THE EVOLUTION OF CLINICAL TRIALS IN T2DM: FROM TARGETING A1C TO TARGETING CARDIOVASCULAR OUTCOMES

Learning Objectives 1) Evaluate the interrelationship between diabetes, glycemic control, and cardiovascular disease. 2) Examine the evolution of type 2 diabetes (T2DM) drug development and factors leading to the requirement to evaluate cardiovascular safety for glucose lowering therapies. 3) Discuss new and emerging cardiovascular outcome trial (CVOT) data for glucose lowering therapies and elucidate the proposed pleiotropic CV effects of these therapies in patients with T2DM. 4) Compare and contrast data from CVOTs with real-world evidence studies of glucose lowering agents and discuss potential implications for T2DM management strategies in patients with and without cardiovascular disease. 5) Explore opportunities for cardiologists to collaborate with endocrinologists, primary care providers, and other members of the healthcare team in order to improve T2DM management and reduce CV risk.

Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of the date of presentation November 13, 2017. The content and views presented in this educational activity are those of the authors/presenters and do not necessarily reflect those of Creative Educational Concepts, Inc. or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Learners should verify all information and data before treating patients or employing any therapies or strategies described in this educational activity.

THE EVOLUTION OF CLINICAL TRIALS IN T2DM: FROM TARGETING A1C TO TARGETING CARDIOVASCULAR OUTCOMES Darren K. McGuire, MD, MHSc Professor of Medicine University of Texas Southwestern Medical Center Dallas, Texas

Guidance for Diabetes Drug Development 1990-2008 The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidelines: 1500 patients exposed 300-600 x 6 months 100 x 1 year Approval based on as little as 250 patient-years of exposure

Paradigm Shift Increasing incidence/prevalence of T2DM ~12% of US adult population 1 Growing awareness of CV impact of T2DM Numerous examples of adverse drug effects On target Off target 1 http://www.diabetes.org/assets/pdfs/basics/cdc-statistics-report-2017.pdf.

Meta-Analysis of Data on TZDs and MI Risk Rosiglitazone Pioglitazone Events (n) Estimate Events (n) Estimate ADOPT DREAM RECORD Nissen Singh GSK 58 25 120 158 177 256 1.40 1.78 1.14 1.43 1.42 1.31 PRO-active Lincoff 263 290 0.83 0.81 0.1 1.0 10.0 0.1 1.0 10.0 Risk ratios (95% CI) Rohatgi A, McGuire DK. Cardiovasc Drugs Ther. 2008; Home PD, et al. Lancet. 2009.

Mortality Rate(%) Mortality Impact of Glycemic Control: UGDP 20 15 10 5 All Causes TOLB (n=204) IVAR (n=204) ISTD (n=210) PLBO (n=205) Total Deaths 30 18 20 21 20 15 10 5 Cardiovascular Causes TOLB (n=204) IVAR (n=204) ISTD (n=210) PLBO (n=205) CV Deaths 26 12 13 10 0 0 1 2 3 4 5 6 7 8 Years of Follow-up N=823 0 0 1 2 3 4 5 6 7 8 Years of Follow-up Meinert CL. Diabetes. 1970.

N=3725 Muraglitazar=2374 vs placebo/pioglitazone=1351 Death/MI/Stroke: 35 (1.47%) vs 9 (0.67%) Death/MI/Stroke/TIA/CHF: 50 (2.11%) vs 11 (0.81%) Nissen SE, et al. JAMA. 2005.

Increasing incidence/prevalence of T2DM ~12% of US adult population Growing awareness of CV impact of T2DM Numerous examples of adverse drug effects On target Off target Paradigm Shift Proliferation of medications available

Number of Medication Classes Half-Century of HTN & T2DM Medications in U.S. 12 11 10 9 8 7 6 5 4 3 2 1 vasodilators insulin peripheral α-1 blockers central α-2 agonists adrenergic diuretics neuronal blockers sulfonylureas ACE Inhibitors angiotensin II receptor blockers renin inhibitors DPP-4 inhibitors amylin mimetics Ca 2+ channel GLP-1 blockers receptor agonists β-blockers meglitinides thiazolidinediones biguanides α-glucosidase inhibitors SGLT-2 inhibitors dopamine agonists bile acid sequestrants 1950 1960 1970 1980 1990 2000 2010 2015 Courtesy of Silvio Inzucchi, MD, Yale University.

Present FDA Regulatory Guidance for Drugs for Type 2 Diabetes sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk. Requires ~15,000 patient-years of exposure www.fda.gov/newsevents/newsroom/pressannouncements/2008/ucm116994.htm.

The Sky is Falling

Cumulative number of cardiovascular participants (thousands) It Was Just an Acorn That Fell. 250 200 (~240,000) 150 100 2008 FDA guidance 50 0 2017 1996 2000 2004 2008 2012 2016 2020 Adapted from Holman RR, et al. Lancet. 2014.

Number of Subjects SAVOR-TIMI 53 Enrollment 18000 16000 Final Enrollment n=16,492 14000 12000 10000 8000 6000 1 st Patient Enrolled May 5, 2010 >300/week Last Patient Enrolled December 12, 2011 4000 2000 0 Scirica BM, et al. N Engl J Med. 2013; Courtesy of Ben Scirica, MD, TIMI Study Group.

There has to be a better way Steg PG, Roussel R. Circulation. 2016; Smith RJ, et al. Diabetes Care. 2016.

Percent with First Adverse Event Small Trials/Data Sets Yield Imprecise Estimates of Effectiveness 5 4 Saxagliptin Controlled Phase 2b/3 Pooled Population Time of Onset to First MACE 3 2 HR 0.44 (95% CI 0.24-0.82) 41 total events Control All Saxa 1 0 BL 24 37 50 63 76 89 102 115 128 Weeks Patients at Risk Control 1251 935 860 774 545 288 144 123 102 57 All Saxa 3356 2615 2419 2209 1638 994 498 436 373 197 Frederich R, et al. Postgrad Med. 2010.

Rare But Serious Adverse Drug Reactions Require Large Exposure Taspoglutide (~600 patient years) Nausea Vomiting Antibody formation Anaphylactoid reactions Fasiglifam (~2,000 patient years) Drug-associated liver injury (10-fold increase in elevated LFTs) Aleglitazar (>14,000 patient years) HF Decline in egfr Bone fracture GI Bleeds Rosenstock J, et al. Diabetes Care. 2013; Lincoff AM, et al. JAMA. 2014; Kaku K, et al Diabetes Obes Metab. 2015.

Gastrointestinal Bleeding Associated with Aleglitazar: ALECARDIO Trial Percent with Event 3.0 2.5 2.0 1.5 Hazard Ratio 1.44; (95% CI 1.03 2.00) Log-rank P=0.03 Aleglitazar, (N=3,587) 1.0, (N=3,587) 0.5 No. of Patients at Risk Aleglitazar 0.0 Baseline Month 6 Month 12 Month 18 Month 24 Month 30 Month 36 Study Month 3587 3587 3478 3461 3381 3357 2852 2823 1795 1765 826 826 125 115 Lincoff AM, et al. JAMA. 2014.

SAVOR-TIMI 53, EXAMINE, and TECOS: Hospitalization for Heart Failure Trial HR (95% CI) P-Value SAVOR-TIMI 53 EXAMINE TECOS SAVOR-TIMI 53 + EXAMINE + TECOS 1.27 (1.07 1.51) 0.007 1.19 (0.89 1.59) 1.00 (0.84 1.20) 1.14 (0.97 1.34) 0.24 >0.99 0.10 0 Favors Treatment 1 Favors 2 McGuire DK, et al. JAMA Cardiol. 2015.

CANVAS Program: Lower-Limb Amputations Event rate per 1000 patient-years Canagliflozin HR (95% CI) All amputations (n=187) 6.30 3.37 1.97 (1.41, 2.75) Minor amputations (71%) 4.48 2.44 1.94 (1.31, 2.88) Toe 3.44 2.16 Transmetatarsal 1.03 0.29 Major amputations (29%) 1.82 0.93 2.03 (1.08, 3.82) Ankle 0.04 0.07 Below-knee 1.16 0.64 Above-knee 0.62 0.21 Neal B, et al. N Engl J Med. 2017. 0.25 1 4 Favors canagliflozin Favors placebo

Conclusions Diabetes is common and increasing, with significant associated CV morbidity and mortality Role of glucose control in CVD risk mitigation remains uncertain What drugs/strategies; what intensity; what timing Side effects both on- and off-target Imperative to at a minimum establish CV safety Evolution of regulatory guidance has dramatically altered the trial landscape of drug development for type 2 diabetes mellitus >250,000 patients enrolled/planned in CV outcomes trials Precise estimates of safety and effectiveness require large outcomes trials

SHOW ME THE DATA: DECIPHERING CARDIOVASCULAR OUTCOME TRIALS (CVOTS) FOR DIABETES THERAPIES Lawrence A. Leiter, MD, FRCPC, FACP, FACE, FAHA Division of Endocrinology & Metabolism, St. Michael s Hospital Professor of Medicine & Nutritional Sciences, University of Toronto Toronto, Canada

Recent and Ongoing CVOTs EXAMINE (Alogliptin, DPP-4i) n=5,380; duration 1.5 yrs Q2 2013 RESULTS SAVOR TIMI-53 (Saxagliptin, DPP-4i) n=16,492; duration 2.1 yrs Q2 2013 RESULTS TECOS (Sitagliptin, DPP-4i) n=14,671; duration 3 yrs Q1 2015 RESULTS SUSTAIN-6 (Semaglutide, GLP-1 RA) n=3,297; duration ~2.1 yrs Q1 2016 RESULTS DEVOTE (Insulin degludec, insulin) n=7,637; duration ~2 yrs Q2 2017 RESULTS ELIXA (Lixisenatide, GLP-1 RA) n=6,000; duration 2.1 yrs Q1 2015 RESULTS LEADER (Liraglutide, GLP-1 RA) n=9,340; duration 3.5 5 yrs Q4 2015 RESULTS EMPA-REG OUTCOME (Empagliflozin, SGLT2i) n=7,028; duration 3.1 yrs Q2 2015 RESULTS CANVAS-R (Canagliflozin, SGLT2i) n=5,700; duration ~3 yrs Q2 2017 RESULTS CANVAS (Canagliflozin, SGLT2i) n=4,330; duration 4+yrs Q2 2017 RESULTS FREEDOM-CVO (ITCA 650-continuous subcut delivery of exenatide, GLP-1 RA) n=4,000; duration ~2 yrs Q2 2016 PRELIMINARY RESULTS EXSCEL (Exenatide ER, QW GLP-1 RA) n=14,752; duration 3.2 yrs Q2 2017 - RESULTS CARMELINA (Linagliptin, DPP-4i) n=7,003; duration ~4 yrs completion Q4 2017 HARMONY OUTCOMES (Albiglutide, QW GLP-1 RA) n~9,400; duration ~2.7 yrs completion Q2 2019 REWIND (Dulaglutide, QW GLP-1 RA) n=9,622; duration ~7 yrs completion Q3 2018 CREDENCE (cardio-renal) (Canagliflozin, SGLT2i) n=4,464; duration ~5.5 yrs completion Q2 2019 PIONEER 6 (Oral semaglutide, daily GLP-1 RA ) n=3,176; duration ~2 yrs completion Q3 2018 DECLARE-TIMI-58 (Dapagliflozin, SGLT2i) n=17,276; duration~6 yrs completion Q2 2019 CAROLINA (Linagliptin, DPP-4i vs SU) n=6,072; duration ~8 yrs completion Q1 2019 VERTIS CV (Ertugliflozin, SGLT2i) n=8,000; duration ~6yrs completion Q4 2019 Ongoing Preliminary results Published results 2013 2014 2015 2016 2017 2018 2019 2020 2021 www.clinicaltrials.gov.

DPP-4i CVOTs SAVOR TIMI 53 Established CVD and/or multiple risk factors AC, % 6.5-12.0 R Duration of Treatment (as part of usual care) Saxagliptin Median FU, y 2.1 Primary End Point CV death, Nonfatal MI, or Nonfatal stroke HR (95% CI) 1.00 (0.89, 1.12) EXAMINE ACS within 15 to 90 days 6.5-11.0 R Alogliptin 1.5 CV death, Nonfatal MI, or Nonfatal stroke 0.96 ( 1.16) TECOS Preexisting CVD 6.5-8.0 R Sitagliptin 3.0 CV death, Nonfatal MI, Nonfatal stroke, or UA requiring hospitalization 0.98 (0.89, 1.08) Randomization Year 1 Year 2 Year 3 Median Duration of Follow-up Green JB, et al. N Engl J Med. 2015; Scirica BM, et al. N Engl J Med. 2013; White WB, et al. N Engl J Med. 2013; www.clinicaltrials.gov.

Hospitalization for Heart Failure SAVOR-TIMI 53, EXAMINE & TECOS SAVOR-TIMI 53 (saxagliptin vs placebo) EXAMINE (alogliptin vs placebo) TECOS (sitagliptin vs placebo) SAVOR-TIMI 53 + EXAMINE + TECOS Study Drug n/n (%) 289/8280 (3.5%) 106/2701 (3.9%) 228/7332 (3.1%) 623/18313 (3.4%) n/n (%) 228/8212 (2.8%) 89/2679 (3.3%) 229/7339 (3.1%) 546/18230 (3.0%) Hazard Ratio 1.27 1.19 1.00 95% CI 1.07, 1.51 0.89, 1.59 0.84, 1.20 1.14 0.97, 1.34 P Value 0.007 0.235 1.000 0.102 0 1 2 Favors Treatment Favors Adapted from Armstrong PW, Van de Werf: TECOS. European Society of Cardiology. 2015; Scirica BM, et al. N Engl J Med. 2013; Zannad F, et al. Lancet. 2015; Green JB, et al. N Engl J Med. 2015.

Safety Data SAVOR-TIMI 53, EXAMINE & TECOS Acute Pancreatitis Pancreatic Cancer SAVOR-TIMI 53 EXAMINE TECOS Saxagliptin n=8280 n=8212 Alogliptin n=2701 n=2679 Sitagliptin n=7332 n=7339 22 16 12 8 23 12 P=0.42 Definite or possible pancreatitis P=0.5 Terms included pancreatitis acute, relapsing pancreatitis, and pancreatitis P=0.07 Confirmed events. P-value for ITT analysis 5 12 0 0 9 14 P=0.095 Recorded as a safety objective Not applicable P=0.32 Scirica BM, et al. N Engl J Med. 2013; White WB, et al. N Engl J Med. 2013; Green JB, et al. N Engl J Med. 2015.

DPP-4i CVOTs SAVOR-TIMI 53 Established CVD and/or multiple risk factors EXAMINE ACS within 15 to 90 days TECOS Preexisting CVD A1C, % 6.5 12.0 6.5 11.0 6.5 8.0 R R R Duration of Treatment (as part of usual care) Saxagliptin Alogliptin Sitagliptin Median FU, y 2.1 1.5 3.0 Primary End Point CV death, Nonfatal MI, or Nonfatal stroke CV death, Nonfatal MI, or Nonfatal stroke CV death, Nonfatal MI, Nonfatal stroke, or UA requiring hospitalization HR (95% CI) 1.00 (0.89, 1.12) 0.96 ( 1.16) 0.98 (0.89, 1.08) CARMELINA High vascular risk CAROLINA High CV risk 6.5 10.0 6.5 8.5 R R Linagliptin Linagliptin Glimepiride Ongoing Ongoing CV death, Nonfatal MI, Nonfatal stroke, or UA requiring hospitalization CV death, Nonfatal MI, or Nonfatal stroke Ongoing Ongoing Randomization Year 1 Year 2 Year 3 Median Duration of Follow-up Green JB, et al. N Engl J Med. 2015; Scirica BM, et al. N Engl J Med. 2013; White WB, et al. N Engl J Med. 2013; www.clinicaltrials.gov.

REPORTED Summary of CVOTs with GLP-1 RAs ELIXA 1 LEADER 2 SUSTAIN-6 3 EXSCEL 4 Intervention Main Inclusion Criteria N Lixisenatide Liraglutide Semaglutide* Exenatide ER* FREEDOM 5 Exenatide REWIND 5 HARMONY- Outcomes 5 Dulaglutide Albiglutide Primary Outcome Follow-up Secondary Outcome Period ACS event 180 days prior to screening 6,068 4P-MACE Expanded MACE Established CVD ( 50 years), or 60 years + 1 CV risk factor Established CVD, HF or CKD stage 3 ( 50 years), or 60 years + 1 CV risk factor Any level of CV risk, including prior CV event Coronary, cerebrovascular or peripheral artery disease Pre-existing vascular dx ( 50 years), or 55 years + subclinical vascular dx, or 60 years + 2 CV risk factors 9,340 3P-MACE Expanded MACE 3,297 3P-MACE Expanded MACE 14,752 3P-MACE All-cause mortality, HHF, hospitalization for ACS 2.1 years median 3.8 years median 2.1 years median 3.2 years median 4,156 4P-MACE Not specified ~2 years 9,622 3P-MACE Established CVD ~9,400 3P-MACE All-cause mortality, HHF, HUA, microvascular endpts Expanded MACE, HHF, initiation of insulin, A1C<7% Up to 6.5 years 3 5 years *once weekly; via DUROS device 1 Pfeffer MA, et al. N Engl J Med. 2015; 2 Marso SP, et al; LEADER Investigators. N Engl J Med. 2016; 3 Marso SP, et al; SUSTAIN-6 Investigators. N Engl J Med. 2016; 4 Holman RR, et al. N Engl J Med. 2017; 5 www.clinicaltrials.gov.

ELIXA, LEADER, SUSTAIN-6 and EXSCEL Study Population ELIXA 1 LEADER 2 SUSTAIN-6 3 EXSCEL 4 N 6,068 9,340 3,297 14,752 Age (years) 60 64 65 62 Diabetes duration (years) 9.3 13 14 12 Baseline A1C (%) 7.7 8.7 8.7 8.0 BMI (kg/m 2 ) 30 33 33 32 % CV disease 100 81 72.2 73.1 % Heart failure 22.4 17.8 23.6 16.2 % egfr <60 ml/min/m 2 23.2 21.7 28.5 21.7 Mortality rate (events/100 patient years) 3.1 3.3 2.1 2.5 1.76-1.82 2.0 2.3 1 Pfeffer MA, et al. N Engl J Med. 2015; 2 Marso SP, et al; LEADER Investigators. N Engl J Med. 2016; 3 Marso SP, et al; SUSTAIN-6 Investigators. N Engl J Med. 2016; 4 Holman RR, et al. N Engl J Med. 2017.

ELIXA, LEADER, SUSTAIN-6 and EXSCEL Study Design ELIXA 1 LEADER 2 SUSTAIN-6 3 EXSCEL 4 Run-in period 1-week 2-week 2-week None Visit interval Follow-up (years) 1-week, 2-week, 6-week, 12-week, every 6 weeks until month 15, followed by every 8 weeks thereafter 1-month, 3-month, 6- month, every 6 months thereafter 2-week, 1-month, 2-month, every 3 months thereafter 1-week, 2 months, 6 months, every 6 months thereafter 2.1 3.8 2.1 3.2 Intervention Lixisenatide 20 mcg vs usual care (no incretin-based drugs) Liraglutide 1.8 mg vs usual care (no incretin-based drugs) Semaglutide 0.5 and 1.0 mg vs usual care (no incretin-based drugs) Exenatide LAR 2.0 mg vs usual care (no GLP-1 RA) 1 Pfeffer MA, et al. N Engl J Med. 2015; 2 Marso SP, et al; LEADER Investigators. N Engl J Med. 2016; 3 Marso SP, et al; SUSTAIN-6 Investigators. N Engl J Med. 2016; 4 Holman RR, et al. N Engl J Med. 2017.

ELIXA, LEADER, SUSTAIN-6 and EXSCEL Primary Endpoint and the Individual Components ELIXA LEADER SUSTAIN-6 EXSCEL P P P P 1 O composite MACE 0.81 0.01 0.02 0.06 CV mortality NS 0.007 NS NS Myocardial infarction NS 0.046 NS NS Stroke NS NS 0.04 NS Unstable angina NS 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) Adapted from Pfeffer MA, et al. N Engl J Med. 2015; Marso SP, et al; LEADER Trial Investigators. N Engl J Med. 2016; Marso SP, et al; SUSTAIN-6 Trial Investigators. N Engl J Med. 2016; Holman RR, et al. N Engl J Med. 2017.

ELIXA, LEADER, SUSTAIN-6 and EXSCEL All-Cause Mortality and Hospitalization for Heart Failure ELIXA LEADER SUSTAIN-6 EXSCEL P P P P 98 for 3 years 106 for 3 years All-cause mortality NS 0.02 NS Nominal P CV mortality NS 0.007 NS NS Hospitalization for heart failure NS NS NS NS 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) 0.4 0.8 1.2 1.6 Hazard Ratio (95% CI) Adapted from Pfeffer MA, et al. N Engl J Med. 2015; Marso SP, et al; LEADER Trial Investigators. N Engl J Med. 2016; Marso SP, et al; SUSTAIN-6 Trial Investigators. N Engl J Med. 2016; Holman RR, et al. N Engl J Med. 2017.

CV Outcomes Trials with GLP-1 RAs GLP-1 RA vs Usual Care Baseline characteristics of study cohort (age, diabetes duration, A1C, % CV disease, etc) Body Weight Hypoglycemia Study setting and follow-up Drugs allowed in Usual Care arm Direct effects on CV system (antiinflammatory, antiatherosclerotic) and other targets Discontinuation rate CV Mortality CV Benefits Unstable Angina Nonfatal MI Nonfatal Stroke Allcause mortality A1C, Blood Pressure, Lipids? Exendin-based GLP-1 RA vs. human GLP-1 RA analogs?

Effects of GLP-1 or GLP-1 RAs in Human Studies with Potential Impact on CV Function Effect GLP-1 [7-36 amide or 7-37] Liraglutide Exenatide Cardioprotection against ischemia Angiogenesis, EC proliferation, CPC survival Endotheliumdependent vasodilation (NO production) Inflammatory cytokines in mononuclear cells LVEF regional wall motility New vessel formation from ECs CPC apoptosis by oxidative stress enos in HUVECs Ach-induced vasodilation (healthy subjects and T2DM with stable CAD) Preserved LVEF after PCI/NSTEMI Not reported TNFα-induced oxidative stress in HUVECs enos ACh-induced forearm blood flow (ns) salvage index after STEMI infarct size Proliferation of coronary artery ECs CPC apoptosis by saturated fatty acids enos in HUVECs postprandial endothelial function IL-6 TNFα, IL-1β, IL-6 TNFα, IL-1β, etc C-reactive protein Not reported by 23% by 61% Nauck MA, et al. Circulation. 2017.

EMPA-REG OUTCOME and CANVAS Baseline Characteristics EMPA-REG OUTCOME CANVAS PROGRAM Study drug Empagliflozin Canagliflozin CV risk Established CVD (99%) Established CVD (65%) / MRF (35%) Sample size, N 7,020 10,142 Mean duration of diabetes, years 57% >10 years 13.5 Mean A1C, % 8.1 8.2 Mean age, years 63 63 History of heart failure, % 10 14.4 ACE-inhibitors / ARBs, % 81 80 Statins, % 77 75 Acetylsalicylic acid, % 83 74 Zinman B, et al. N Engl J Med. 2015; Neal B, et al. N Engl J Med. 2017.

EMPA-REG OUTCOME: 3-point MACE Primary outcome: Patients with event/analysed Empagliflozin HR (95% CI) P-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Cox regression analysis. 3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke. *95.02% CI 0.25 0.50 1.00 2.00 Favors empagliflozin Favors placebo Zinman B, et al. N Engl J Med. 2015.

Patients with event (%) EMPA-REG OUTCOME: CV Death 9 8 7 6 5 Empagliflozin (pooled) HR 0.62 (95% CI 0.49, 0.77) P<0.0001 Empagliflozin 4 3 Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85), P=0.0016 2 1 Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77), P=0.0001 0 No. of patients Empaglifozin 0 6 12 18 24 30 36 42 48 Months 4687 2333 4651 2303 4608 2280 4556 2243 4128 2012 3079 1503 2617 1281 1722 825 414 177 Zinman B, et al. N Engl J Med. 2015.

Patients with event (%) EMPA-REG OUTCOME: Hospitalization for HF 7 6 5 4 Empagliflozin (pooled) HR 0.65 (95% CI 0.50, 0.85) P=0.0017 Empagliflozin No. of patients Empaglifozin 3 2 1 0 Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86), P=0.0044 Empagliflozin 25 mg HR 0.68 (95% CI 0.50, 0.93), P=0.0166 0 6 12 18 24 30 36 42 48 4687 2333 4614 2271 4523 2226 4427 2173 3988 1932 Months 2950 1424 2487 1202 1634 775 395 168 Zinman B, et al. N Engl J Med. 2015.

EMPA-REG OUTCOME: Adverse Events (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate n (%) Rate n (%) Rate Events consistent with UTI 423 (18.1%) 8.21 426 (18.2%) 8.02 416 (17.8%) 7.75 Male 158 (9.4%) 3.96 180 (10.9%) 4.49 170 (10.1%) 4.09 Female 265 (40.6%) 22.81 246 (35.5%) 18.83 246 (37.3%) 20.38 Events consistent with genital infection 42 (1.8%) 0.73 153 (6.5%) 2.66 148 (6.3%) 2.55 Male 25 (1.5%) 0.60 89 (5.4%) 2.16 77 (4.6%) 1.78 Female 17 (2.6%) 1.09 64 (9.2%) 3.93 71 (10.8%) 4.81 Events consistent with volume depletion 115 (4.9%) 2.04 115 (4.9%) 1.97 124 (5.3%) 2.11 Diabetic ketoacidosis 1 (<0.1%) 0.02 3 (0.1%) 0.05 1(<0.1%) 0.02 Acute renal failure 155 (6.6%) 2.77 121(5.2%) 2.07 125 (5.3%) 2.12 Bone fractures 91(3.9%) 1.61 92(3.9%) 1.57 87(3.7%) 1.46 Participants treated with 1 dose of study drug Rate=per 100 patient-years Zinman B, et al. N Engl J Med. 2015.

Patients with event (%). CANVAS: Primary Outcome 20 15 10 HR: 0.86 (95% CI, 0.75, 0.97) P<0.001 for noninferiority P=0.02 for superiority Canagliflozin 5 No. of Risk Canagliflozin 0 0 26 52 78 104 130 156 182 208 234 260 286 312 338 Weeks since randomization 4347 5795 4239 5672 4153 5566 4061 5447 2942 4343 1626 2984 1240 2555 1217 2513 1187 2460 1156 2419 1120 2363 1095 2311 789 1661 216 448 Neal B, et al. N Engl J Med. 2017.

CANVAS CV Death, Non-Fatal MI and Non-Fatal Stroke Canagliflozin (n=5795) No. of participants per 1000 patient yr n/n No. of participants per 1000 patient yr (n=4347) HR (95% CI) P n/n 3-point MACE 26.9 585/5795 31.5 426/4347 0.86 (0.75, 0.97) 0.02 CV death 11.6 268/5795 12.8 185/4347 0.87 (0.72, 1.06) NR Non-fatal MI 9.7 215/5795 11.6 159/4347 0.85 0.69, 1.05) NR Non-fatal stroke 7.1 158/5795 8.4 116/4347 0.90 (0.71, 1.15) NR Participants treated with 1 dose of study drug Rate=per 100 patient-years =P-value for superiority 0.25 0.50 1.00 2.00 Neal B, et al. N Engl J Med. 2017. Favors canagliflozin Favors placebo

Patients with event (%) CANVAS: Hospitalization for Heart Failure No. of Risk Canagliflozin 8 7 6 5 4 3 2 1 0 0 26 52 78 104 130 156 182 208 234 260 286 312 338 4347 5795 HR: 0.67 (95% CI, 0.52, 0.87) no P Value reported 4267 5732 4198 5653 4132 5564 3011 4437 Weeks since randomization 1667 3059 1274 2643 1256 2610 1236 2572 1210 2540 1180 2498 1158 2451 Canagliflozin 829 1782 233 490 Neal B, et al. N Engl J Med. 2017.

CANVAS: Adverse Events Event (n=4347) P values were estimated from Cox regression models; Low-trauma fracture was the prespecified primary fracture outcome, and all fracture was a secondary outcome; Infection of male genitalia included balanitis, phimosis, and events leading to circumcision. Canagliflozin (n=5795) Event rate per 1000 patient yr Mycotic genital infection in women 17.5 68.8 <0.001 Infection of male genitalia 10.8 34.9 <0.001 Urinary tract infection 37.0 40.0 0.38 Osmotic diuresis 13.3 34.5 <0.001 Volume depletion 18.5 26.0 0.009 Acute kidney injury 4.1 3.0 0.33 Hyperkalemia 4.4 6.9 0.10 Amputation 3.4 6.3 <0.001 Fracture (adjudicated) All Low-trauma 11.9 9.2 15.4 11.6 0.02 0.06 Diabetic ketoacidosis (adjudicated) 0.3 0.6 0.14 P Neal B, et al. N Engl J Med. 2017.

Proposed Mechanism of Cardiorenal Protection With SGLT2 Inhibitors Verma S, et al. JAMA Cardiol. 2017.

SGLT-2 Inhibitor CV Safety Trials Currently In Progress ERTUGLIFLOZIN Ertugliflozin vs N=3,900 CREDENCE Canagliflozin vs N=3,700 2012 2013 2014 2015 2016 2017 2018 2019 2020 All are large, non-inferiority, event driven CV safety studies on individuals with T2DM who are at high baseline CV risk DECLARE-TIMI 58 Dapagliflozin vs N=17,150 www.clinicaltrials.gov.

Benefits of the FDA Guidance to Date Established CV safety of AHAs and, in some cases, CV benefit Provided insight into secondary cardiovascular outcomes (eg, heart failure, kidney endpoints) Afforded recognition of unexpected side effects Questionable HF with saxa and alo Questionable pancreatitis with DPP4i Questionable retinopathy with GLP-1 RA Data collected from evaluation of high-risk subjects AHAs=antihyperglycemic agents Menon V, Lincoff AM. Circulation. 2014.

Adverse Consequences/ Limitations of the FDA Guidance These studies have added tremendously to the cost of developing AHAs but there is no evidence that this has been a major detriment to date But someone has to pay this cost! Loss of focus on benefit?inappropriate CV endpoints Inappropriate standard of care arm (ie, placebo) Lack of generalizability to broader population of patients with DM Relatively short duration of trials which limits knowledge of both long term efficacy and safety Comparative balance of benefits and risks over time Menon V, Lincoff AM. Circulation. 2014; Holman RR, et al. Lancet. 2014; Cefalu WT, et al. Diabetes Care. 2016.

Prevalence and Co-prevalence of Comorbidities in T2DM (Q-EMR) N=1.39 million Total CKD: 24.1% Total CVD: 21.6% CKD No CVD CVD No CKD 15.5% CVD + CKD 8.6% 13.0% T2DM 62.9% No CKD No CVD Patients with CVD represent only 21.6% of all patients with DM CKD was defined based on the presence of an ICD-9-CM diagnosis code or, if a code was not present, an estimated glomerular filtration rate (egfr) < 60 ml/min/1.73m 2 using the most recent measurement prior to the index date. If not already estimated in the database, egfr was calculated using the Modification of Diet in Renal Disease (MDRD) study equation. Iglay K, et al. Curr Med Res Opin. 2016.

Conclusions Cardiovascular SAFETY (FDA criteria) has been established for alogliptin, saxagliptin, sitagliptin, liraglutide, lixisenatide, semaglutide, exenatide, canagliflozin and empagliflozin Cardiovascular SUPERIORITY (FDA criteria) has been established for canagliflozin, empagliflozin, liraglutide and semaglutide in T2D patients with CVD Presence of cardiovascular disease is a priority consideration for individualizing therapy TREATMENT MUST BE INDIVIDUALIZED

TRANSLATING CLINICAL TRIALS TO CLINICAL PRACTICE: REAL-WORLD EVIDENCE FOR GLUCOSE LOWERING THERAPIES AND CV OUTCOMES Mikhail Kosiborod, MD, FACC, FAHA Professor of Medicine Saint Luke s Mid America Heart Institute University of Missouri-Kansas City Kansas City, Missouri

Why are RCTs Seen as the Gold Standard? Randomization avoids bias, ensuring that treatment groups are similar in every respect apart from the investigative treatment For factors which are known to be important, and for factors whose impact is unknown Blinding ensures that the assessment of outcomes is not affected by knowledge of the patient s assigned treatment (by patient, investigator or operational staff) High internal validity Gordis L. Epidemiology. 2009.

But RCTs are typically highly selective, often excluding: Elderly patients (aged 65 and over) Patients with certain co-morbidities Patients at very low risk Patients seen in real-world practice may be: Mostly aged over 65 years Suffering from several diseases Taking multiple drugs Diverse and complex or very low risk How can I be sure that RCT results are applicable to my patients? Does your drug work in the real world? Saturni S, et al. Pulm Pharmacol Ther. 2014.

Real-World Studies Follow up patients in a normal real world environment, rather than in an artificial clinical trial setting Examine the use of the drug in patients with: Comorbidities Concomitant medications Those at very low risk Typically much less expensive than RCTs Have good external validity RCT Data Real World Evidence (RWE) Can it work? Does it work? Luce BR, et al. Milbank Q. 2010.

Big Data Studies Glucose Lowering Medications Metformin TZDs Incretin-based therapies SGLT2 inhibitors (CVD-REAL study)

Pooled, Adjusted Risk Ratios for Metformin Compared With Other Treatments For All-cause Mortality Study or subgroup log [risk ratio] SE Weight Risk ratio IV, random, 95% CI Year Evans 0.5108 0.25 2.6% 0.60 (0.37, 0.98) 2005 Eurich 0.4156 0.2 4.1% 0.66 (0.45, 0.98) 2005 Masoudi 0.1393 0.06 29.0% 0.87 (0.77, 0.98) 2005 Inzucchi 0.0834 0.13 8.9% 0.92 (0.71, 1.19) 2005 Shah 0.2357 0.4 1.1% 0.79 (0.36, 1.73) 2010 MacDonald 0.4308 0.15 6.9% 0.65 (0.48, 0.87) 2010 Roussel 0.3711 0.13 8.9% 0.69 (0.53, 0.89) 2010 Andersson 0.1625 0.0682 24.6% 0.85 (0.74, 0.97) 2010 Aguilar 0.2744 0.1 13.9% 0.76 (0.62, 0.92) 2011 Total (95% CI) 100.0% 0.80 (0.74, 0.87) Favors Metformin Control Eurich DT, et al. Circ Heart Fail. 2013. Heterogeneity: Tau 2 =0.00; Chi 2 =9.45, df=8 (P=0.31); I 2 =15% Test for overall effect: Z=5.35 (P<0.00001) 0.5 0.7 1 1.5 2

Meta-Analysis of HF Risk in Patients Exposed to TZDs Review: Comparison: Outcome: Randomized controlled trials of TZDs Thiazolidinedione vs placebo All Heart Failure Adverse Events Review: Comparison: Outcome: Observational studies of TZDs and heart failure Thiazolidinedione exposure vs no exposure Heart Failure Study OR (random) 95% CI Weight % OR (random) 95% CI GSK211 30.65 2.17 [0.96, 4.91] PROActive 54.51 1.49 [1.23, 1.80] DREAM 14.84 7.03 [1.60, 30.96] Total (95% CI) 100.00 2.10 [1.08, 4.08] Study OR (random) 95% CI Weight % OR (random) 95% CI Delea 27.85 1.67 [1.37, 2.05] Hartung 15.42 1.96 [1.41, 2.73] Inzucchi 36.71 1.35 [1.17, 1.56] Karter 20.02 1.49 [1.14, 1.96] Total (95% CI) 100.00 1.55 [1.33, 1.80] 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 Treatment protective Treatment harmful Treatment protective Treatment harmful Total events: 314 (Treatment), 210 (Control) Test for heterogeneity: Chi 2 =4.86, df=2 (P=0.09), I 2 =58.8% Test for overall effect: Z=2.19 (P=0.03) Test for heterogeneity: Chi 2 =5.65. df=3 (P=0.13), I 2 =46.9% Test for overall effect: Z=5.61 (P<0.00001) Singh S, et al. Diabetes Care. 2007.

SAVOR-TIMI 53 Randomized Trial: K-M Failure Estimates of Hospitalization for HF by Treatment - Saxagliptin vs. Scirica BM, et al. Circulation. 2014.

Sitagliptin Effect on CV Outcomes in T2DM Rates of Hospitalization for HF Green JB, et al. N Engl J Med. 2015.

Association Between Treatment with Incretin-Based Drugs and the Risk of Hospitalization for HF No History of Heart Failure Hazard Ratio (95% CI) Alberta 0.57 (0.37-0.87) Manitoba 0.41 (0.21-0.79) Ontario 0.79 (0.66-0.94) Saskatchewan 0.53 (0.19-1.45) United Kingdom 1.10 (0.90-1.34) United States 0.98 (0.92-1.04) Random-effects model 0.82 (0.67-1.00) Heterogeneity: I 2 =75.6%, Tau 2 =0.0351, P=0.001 History of Heart Failure Alberta 0.21 (0.03-1.41) Manitoba 0.61 (0.22-1.66) Ontario 0.85 (0.69-1.04) Saskatchewan 0.30 (0.08-1.10) United Kingdom 0.91 (0.44-1.90) United States 1.20 (1.03-1.39) Random-effects model 0.86 (0.62-1.19) Heterogeneity: I 2 =66%, Tau 2 =0.0688, P=0.01 0.1 0.5 1 2 10 Decreased Risk Increased Risk Filion KB, et al. N Engl J Med. 2016.

Key Outcomes in the CANVAS Program and EMPA-REG OUTCOME CV death, nonfatal myocardial infarction, or nonfatal stroke CV Death Nonfatal myocardial infarction Nonfatal stroke Hospitalization for heart failure CV death or hospitalization for heart failure All cause mortality Progression to macroalbuminuria* Renal composite* Hazard Ratio (95% CI) CANVAS Program EMPA-REG OUTCOME *CANVAS Program endpoints comparable with EMPA-REG OUTCOME Zinman B, et al. N Engl J Med. 2017; Wanner C, et al. N Engl J Med. 2016; Courtesy of David Matthews. 0.25 0.5 1 2 Favors SGLT2i Favors

How Does Data From Randomized Clinical Trials Compare With Real-World Clinical Practice?

Study Objectives Primary To compare the risk of HHF in patients with T2DM newly initiated on SGLT2 inhibitors versus other glucose-lowering drugs Secondary To compare the risk of all-cause death between the two treatment groups To compare the risk of the composite of HHF or all-cause death between the two treatment groups Kosiborod M, et al. Circulation. 2017.

Study Design

Cohort 1 HHF Data Sources US Truven Health MarketScan Claims and Encounters and linked Medicare Supplemental and Coordination of Benefits (Medicare Supplemental) databases Norway Linked Prescribed Drug, National Patient and Cause of Death Registries Sweden Linked Prescribed Drug, National Patient and Cause of Death Registries Cohort 2 All-cause death and composite HHF/all-cause death Denmark Linked Prescribed Drug, National Patient and Cause of Death Registries UK Clinical Practice Research Datalink (CPRD) dataset The Health Improvement Network (THIN) dataset Germany Diabetes-Patienten-Verlaufsdokumentation (Diabetes Prospective Follow-Up; DPV) Kosiborod M, et al. Circulation. 2017.

Inclusion/Exclusion Criteria Inclusion Criteria New users receiving SGLT2 inhibitors or other glucose-lowering drugs Established T2DM on or prior to the index date 18 years old >1 year* historical data available prior to the index date Exclusion Criteria Patients with type 1 diabetes Patients with gestational diabetes In Germany, >6 months Kosiborod M, et al. Circulation. 2017.

Patient Population For All Countries/Databases Combined 1,392,254 new users of SGLT2 inhibitor or other glucoselowering drug fulfilling the eligibility criteria 166,033 SGLT2 inhibitor 1,226,221 other glucoselowering drug 11,505 (7%) excluded during 1:1 match process 1:1 propensity match 1,071,693 (87%) excluded during 1:1 match process 154,528 SGLT2 inhibitor 154,528 other glucoselowering drug Kosiborod M, et al. Circulation. 2017.

Baseline Characteristics

Baseline Characteristics For The Full Propensity Matched Cohort SGLT2 Inhibitor (N=154,528) Other Glucose-lowering Drug (N=154,528) Age (years), mean (SD) 56.9 (10.0) 57.0 (10.6) Women 68,420 (44.3) 68,772 (44.5) Established cardiovascular disease 20,044 (13.0) 20,302 (13.1) Acute myocardial infarction 3,793 (2.5) 3,882 (2.5) Unstable angina 2,529 (1.6) 2,568 (1.7) Heart failure 4,714 (3.1) 4,759 (3.1) Atrial fibrillation 5,632 (3.6) 5,698 (3.7) Stroke 6,337 (4.1) 6,394 (4.1) Peripheral arterial disease 5,239 (3.4) 5,229 (3.4) Frailty (yes) 11,982 (7.8) 12,731 (8.2) Microvascular disease 42,217 (27.3) 42,215 (27.3) Chronic kidney disease 3,920 (2.5) 4,171 (2.7) Data are n (%) unless otherwise stated; Myocardial infarction, unstable angina, stroke, heart failure, transient ischemic attack, coronary revascularization or occlusive peripheral artery disease; in UK CPRD/THIN, frailty defined as 1 hospitalization within 1 year prior to or on index date; in other databases defined as 1 hospital stay of 3 days within 1 year prior to the index date Kosiborod M, et al. Circulation. 2017.

Baseline Characteristics for the Full Propensity Matched Cohort (continued) SGLT2 inhibitor* N=154,528 Other glucose-lowering drug*n=154,528 Cardiovascular therapies Antihypertensive therapy 123,696 (80.0) 123,563 (80.0) Loop diuretics 14,280 (9.2) 14,314 (9.3) Thiazides 42,446 (27.5) 42,510 (27.5) ACE inhibitors 66,812 (43.2) 67,067 (43.4) ARBs 48,718 (31.5) 48,443 (31.4) Statins 103,968 (67.3) 104,128 (67.4) Diabetes therapies Metformin 121,500 (78.6) 123,432 (79.9) Sulfonylurea 59,406 (38.4) 59,788 (38.7) DPP-4 inhibitor 51,400 (33.3) 50,088 (32.4) Thiazolidinedione 13,650 (8.8) 12,970 (8.4) GLP-1 receptor agonist 31,355 (20.3) 27,088 (17.5) Insulin 45,573 (29.5) 45,097 (29.2) *Data are n (%); Includes angiotensin converting enzyme inhibitors, angiotensin receptor blockers, Ca 2+ channel blockers, β-blockers, thiazides Kosiborod M, et al. Circulation. 2017.

Proportion of exposure time (%) Contribution of SGLT2i Compounds All Countries Combined US Only Europe Only 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5.5% 6.7% 5.6% 41.8% 52.7% hhf 51% 49.1% 42.3% 45.3% All-cause Mortality hhf + Allcause Mortality 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5.1% 5.3% 5.3% 19% 19.3% 19.3% 75.9% 75.4% 75.4% hhf All-cause Mortality hhf + Allcause Mortality 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 6.3% 8.3% 6.1% 91.9% 90.1% 92.2% 1.8% 1.5% 1.7% hhf All-cause Mortality hhf + Allcause Mortality Canagliflozin Dapagliflozin Empagliflozin hhf=hospitalization for heart failure; SGLT2i=sodium glucose co-transporter 2 inhibitor Kosiborod M, et al. Circulation. 2017.

Key Study Results

Hospitalization For Heart Failure Primary Analysis P-value for SGLT2 inhibitor vs other glucose-lowering drug <0.001 Heterogeneity P-value=0.169 Data are on treatment, unadjusted Kosiborod M, et al. Circulation. 2017.

Hospitalization for Heart Failure or All-Cause Death Primary Analysis P-value for SGLT2i vs other glucose-lowering drug <0.001 Heterogeneity P-value=0.166 Data are on treatment, unadjusted Kosiborod M, et al. Circulation. 2017.

Event Rate per 100 Patient-Years Absolute Rates of CV Events in Patients Treated with SGLT2i and ogld P<0.001 for all comparisons 10 Established Cardiovascular Disease No Known Cardiovascular Disease 8 SGLT-2i ogld 6.8 SGLT-2i ogld 6 4 2 0 2.2 3.4 3.5 1.4 3.6 0.1 0.2 0.8 1.0 0.4 0.5 Heart Failure Death Heart Failure Heart Failure Death Heart Failure or Death or Death SGLT2i=sodium-glucose cotransporter-2 inhibitors ogld=other glucose-lowering drug Cavender M, at al. Presented at ADA Scientific Sessions. 2017.

Outcome: HF or Death Norhammar A, et al. Presented at ESC Congress 2017.

Strengths and Limitations

Limitations Possibility of unmeasured confounding cannot be definitively excluded Safety events not examined SGLT2 inhibitor experience in real-world practice is still relatively limited Longer-term follow up required to examine whether effects are sustained over time Kosiborod M, et al. Circulation. 2017.

Clinical Implications No significant heterogeneity across countries, despite geographic variations in use of SGLT-2i (predominance of canagliflozin in US and dapagliflozin in other countries) The observed cardiovascular benefits are likely class-related Broad population of patients with type 2 diabetes in general practice, the overwhelming majority (87%) of whom did not have known cardiovascular disease Benefits may extend to those at the lower end of the risk spectrum Kosiborod M, et al. Circulation. 2017.

Conclusions RWE provide important complimentary data Efficacy Safety Practical information applicable to clinical practice Multiple examples across classes of glucose-lowering drugs of RWE confirming results of CVOTs SGLT-2i associated with lower risk of HF and death trials and real world data suggest this may be a class effect, and may extend to lower risk T2DM populations