2004;27: | 8 DREAM Trial Investigators. Lancet. 2006;368; | 9 DREAM Trial Investigators. N Engl J Med. 2006;355: | 10 DeFronzo RA et al. N Engl J Med. 2011;364: | 11 ORIGIN Trial Investigators. Am Heart J. 2008;155: IFG: impaired fasting glucose IGT: impaired glucose tolerance GDM: gestational diabetes mellitus NS: not significant Medication Behavior

11 Slide Source: Lipids Online Slide Library Screening and Diagnosis of Disorders of Glucose Metabolism 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 IFG or IGT IFG and IGT + Other Features* DiabetesDiabetes Screen for Diabetes: Fasting plasma glucose or 2-hour, 75-g oral glucose tolerance test Screen for Diabetes: Fasting plasma glucose or 2-hour, 75-g oral glucose tolerance test Lifestyle Intervention Lifestyle Intervention and / or Metformin Lifestyle Intervention + Metformin *<60 years of age, reduced HDL-C, BMI ≥35 kg/m 2, hypertension, elevated triglycerides, A1C >6.0%, family history of diabetes in first-degree relative IFG=impaired fasting glucose; IGT=impaired glucose tolerance

12 Slide Source: Lipids Online Slide Library 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! American Diabetes Association. Diabetes Care. 2005;28:S4-S36 | International Diabetes Federation. Diabetic Med. 1999;16:

13 Slide Source: Lipids Online Slide Library ACCORD Study Group. N Engl J Med. 2008;358: | ADVANCE Collaborative Group. N Engl J Med. 2008;358: ,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 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 Standard A1C 7.0%–7.9% Standard A1C 7.0%–7.9% ACCORDADVANCE Intensive A1C <6.0% Intensive A1C <6.0% 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). 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 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 usual care Standard A1C usual care Intensive A1C ≤6.5% Intensive A1C ≤6.5% 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 Main Findings from the ACCORD and ADVANCE Studies

14 Slide Source: Lipids Online Slide Library 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 Inzucchi SE et al. Diabetes Care 2012;35: | American Diabetes Association. Diabetes Care. 2008;31:S12-S54.

15 Slide Source: Lipids Online Slide Library [Insert Title Here].ppt 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 T2DM = type 2 diabetes mellitus ACCORD Study Group. N Engl J Med. 2008;358: | ADVANCE Collaborative Group. N Engl J Med. 2008;358:

16 Slide Source: Lipids Online Slide Library Reprinted from Holman RR et al. N Engl J Med. 2008;359: Copyright © 2008 Massachusetts Medical Society. All rights reserved. Proportion with Event Years Since Randomization P=0.01 No. at Risk Conventional Therapy Sulfonylurea–insulin UKPDS Kaplan–Meier Curves for Prespecified Aggregate Clinical Outcome: Myocardial Infarction Conventional Therapy Sulfonylurea–insulin

17 Slide Source: Lipids Online Slide Library Reprinted from Holman RR et al. N Engl J Med. 2008;359: Copyright © 2008 Massachusetts Medical Society. All rights reserved. Proportion with Event Years Since Randomization P=0.005 No. at Risk Conventional Therapy Metformin UKPDS Kaplan-Meier Curves for a Prespecified Aggregate Clinical Outcome: Myocardial Infarction Conventional Therapy Metformin

18 Slide Source: Lipids Online Slide Library Most Intensive Less Intensive Least Intensive Patient Age Disease Duration Other Comorbidities None Few/MildMultiple/Severe Hypoglycemia Risk Low HighModerate 8.0% 6.0%7.0% Established Vascular Complications NoneEarly MicrovascularAdvanced Microvascular 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 Cardiovascular Reprinted with permission from Ismail-Beigi F et al. Ann Intern Med 2011;154: Copyright © 2011 American College of Physicians. All rights reserved. Individualizing A1C Targets in Type 2 Diabetes

19 Slide Source: Lipids Online Slide Library Therapy for Type 2 Diabetes: Sites of Action Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661–1669 | Drucker DJ. Mol Endocrinol. 2003;17:161–171. Alpha-glucosidase inhibitors Incretins Incretins  Insulin secretion  Glucagon secretion Inhibit carbohydrate breakdown Incretins Slow gastric emptying Secretagogues Simulate insulin secretion Thiazolidinediones  Glucose intake  FFA output Metformin Thiazolidinediones Metformin Thiazolidinediones  Glucose metabolism Metformin Thiazolidinediones Metformin Thiazolidinediones Suppress glucose production

20 Slide Source: Lipids Online Slide Library Initial drug monotherapy ADA/EASD Position Statement Reprinted with permission from Inzucchi SE et al. Diabetes Care. 2012;35: Copyright © 2012 American Diabetes Association. All rights reserved. Combination therapy: 2 drugs Efficacy (A1C) Hypoglycemia Weight Side effects Costs More-complex insulin strategies Combination therapy: 3 drugs Efficacy (A1C) Hypoglycemia Weight Side effects Costs

21 Slide Source: Lipids Online Slide Library ADOPT: A Diabetes Outcome Progression Trial Reprinted with permission from Kahn SE et al. N Engl J Med. 2006;355: Copyright © 2006 Massachusetts Medical Society. All rights reserved. Fasting Plasma Glucose (mg/dl) Time (years) Rosiglitazone Sustained Fasting Plasma Glucose Over Time Number of patients: 4118 SU MET RSG 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

22 Slide Source: Lipids Online Slide Library 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)

23 Slide Source: Lipids Online Slide Library Incretin Hormones in Type 2 Diabetes

24 Slide Source: Lipids Online Slide Library 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

25 Slide Source: Lipids Online Slide Library The Incretin Effect: Insulin Secretion Is Greater in Response to Oral vs IV Glucose Time (min) Glucose (mg/dL) Insulin (pmol/L) Time (min) Oral IV Nauck M et al. J Clin Endocrinol Metab. 1986;63: Effect diminished in diabetes

26 Slide Source: Lipids Online Slide Library Role of Incretins in Glucose Homeostatis DPP-4=dipeptidyl peptidase–4 GIP=glucose-dependent insulinotropic peptide GLP-1=glucagon-like peptide–1 Beta cells Alpha cells Beta cells Alpha cells Inactive GLP-1 Blood Glucose Blood Glucose GI tract Release of gut hormones – Incretins Ingestion of food Glucose uptake by muscles Glucose production by liver Inactive GIP DPP-4 enzyme Glucose dependent glucagon from alpha cells (GLP-1) Glucose- dependent insulin from beta cells (GLP-1, GIP) Active GLP-1 & GIP Pancreas

27 Slide Source: Lipids Online Slide Library Metabolism of Glucagon-Like Peptide–1 and Glucose-Dependent Insulinotropic Peptide DPP-4 Capillary 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 Active Hormones GLP-1 [7-36NH 2 ] GLP-1 [7-36NH 2 ] GIP [1-42] GIP [1-42] Inactive Metabolites GLP-1 [9-36NH 2 ] GLP-1 [9-36NH 2 ] GIP [3-42] GIP [3-42] GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1

28 Slide Source: Lipids Online Slide Library Glucagon-Like Peptide–1 (GLP-1) Increases -Cell Response and Decreases -Cell Workload Larsson H et al. Acta Physiol Scand.1997;160: | Drucker DJ. Diabetes. 1998;47: Stomach: Helps regulate gastric emptying   -Cell workload   -Cell response -Cells: Enhance glucose- dependent insulin secretion GLP-1 secreted upon the ingestion of food -Cells:  Postprandial glucose secretion Promotes satiety and reduces appetite Liver:  Glucagon reduces hepatic glucose output

29 Slide Source: Lipids Online Slide Library Glucagon-Like Peptide–1 Actions Are Glucose Dependent in Patients with Type 2 Diabetes Nauck NA et al. Diabetologia. 1993;36: 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

30 Slide Source: Lipids Online Slide Library Glucagon-Like Peptide–1 Normalizes Postprandial Hyperglycemia in Patients with Type 2 Diabetes Nauck MA et al. Acta Diabetol. 1998;35: Time (h) Plasma glucose (mg/dl) –1 Infusion GLP-1 [7-36 amide] 1.2 pmol/kg/min Placebo Liquid meal –1 Infusion GLP-1 [7-36 amide] 1.2 pmol/kg/min Placebo Liquid meal Plasma glucose (mg/dl) Healthy subjects T2DM patients Time (h)

31 Slide Source: Lipids Online Slide Library Continuous Glucagon-Like Peptide–1 Infusion Reduces Appetite over 6 Weeks All data for patients treated with glucagon-like peptide–1 (n = 10). No changes in these parameters were observed in the saline group. Mean (SE) AUC for Visual Analogue Score (mm) vs Time (h) Time (wk) 610 Zander M et al. Lancet. 2002;359:824–830. Time (wk) *Prospective food intake *Hunger *Satiety *Fullness *p<.05

32 Slide Source: Lipids Online Slide Library 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

33 Slide Source: Lipids Online Slide Library 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 Ranganath LR et al. J Clin Pathol. 2008;61:

34 Slide Source: Lipids Online Slide Library Glucagon secretion Glucose production Glucose disposal Insulin secretion Insulin biosynthesis  cell proliferation  cell apoptosis Gastric emptying Cardioprotection Cardiac output Appetite Neuroprotection Lipogenesis Osteoblast GLP-1 GIP Physiological Actions of GLP-1 and GIP Sodium excretion

35 Slide Source: Lipids Online Slide Library Comparison of Incretin Mimetics Available Nauck M et al. In: Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. 2007: 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

36 Slide Source: Lipids Online Slide Library Exenatide + Oral Agents Summary of A1C Changes Buse JB et al. Diabetes Care. 2004;27: | Defronzo RA et al. Diabetes Care. 2005;28: | Kendall DM et al. Diabetes Care. 2005; 28: “THE 3 AMIGOS TRIAL” 30-Week, Randomized, Placebo-Controlled “THE 3 AMIGOS TRIAL” 30-Week, Randomized, Placebo-Controlled *p<0.01 vs. Placebo  A1C (%) Exenatide + Sulfonylurea (n = 377) Exenatide + Metformin (n = 336) Exenatide + Sulfonylurea + Metformin (n = 733) Placebo Exenatide 5 µg Exenatide 10 µg 0.12% -0.46% * -0.86% * 0.08% 0.23% -0.40% * -0.55% * -0.78% * -0.77% * 8.6%8.6%8.2%8.2%8.5%8.5%

37 Slide Source: Lipids Online Slide Library Efficacy of Exenatide BID in Clinical Trials Background Therapy a Mean Disease Duration (y) ΔA1C (%) Exenatide BIDPlacebo Monotherapy 1 2 ‒ 0.9 ‒ 0.2 b MET 2 5–6 ‒ b SU 3 6–7 ‒ b TZD ± MET 4,c 7–8 ‒ b SU + MET 5 9 ‒ b 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 1 Moretto TJ et al. Clin Ther. 2008;30: | 2 Defronzo RA et al. Diabetes Care. 2005;28: | 3 Buse JB et al. Diabetes Care. 2004;27: | 4 Zinman B et al. Ann Intern Med. 2007;146: | 5 Kendall DM et al. Diabetes Care. 2005; 28: | 6 Klonoff DC et al. Curr Med Res Opin. 2008;24:

38 Slide Source: Lipids Online Slide Library Background Therapy a Mean Disease Duration (y) ΔA1C (%) LiraglutideComparators Monotherapy 1 5–6 1.2 mg: ‒ mg: ‒ 1.1 Glim: ‒ 0.5 b SU 2 6–7 1.2 mg: ‒ mg: ‒ 1.1 Placebo: +0.2 b Rosi: ‒ 0.4 b Met 3 7–8 1.2 mg: ‒ mg: ‒ 1.0 Placebo: +0.1 b Glim: ‒ 1.0 Rosi ± Met 4,c mg: ‒ mg: ‒ 1.5 Placebo: ‒ 0.5 b 1 Garber A, et al. Lancet. 2009;373: | 2 Marre M et al. Diabet Med. 2009;26: | 3 Nauck M et al. Diabetes Care. 2009;32:84-90 | 4 Zinman B et al. Ann Intern Med. 2007;146: | 5 Garber A et al. Diabetes Obes Metab. 2011;13: Efficacy of Liraglutide versus Oral Agents in Liraglutide Effect and Action in Diabetes (LEAD) Trial Series a 26 weeks (except 52 weeks for monotherapy), mean baseline A1C: 8.2–8.6% b p <0.005 vs liraglutide

39 Slide Source: Lipids Online Slide Library Efficacy of Exenatide QW versus Oral Agents in the DURATION Trial Series Maintenance of glycemic control has been demonstrated over 3 years (ΔA1C = –1.6%) 3 a 26 weeks, baseline A1C: 8.5–8.6% b p <0.05 vs exenatide QW 1 Russell-Jones D et al. Diabetes Care. 2012;35: | 2 Bergenstal RM et al. Lancet. 2010; 376: | 3 MacConell L et al. Presented at 71st ADA Scientific Sessions (abstract 969-P), San Diego, CA, June DURATION = Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once-Weekly Background Therapy a Mean Disease Duration (y) ΔA1C (%) Exenatide QWComparators Monotherapy 1 3 ‒ 1.5 Met: ‒ 1.5 Pio: ‒ 1.6 Sita: ‒ 1.2 b Met 2 5–6 ‒ 1.5 Pio: ‒ 1.2 b Sita: ‒ 0.9 b

40 Slide Source: Lipids Online Slide Library Glycemic Control with GLP-1 Receptor Agonists in Head-to-Head Clinical Trials *Significant difference vs comparator GLP-1 receptor agonist 1 Buse JB et al. Lancet. 2009;374:39-47 | 2 Drucker DJ et al. Lancet. 2008;372: | 3 Blevins T, et al. J Clin Endocrinol Metab. 2011;96: | 4 Buse JB et al. Presented at 47th EASD Annual Meeting, Lisbon, Portugal, 14 September Trial: Size (N): Study length (weeks): LEAD DURATION DURATION DURATION * * * EXN BID LIRA EXN QW

41 Slide Source: Lipids Online Slide Library Exenatide + Oral Agents Summary of Weight Changes “THE 3 AMIGOS TRIAL” 30-Week, Randomized, Placebo-Controlled “THE 3 AMIGOS TRIAL” 30-Week, Randomized, Placebo-Controlled *p<0.01 vs. placebo  Weight (kg) Placebo Exenatide 5 µg Exenatide 10 µg * * -2.8 * -1.6 * Buse JB et al. Diabetes Care. 2004;27: | Defronzo RA et al. Diabetes Care. 2005;28: | Kendall DM et al. Diabetes Care. 2005; 28: Exenatide + Sulfonylurea (n = 377) Exenatide + Metformin (n = 336) Exenatide + Sulfonylurea + Metformin (n = 733)

42 Slide Source: Lipids Online Slide Library Changes in Body Weight with Exenatide versus Insulin Reprinted with permission from Heine R et al. Ann Intern Med. 2005;143:559–569. Copyright © 2005 American College of Physicians. All rights reserved. *P< compared with insulin glargine measure at the same time point. Change in Body Weight (kg) Weeks Exenatide group (n = 275) * * * * * * Insulin glargine group (n = 260)

43 Slide Source: Lipids Online Slide Library Distribution of Weight Loss and A1C Change with Exenatide BID and Exenatide QW Reprinted with permission from Drucker DJ et al. Lancet. 2008;372: Copyright © 2008 Elsevier. All rights reserved. Once a week (73%) Twice a day (74 %) Once a week (1%) Twice a day (5%) Once a week (3%) Twice a day (5%) Once a week (23%) Twice a day (16%) A1C Change (%) Weight Change (kg)

44 Slide Source: Lipids Online Slide Library Comparison of Incretin Modulators GLP-1 AnaloguesDPP-4 Inhibitors Administration routeInjectionOral  GLP-1SustainedMeal-related Effect on A1C  Effects on body weight     Side effects Nausea, Rare: pancreatitis (Well tolerated) Nasopharyngitis, skin rashes, Stevens-Johnson syndrome -cell function  GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase – 4

45 Slide Source: Lipids Online Slide Library 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

46 Slide Source: Lipids Online Slide Library 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 Additive effects

47 Slide Source: Lipids Online Slide Library Exenatide BID Combined with Basal Insulin More patients discontinued EXN BID (9%) vs PBO (1%) due to adverse events (p <0.01) 1 Significant A1C reduction regardless of intensification order 2 – EXN BID + insulin glargine – Insulin glargine + EXN BID 1 Buse JB et al. Ann Intern Med. 2011;154: | 2 Levin PA, et al. Endocr Pract. 2012;18: EXN BID + GLAR vs PBO + GLAR 1 30-Week Trial (N = 259) p <0.001

48 Slide Source: Lipids Online Slide Library 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 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

49 Slide Source: Lipids Online Slide Library Relative Risk of Acute Pancreatitis (±95% CI) The absolute risk of acute pancreatitis was comparable among initiators of exenatide and sitagliptin Dore DD et al. Curr Med Res Opin. 2009;25(4):1019–1027. Absolute and Relative Risk of Acute Pancreatitis with Antidiabetic Agents in Human Subjects Exenatide-Met/Gly Sitagliptin-Met/Gly 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)

50 Slide Source: Lipids Online Slide Library 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

51 Slide Source: Lipids Online Slide Library 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) Amylin Pharmaceuticals, Bydureon prescribing information, January 2012 | Novo Nordisk, Victoza prescribing information, April 2012.

52 Slide Source: Lipids Online Slide Library DPP-4 Inhibitors vs. GLP-1 Agonists DPP-4 inhibitors – 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

53 Slide Source: Lipids Online Slide Library Comparison of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors SitagliptinLinagliptinSaxagliptinVildagliptin Usual phase 3 dose100 mg QD5 mg QD 50 mg BD Half-life (t 1/2 ), h – –3.81.3–2.4 DPP-4 inhibition at 24 h ~80% ~80% (25 mg)~55% (5 mg)50% (100 mg) EliminationKidney (mostly unchanged) Bile but not kidney (mostly unchanged) Liver and kidney Active metabolite Kidney>>Liver Inactive metabolite Renal dose adjustments required YesNoYesNone 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 Low Food effectNo

54 Slide Source: Lipids Online Slide Library Properties of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors Nauck M et al. In: Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. 2007: Oral administration Oral administration GLP-1/GLP-1 receptor agonist concentration elevated 3–6 hours after meals when secretion from endogenous sources is stimulated 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) GLP-1 concentration close to physiological concentration (~ x 2–3) Action through GLP-1 receptors and possibly GIP receptors and/or other receptors Action through GLP-1 receptors and possibly GIP receptors and/or other receptors GLP-1 action probably through nerves more than circulation GLP-1 action probably through nerves more than circulation A1C reduction −0.5% to −1.1% A1C reduction −0.5% to −1.1% Weight change ±0 kg Weight change ±0 kg -Cell mass effects probable in animals, no human data -Cell mass effects probable in animals, no human data

55 Slide Source: Lipids Online Slide Library Mean Change from Baseline in A1C (%) –0.9 – –0.8 –1.0 vs Placebovs RSGvs Met Monotherapy *Initial combination therapy All statistically significant Insulin >30 U/d Pio 45 mg qd –1.9 Add-on Combination Therapy Met ≥1500 mg/d Pio* 30 mg qd –0.5 –0.9 –0.8 Vildagliptin: A1C Changes Reprinted with permission from Rosenstock J et al. Curr Opin Endocrinol Diabetes Obes. 2007;14: Copyright © 2007 Wolters Kluwer Health. All rights reserved. Study duration (wks) N (ITT population) Baseline A1C (%)

56 Slide Source: Lipids Online Slide Library vs Placebo Mean change from baseline in HbA1c (%) vs Glipizide Pio 30–45 mg/d Met* 2000 mg/d -1.9 Sitagliptin: A1C Changes Study duration (wks) N (ITT population) Baseline A1C (%) *Initial combination therapy All statistically significant vs Placebo MonotherapyAdd-on Combination Therapy Met ≥1500 mg/d Reprinted with permission from Rosenstock J et al. Curr Opin Endocrinol Diabetes Obes. 2007;14: Copyright © 2007 Wolters Kluwer Health. All rights reserved.

57 Slide Source: Lipids Online Slide Library Efficacy of Add-on Sitagliptin LSM  = least- squares mean change 1 Charbonnel B et al. Diabetes Care 2006;29: | 2 Rosenstock J et al. Clin Ther 2006;28: –0.65% (P<0.001) –0.70% (P<0.001) 12

58 Slide Source: Lipids Online Slide Library Similar Glycemic Control with Sitagliptin vs Glipizide Added to Metformin Sitagliptin 100 mg qd (n=382) Glipizide (n=411) Mean change in A1C Mean change from baseline (for both groups)*: –0.67% Time (weeks) *Per protocol analysis; –0.51% and –0.56% for sitagliptin and glipizide, respectively, in last observation carried forward (LOCF) analysis Reprinted with permission from Nauck MA et al. Diabetes Obes Metab. 2007; 9: Copyright © 2007 John Wiley and Sons. All rights reserved.

59 Slide Source: Lipids Online Slide Library –0.54* –0.45*–0.43* Adjusted mean ± SE change in A1C (%) Reprinted with permission from Rosenstock J et al. Curr Med Res Opin. 2009; 25: Copyright © 2009 Informa Healthcare. All rights reserved. Saxagliptin Monotherapy in Treatment-Naïve Patients with Type 2 Diabetes *P< vs PBO BL Weeks Mean ± SE change in A1C from baseline (%) PBO SAXA 5 mg SAXA 2.5 mg SAXA 10 mg Dose Baseline mean A1C (%) PBO SAXA (mg) PBO Dose n = SAXA (mg) Baseline mean A1C (%)

60 Slide Source: Lipids Online Slide Library BL Saxagliptin Add-on to Metformin: Reduction in A1C in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone Reprinted with permission from DeFronzo RA et al. Diabetes Care. 2009;32: Copyright © 2009 American Diabetes Association. All rights reserved. A1C, Mean ± SE Change from Baseline (%) SAXA 5 mg + MET SAXA 2.5 mg + MET SAXA 10 mg + MET PBO + MET 6

61 Slide Source: Lipids Online Slide Library Efficacy of Saxagliptin Monotherapy Therapy over 24 Weeks Compared with Placebo SAXA = saxagliptin FPG = fasting plasma glucose PPG-AUC = postprandial glucose area under the curve * Placebo-subtracted difference † Statistically significant decrease from baseline 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†− mg once daily−0.64†−15†−6249† 10.0 mg once daily−0.73†−23†−7437† Rosenstock J et al. Curr Med Res Opin. 2009;25:

62 Slide Source: Lipids Online Slide Library 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) p<0.001 for difference between treatment groups Reprinted with permission from Ahrén B et al. Diabetes Care. 2010;33: Copyright © 2010 American Diabetes Association. All rights reserved.

63 Slide Source: Lipids Online Slide Library Vildagliptin Glimepiride Insulin Secretory Rate Relative to Glucose (pmol/min/m 2 /mmol/L) p=0.022 for difference between treatment groups Insulin Secretory Rate Relative to Glucose after up to 2 Years Add-on Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Ahr é n B et al. Diabetes Care. 2010;33:

64 Slide Source: Lipids Online Slide Library Adverse Events with Dipeptidyl Peptidase–4 (DPP-4) Inhibitors Amori RE et al. JAMA. 2007;298: Adverse Events No. of Studies Risk Ratio DPP-4 vs. Control Mean % Experiencing Outcome DPP-4Control Hypoglycemia %1.4% Nausea %3.1% Vomiting %1.5% Diarrhea %4.0% Abdominal pain %3.2% Cough %2.4% Influenza %4.7% Nasopharyngitis %6.1% Upper respiratory tract infection %6.4% Sinusitis %3.4% Urinary tract infection %2.4% Headache %3.9%


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