Type 2 diabetes and cardiovascular risk: the role of GLP-1

Type 2 diabetes and cardiovascular risk: the role of GLP-1 Dr Isidora Kitsou-Mylona, PhD Novo Nordisk Regional Medical Advisor Business Area Africa, Gulf & India

Disclaimer I am an employee of Novo Nordisk

Agenda Background on type 2 diabetes and CVD Effects of GLP-1 on CV function Effects of GLP-1 receptor agonists on CV risk factors MACE analysis for incretin therapies CV outcomes trials

CVD related mortality increases in patients with type 2 diabetes People with type 2 diabetes: will die 5 10 years before people without diabetes are twice as likely to have a heart attack or stroke as people who do not have diabetes are 15 40 times more likely to have a lower limb amputation Other deaths CVD deaths CVD, cardiovascular disease 1 AHA in http://www.americanheart.org/downloadable/heart/1236204012112intl.pdf 2 Morish et al. Diabetologia 2001;44(Suppl 2):S14-S21. Lancet 1997;350(Suppl. 1):SI23 8

Type 2 diabetes is an independent cardiovascular risk factor Incidence of MI (%) over 7 years 50 40 30 20 10 Without diabetes (n=1373) With diabetes (n=1059) 0 No prior MI Prior MI MI, myocardial infarction Haffner et al. N Engl J Med 1998;339:229 34

Diabetes and hyperglycaemia co-exist with other well-established CVD risk factors Patients with type 2 diabetes (%) Several conditions that commonly coexist with type 2 diabetes are also risk factors for micro- and macrovascular disease CVD, cardiovascular disease 1 Center for Financing, Access, and Cost Trends, AHRQ, Total Adult Population Medical Expenditure Panel Survey-Household Component, 2001. http://www.meps.ahrq.gov/mepsweb/data_files/publications/st34/stat34.pdf 2 Jacobs et al. Diabetes Res Clin Pract 2005;70:263-9

The risk of CVD increases gradually as glucose metabolism deteriorates Rate of cardiovascular disease events (%) CVD, cardiovascular disease Khaw et al. Ann Intern Med 2004;141:413 20

All-cause mortality increases with increasing body mass index Yearly deaths per 1000 (95% CI) 64 32 16 Male Female Mortality is lowest at a BMI range of 22.5 25 kg/m 2 Each five-unit increase in BMI is associated with a 30% higher all-cause mortality 8 0 15 20 25 30 35 40 45 Baseline BMI (kg/m 2 ) BMI, body mass index; CI, confidence interval Prospective Studies Collaboration. Lancet 2009;373:1083 96

Visceral adiposity is strongly associated with cardiovascular disease Frequency of cardiovascular disease (%) 15 10 5 0 Male <84 84 92 92 99 99 107 107 15 10 5 0 Female <76 76 84 84 92 92 101 101 Waist circumference (cm) Waist circumference (cm) Waist circumference correlates strongly with visceral adipose tissue Balkau et al. Circulation 2007;116:1942 51

Effect of more vs. less intensive BPlowering regimens on CV outcomes BP (mmhg) More vs. less intensive treatment Major CV events Diabetes No diabetes Overall 6.0/ 4.6 3.7/ 3.3 CV deaths Diabetes No diabetes Overall 6.0/ 4.6 3.7/ 3.3 Total mortality Diabetes No diabetes Overall 6.0/ 4.6 3.7/ 3.3 BP, blood pressure; CV, cardiovascular 0.5 1.0 2.0 Relative risk Blood Pressure Lowering Treatment Trialists Collaboration. Arch Intern Med 2005;165:1410 19

Effect of more vs. less intensive BP-lowering regimens on CV outcomes BP (mmhg) More vs. less intensive treatment Stroke Diabetes No diabetes Overall 6.0/ 4.6 3.7/ 3.3 CHD Diabetes No diabetes Overall 6.0/ 4.6 2.9/ 3.0 Heart failure Diabetes No diabetes Overall 6.0/ 4.6 3.7/ 3.3 CHD, coronary heart diseae 0.5 1.0 2.0 Relative risk Blood Pressure Lowering Treatment Trialists Collaboration. Arch Intern Med 2005;165:1410 19

Benefit of different interventions in patients with diabetes treated for 5 years Change in CV death rate (%) CV, cardiovascular; LDL-C low-density lipoprotein-cholesterol; SBP, systolic blood pressure Ray et al. Lancet 2009;373:1765-72; Kearney et al. Lancet 2008;371:117; Turnbull et al. Arch Intern Med 2005;165:1410-19

Intensive, multifactorial intervention halves the risk of macrovascular complications STENO-2 Primary composite endpoint (%) 60 50 40 30 20 10 p=0.007 Conventional therapy Intensive therapy 0 0 12 24 36 48 60 72 84 96 Months of follow-up Composite endpoint included cardiovascular death, myocardial infarction, revascularisation, stroke and amputation Gaede et al. N Engl J Med 2003;348:383 93

Agenda Background on type 2 diabetes and CVD Effects of GLP-1 on CV function Effects of GLP-1 receptor agonists on CV risk factors MACE analysis for incretin therapies CV outcomes trials

Physiological actions of GLP-1 relevant to cardioprotection: an overview GLP-1 receptors are expressed in the CV system, pancreas, intestines, and nervous system 1,2 GLP-1: reduces blood glucose levels 1 reduces weight 2 increases satiety 1 reduces gastric emptying 1 and calorie intake 3 reduces systolic blood pressure 1 increases diuresis 4 increases vasodilation 5 modest beneficial effects on lipids 6-9 is cardioprotective in animal models of ischaemia 10 CV, cardiovascular; GLP-1, glucagon-like peptide-1 1. Baggio and Drucker, Gastroenterology 2007;132:2131 57; 2. Zander et al. Lancet 2002;359:824 30; 3. Verdich et al. J Clin Endocrinol Metab 2001;86:4382 9; 4. Gutzwiller et al. J Clin Endocrinol Metab 2004;89:3055 61; 5. Basu et al. Am J Physiol Endocrinol Metab 2007;293:E1289 95; 6. Plutzky et al. Diabetologia 2009;52(Suppl. 1):S299. 7. Drucker et al. Lancet 2008;372:1240 50; 8. Diamant et al. Lancet 2010;26;375:2234 43; 9. Boardman et al. EASD 2011; 10. Bose et al. Diabetes 2005;54:146 51

Native GLP-1 has beneficial effects on endothelial function Native GLP-1: increases basal vasodilation 1 enhances acetylcholine-mediated vasodilation 1 improves endothelial function in patients with T2D and coronary artery disease 2 GLP-1, glucagon-like peptide-1; T2D, type 2 diabetes 1. Basu et al. Am J Physiol Endocrinol Metab 2007;293:E1289 95; 2. Nyström et al. Am J Physiol Endocrinol Metab 2004;287:E1209 15

GLP-1 receptors on vessels and heart Cardiomyocytes Endomyocardium Vascular Endothelium GLP-1 receptors are present on vascular tissues including endothelium GLP-1, glucagon-like peptide-1 Ban et al. Circulation 2008:117;2340 50

Native GLP-1 improves endothelial function in patients with T2D and coronary artery disease FMD (%) change from baseline 7 6 5 4 3 2 1 0 Saline p<0.05 GLP-1 FMD of the brachial artery is a measure of endothelial function FMD correlates well with endothelial dysfunction in the coronary circulation Native GLP-1 improves FMD FMD, flow-mediated dilation; GLP-1, glucagon-like peptide-1; T2D, type 2 diabetes Nyström et al. Am J Physiol Endocrinol Metab 2004;287:E1209 15

Native GLP-1 limits infarct size in a rat model of myocardial infarction Rat model of ischaemia Infarct size (%) 70 60 50 40 30 20 10 * In vivo protection against MI Protection abolished by GLP-1 receptor antagonist Native GLP-1 protection mediated by the induction of multiple pro-survival kinases 0 Saline DPP-4 inhibitor Native GLP-1 + DPP-4 *p<0.001 vs. saline and DPP-4; infarction relative to the area at risk after vessel occlusion; data are mean + SE DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; MI, myocardial infarction Bose et al. Diabetes 2005;54:146 51

GLP-1 infusion improves left ventricular function in patients with heart failure GLP-1 + standard therapy* (n=12) Standard therapy (n=9) LVEF (%) 30 25 20 15 10 5 0 Baseline p<0.001 5 weeks *Standard therapy: stable heart failure medication regimen including angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, β-blocker, aldosterone antagonist, loop diuretic and digoxin GLP-1, glucagon-like peptide-1; LVEF, left ventricular ejection fraction Sokos et al. J Cardiac Failure 2006;12:694 99

Agenda Background on type 2 diabetes and CVD Effects of GLP-1 on CV function Effects of GLP-1 receptor agonists on CV risk factors MACE analysis for incretin therapies CV outcomes trials

In patients with type 2 diabetes, GLP-1 RAs promote weight loss Exenatide Exenatide Liraglutide Liraglutide 10 µg BID 1 3 2 mg OW 12 17 1.2 mg OD 4 7,10 1.8 mg OD 4 10 Change in body weight (kg) Change in waist circumference (cm) 1.6 to 2.8 2.0 to 3.7 +0.3 to 2.9 0.2 to 3.4 Not reported 2.1 14 0.1 to 3.6 11 0.2 to 3.7 11 BID, twice-daily; GLP-1 RAs glucagon-like peptide-1 receptor agonists; OD, once-daily; OW, once-weekly 1. DeFronzo et al. Diabetes Care 2005;28:1092 100; 2. Buse et al. Diabetes Care 2004;27:2628 35; 3. Kendall et al. Diabetes Care 2005;28:1083 91; 4. Marre et al. Diabet Med 2009;26:268 78; 5. Nauck et al. Diabetes Care 2009;32:84 90; 6. Garber et al. Lancet 2009;373:473 81; 7. Zinman et al. Diabetes Care 2009;32:1224 30; 8. Russell-Jones et al. Diabetologia 2009;52:2046 55; 9. Buse et al. Lancet 2009;374:39 47, 10. Pratley et al. Lancet 2010;375:1447 56; 11. Data on file, Novo Nordisk; 12. Drucker et al. Lancet 2008;372:1240 50; 13. Bergenstal et al. Lancet 2010;376:431 9; 14. Diamant et al. Lancet 2010;26;375:2234 43; 15. Boardman et al. EASD 2011; 16. Blevins et al. J Clin Endocrinol Metab 2011;96:1301 10; 17. Buse et al. EASD 2011

Weight change across the LEAD programme LEAD-3 Monotherapy LEAD-2 MET combination LEAD-1 SU combination LEAD-4 MET + TZD combination LEAD-5 MET + SU combination LEAD-6 MET ± SU combination Lira vs. Sita MET combination Baseline (kg) Change in body weight (kg) 93 93 93 *** *** NR NR NR NR 80 83 81 82 NR NR NR 86 85 86 93 93 94 95 93 *** *** *** *** *** *** *** *** *** Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Rosiglitazone Glargine Placebo Exenatide Sitagliptin *p<0.01, ***p 0.0001 vs. active comparator; p 0.01, p 0.0001 vs. placebo. [Active comparators vs. placebo not shown]. Data from core trials LEAD: Liraglutide Effect and Action in Diabetes. Marre et al. Diabet Med 2009;26;268 78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84 90 (LEAD-2); Garber et al. Lancet 2009;373:473 81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224 30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046 55 (LEAD-5); Buse et al. Lancet 2009;374:39 47 (LEAD-6); Pratley et al. Lancet 2010;375:1447 56 (lira vs. sita)

Liraglutide consistently reduces SBP All subjects. ***p 0.0001, **p<0.001, *p<0.05 vs. comparator Marre et al. Diabetic Med 2009;26;268 78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84 90 (LEAD-2); Garber et al. Lancet 2009;373:473 81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224 30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046 55 (LEAD-5); Buse et al. Lancet 2009; 374:39 47 (LEAD-6); Pratley et al. Lancet 2010:375;1447 56 (lira DPP-4i)

Liraglutide improves SBP further in type 2 patients with higher SBP at baseline Fonseca et al. Diabetes 2009;58(Suppl. 1):A146.

SBP reduction with liraglutide independent of concomitant antihypertensives Reductions with liraglutide were seen in overall patient group ( 2.55 mmhg; p<0.01 vs. baseline) and in those not taking or taking antihypertensive (AH) medication Additional SBP reductions with liraglutide can be achieved on top of reductions from concomitant AH medications *p<0.05; **p<0.001 vs. baseline Fonseca et al. Diabetes 2010;59(Suppl. 1):A79 (296-OR)

Proposed Mechanisms for a Beneficial Impact of GLP-1 and GLP-1RAs on Blood Pressure Increased urine volume and sodium excretion 1 3 Increased baseline and ACh-induced vasodilation independent of alterations in glucose or insulin concentrations 1,3 ACh, acetylcholine; CV, cardiovascular; GLP-1, glucagon-like peptide-1. 1. Baggio & Drucker. Gastroenterology. 2007;132:2131-2157; 2. Gutzwiller et al. J Clin Endocrinol Metab. 2004;89:3055-3061; 3. Basu et al. Am J Physiol Endocrinol Metab. 2007;293:E1289-E1295.

Liraglutide Improves Mean Post-prandial Triglyceride Profiles in Subjects With T2D 4.0 Liraglutide 1.8 mg Placebo Triglycerides (mmol/l) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0 1 2 3 4 5 6 7 8 Time after meal (h) Data are mean±se. SE, standard error; T2D, type 2 diabetes. Hermansen et al. Diabetes. 2012;61(suppl 1):A272 (1058-P).

Liraglutide Reduces Fasting Lipid Levels in Patients With T2D LEAD 1-6: meta-analysis Total cholesterol LDL-C Triglyceride *** *** ** *** ** LDL-C, low-density lipoprotein cholesterol; T2D, type 2 diabetes. *p<0.05; **p<0.01; ***p<0.0001 all vs. baseline; is used instead of * to indicate a significant increase from baseline. Fonseca et al. International Diabetes Federation 21st World Diabetes Congress, 4-8 December 2011, Dubai, UAE.

Proposed Mechanisms for a Beneficial Impact of GLP- 1 and GLP-1RAs on Post-prandial Lipid Profiles Ileal brake effects on nutrient absorption and lymph flow 1 Inhibition of hepatic VLDL-TG production (does not change the VLDL composition) 2 Altered hepatic expression of genes involved in VLDL production, lipogenesis, and lipid homeostasis 2 GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonists; TG, triglycerides; VLDL, very-low-density lipoprotein. 1. Qin et al. Am J Physiol Gastrointest Liver Physiol. 2005;288:G943-G949; 2. Parlevliet et al. PLOS One. 2012;7:e49-e52.

Agenda Background on type 2 diabetes and CVD Effects of GLP-1 on CV function Effects of GLP-1 receptor agonists on CV risk factors MACE analysis for incretin therapies CV outcomes trials

FDA guidance for industry In December 2008, the US FDA issued guidance to industry for evaluating CV safety in diabetes drugs Industry should demonstrate new therapy will not result in an unacceptable increase in CV risk The upper bound of the two-sided 95% CI of the risk ratio should be <1.8 CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration FDA. Guidance for Industry: Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf

FDA guidance for CV safety studies For new studies in the planning stage: CV events in all phase 2 and 3 trials should be prospectively adjudicated by an independent committee A meta-analysis should be performed on completion To obtain sufficient endpoints, patients at high risk of CV events should be included A protocol describing the statistical methods for the meta-analysis should be provided Similarities and/or differences between subgroups (e.g. age, sex, race, etc.) should be explored if possible CV, cardiovascular; FDA, Food and Drug Administration FDA. Guidance for Industry: Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf

FDA guidance for CV safety studies For completed studies prior to new drug application: Perform an integrated meta-analysis of phase 2/3 trials to compare CV events in patients randomised to the investigational drug vs. control Demonstrate that the new therapy will not result in an unacceptable CV risk Estimated risk ratio for the upper bound of the two-sided CI for the investigational drug should be <1.8 If upper CI=1.3 1.8, a postmarketing CV surveillance trial may be required to demonstrate safety CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration FDA. Guidance for Industry: Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf

Exenatide is not associated with an increased CV risk FDA upper bound 95% criterion for approvability Primary MACE 0.70 Secondary MACE 0.69 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Risk ratio Exenatide better Control better CV, cardiovascular; FDA, food and drugs administration; MACE, major adverse cardiovascular event(s) Ratner et al. BMC Cardiovascular Diabetology 2011;10:22

Summary of exenatide MACE analysis The hazard ratio point estimates were <1 for the primary and secondary MACE analyses with the upper 95% confidence limits <1.8 Exenatide does not appear to increase the risk of cardiovascular risk in T2D patients MACE, major adverse cardiovascular event(s); T2D, type 2 diabetes

MACE analysis of sitagliptin Pooled analysis of 19 double-blind randomised studies in T2D MACE incidence rate/100 patient-years (64 total events) Sitagliptinexposed (100 mg OD) (n=5429) Non-exposed (placebo or active comparator) (n=4817) Betweengroup difference [95% CI] 0.6 0.9 0.3 [ 0.7 to 0.1] Risk ratio [95% CI] 0.68 [0.41 to 1.12] CI, confidence interval; MACE, major adverse cardiovascular event(s); T2D, type 2 diabetes Williams-Herman et al. BMC Endocrine Disorders 2010;10:7

Summary of sitagliptin MACE analysis The MACE analysis revealed 0.6 events per 100 patient-years for sitagliptin-treated patients compared with 0.9 events per 100 patient-years for non-exposed patients Sitagliptin does not appear to increase the risk of cardiovascular events in T2D patients The impact of sitagliptin on CV outcomes will be investigated in the TECOS trial CV, cardiovascular; MACE, major adverse cardiovascular event(s); T2D, type 2 diabetes; TECOS, Sitagliptin Cardiovascular Outcome Study

Saxagliptin is not associated with an increased CV risk Primary MACE Cox hazard ratio Incidence rate ratio Incidence ratio Secondary MACE Cox hazard ratio Incidence rate ratio Incidence ratio Acute CV events Cox hazard ratio Incidence rate ratio Incidence ratio 0.24 0.44 0.82 0.24 0.45 0.26 0.49 0.83 0.25 0.45 0.81 0.25 0.46 0.82 0.90 0.27 0.49 0.88 0.35 0.59 1.00 0.36 0.61 1.02 0.39 0.65 1.09 FDA upper bound 95% criterion for approvability 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Ratio of saxagliptin to control Saxagliptin better Control better CV, cardiovascular; FDA, Food and Drug Administration; MACE, major adverse cardiovascular event(s) FDA. Briefing document. 2009. www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/ Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148109.pdf; Frederich et al. Postgrad Med 2010;122:16 27

Summary of saxagliptin MACE analysis Overall, the saxagliptin MACE analysis demonstrated consistent results No evidence for increased CV risk with saxagliptin use In each pooled assessment, the point estimate of the relative risk was always <1, with the upper 95% confidence limit <1.4 CV, cardiovascular; MACE, major adverse cardiovascular event(s)

MACE analysis for linagliptin Primary CV endpoint, incidence rate/1000 PY Secondary CV endpoints, incidence rate/1000 PY CV death, stroke or MI All adjudicated CV events FDA-custom MACE Tertiary CV endpoints, incidence rate/1000 PY CV death Nonfatal MI Nonfatal stroke TIA Hospitalisation for unstable angina pectoris Linagliptin (n=3319) Comparator (n=1920) Hazard ratio (95% CI) 5.3 16.8 0.34 (0.16,0.70) * 4.8 12.6 4.3 1.0 2.9 1.0 0.5 0.5 14.6 23.4 13.9 1.5 5.1 8.0 2.9 2.2 0.36 (0.17,0.78) * 0.55 (0.33,0.94) * 0.34 (0.15,0.75) * 0.74 (0.10,5.33) 0.52 (0.17,1.54) 0.11 (0.02,0.51) * 0.17 (0.02,1.53) 0.24 (0.02,2.34) *Significantly lower hazard ratio (upper 95% CI <0.01; p<0.05) CV, cardiovascular; FDA, Food and Drug Administration; MACE, major adverse cardiovascular event(s); MI, myocardial infarction; PY, patient-year; TIA, transient ischaemic attack Johansen et al. Diabetes 2011;60(Suppl. 1A):LB9

MACE analysis for linagliptin conclusions A greater than 30% excess risk of CV events with linagliptin vs. comparators was ruled out by linagliptin s MACE meta-analysis However, the FDA did not considered this result robust because: The trials were not prospectively designed to evaluate CV safety The population included was at low risk for CV events There were inconsistent findings in sensitivity analyses Thus, the FDA requested the conduct of a post-approval CV outcomes trial CV, cardiovascular; FDA, Food and Drug Administration; MACE, major adverse cardiovascular event(s) Johansen et al. Diabetes 2011;60(Suppl. 1A):LB9

MedDRA definitions of cardiovascular events used in MACE analysis of liraglutide CV death FDA list of adverse events Custom MACE MI: 6 terms Stroke: 30 terms MedDRA-defined list (narrow) MI: 10 terms Stroke: 95 terms SMQ Narrow MedDRA-defined list (broad) MI: 28 terms Stroke: 125 terms SMQ Broad CV, cardiovascular; FDA, US Food and Drug Administration; MACE, major adverse cardiovascular event(s) MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; SMQ, standard MedDRA query defined list of adverse events belonging to the same category Marso et al. Diab Vasc Dis Res 2011;8:237 40

Liraglutide is not associated with an increased CV risk IR 95% CI Number of events SMQ, broad 0.73 (0.38;1.41) 39 SMQ, narrow 0.73 (0.38;1.41) 39 Custom 0.72 (0.35;1.50) 31 0.1 1 10 Incidence ratio CI, confidence interval; CV, cardiovascular; IR, incidence ratio; SMQ, standard Medical Dictionary for Regulatory Activities query Marso et al. Diab Vasc Dis Res 2011;8:237 40

Agenda Background on type 2 diabetes and CVD Effects of GLP-1 on CV function Effects of GLP-1 receptor agonists on CV risk factors MACE analysis for incretin therapies CV outcomes trials

LEADER : Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

LEADER trial design Inclusion criteria T2D patients: HbA 1c 7.0% Antidiabetic drug naïve or treated with one or more OADs or treated with basal or premix insulin (alone or in combination with OADs) Run-in 2 weeks R A N D O M I S A T I O N Standard of care + liraglutide Double-blinded treatment 42 60 months Standard of care + placebo High-risk CV profile Clinicaltrials.gov identifier: NCT01179048 First patient first visit: 1 September 2010 Last patient last visit: January 2016 (estimated) Approximately 9000 patients enrolled in more than 30 countries Several visits during first 6 months, then one visit every 6 months for up to 4.5 years CV, cardiovascular; OADs, oral antidiabetic drugs; T2D, type 2 diabetes

LEADER trial objective and primary endpoint Trial objective To determine the long-term effect of liraglutide on CV outcomes and other clinically important events in high CVD risk adults with T2D Primary endpoint First occurrence of either CV death, nonfatal MI or non-fatal stroke CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction; T2D, type 2 diabetes

CV outcome trials overview Trial Company Drug Timing of initiation LEADER Liraglutide Post-approval EXSCEL Exenatide QW Post-approval ELIXA Lixisenatide Pre-approval REWIND Dulaglutide Pre-approval SAVOR-TIMI 53 Saxagliptin Post-approval EXAMINE Alogliptin Pre-approval CAROLINA Linagliptin Pre-approval TECOS Sitagliptin Post-approval Duration Start end 5 years Sep 2010 2016 5.5 years June 2010 2017 4 years June 2010 2014 6.5 years July 2011 2019 4 years May 2010 2014 Up to 4.75 years Sep 2009 2015 8 years Oct 2010 2018 Up to 5 years Dec 2008 2014 QW, once weekly

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