Can We Reduce Heart Failure by Treating Diabetes? CVOT Data on SGLT2 Inhibitors and GLP-1Receptor Agonists

Can We Reduce Heart Failure by Treating Diabetes? CVOT Data on SGLT2 Inhibitors and GLP-1Receptor Agonists Robert R. Henry, MD Professor of Medicine University of California, San Diego

Relevant Conflict Disclosure CONSULTANT/ADVISORY BOARDS: Alere/Abbott, AstraZeneca,, BoehringerIngelheim/Lilly, Bristol Myers Squibb, Elcelyx, Ionis, Intarcia,Janssen,Lexicon, Ligand, Merck, Novo Nordisk, Sanofi, Servier GRANTS: Astareal, AstraZeneca, Lexicon, Lilly, ViaCyte, NIH-NIDDK, Novo Nordisk, VA NODES, Xeris

Increase Risk of Mortality and CVD in T2D Rawshani A, et al. N Engl J Med. 2017;376:1407-1418.

Why Do CVOTs and What Do They Mean? In 2008, FDA guidance document required CVOTs for new antihyperglycemic agents for diabetes to demonstrate CV safety Since 2015, 2 CVOTs from the SGLT2 inhibitor class (EMPA-REG and CANVAS) and 2 from GLP-1 RA class (LEADER and SUSTAIN-6) published beneficial CV Outcomes (MACE) These 4 recently published superiority CV outcome trials will be compared for: Patient populations: similarities and differences Headline results and timing of the CV details FDA Guidance for Industry 2008.

Completed and Ongoing CVOTs Study Populations TRIAL AGENT CVD INCLUSION CRITERIA Saxagliptin >40y + CV disease (CHD, CVD, PVD) or >55y with >1 CV risk factor EXAMINE Alogliptin Acute coronary syndrome 15-90 days before randomization TECOS Sitagliptin Established CV disease (CHD, CVD, PVD) ELIXA Lixisenatide Acute coronary event <180 days before screening LEADER Liraglutide >50y + CV disease (CHD, CVD, PVD, HF) or >60y with >1 CV risk factor Semaglutide sc >50y + CV disease (CV event, CVD, PVD, HF) or >60y with >1 CV risk factor EMPA-REG OUTCOME Empagliflozin Established CV disease (MI, CHD, CVD, PVD) CANVAS PROGRAM Canagliflozin >30y + CV disease (CHD, CVD, PVD) or >50y with >2 CV risk factor DEVOTE Degludec vs glargine >50y + CV disease or CKD or >60y with >1 CV risk factor EXSCEL Exenatide QW A1c:6.5-10%>, 70% previous CVD Dulaglutide >50y + established vascular disease or 1 CV risk factor Dapagliflozin >40y + high risk CV events Exenatide implant >40y + established coronary disease, CVD, PAD CAROLINA Linagliptin >40y 85y + CVD or diabetes end-organ damage or 70y or 2 CV risk factors CARMELINA Linagliptin >18y + high risk CV events TOSCA-IT Pioglitazone >50y 75y VERTIS Ertugliflozin >40y + CV disease Published Results SAVOR-TIMI 53 SUSTAIN-6 REWIND DECLARE-TIMI ITCA 650 Scirica BM, et al. New Engl J Med. 2013;369:1317-1326; White WB, et al. N Engl J Med. 2013;369:1327-1335; Bethel X, et al. 2015; Zinman B, et al. Cardiovasc Diabetol. 2014;13:102110.; Pfeffer M, et al, N Engl J Med. 2015; 373:2247-2257. Marso SP, et al, N Engl J Med. 2016; 375: 311-322; Marso SP, et al, N Engl J Med. 2016, 375: 1834-44. Neal B, et al. N Engl J Med. 2017 Jun 12. Marso SP, XX.

Large CV Outcomes Trials in Diabetes ORIGIN1 glargine standard-of-care 12,537 2012 Study Basal insulin Comparator N Results Study GLP1-RA Comparator N (randomized or est. enrollment) Results or completion date LEADER3 liraglutide placebo 9340 2016 Study SGLT-2-i Comparator N (randomized or est. enrollment) Results or completion date EMPA-REG8 empaglifozin placebo 7028 2015 ORIGIN 2012 ELIXA4 lixisenatide placebo 6068 2015 EMPA-REG; ELIXA 2015 DEVOTE; LEADER; SUSTAIN 6: 2016 DEVOTE2 degludec glargine 7637 2016 SUSTAIN 65 semaglutide lacebo 3297 2016 CANVAS9 canagliflozin placebo 4323 2017 CANVAS 2017 EXSCEL6 exenatide LR placebo 14,000 2018 DECLARE10 dapagliflozin placebo 17,150 2019 REWIND 7 dulaglutide placebo 9622 2018 NCT0198688111 ertugliflozin placebo 8000 2019 DECLARE; NCT01986881 2019 EXSCEL; REWIND 2018 1. ORIGIN Trial Investigators, et al. N Engl J Med. 2012;367(4):319-328; 2. Marso SP, et al. Am Heart J. 2016;179:175-83; 3. Marso SP, et al. N Engl J Med. 2016;375(4):311-322; 4. Pfeffer MA, et al. N Engl J Med. 2015;373(23):2247-2257; 5. Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844; 6. ClinicalTrials.gov. Identifier: NCT01144338. Available at: https://www.clinicaltrials.gov/ct2/show/nct01144338. Accessed Mar 13, 2017; 7. ClinicalTrials.gov. Identifier: NCT01394952. Available at: https://www.clinicaltrials.gov/ct2/show/nct01394952. Accessed Mar 13, 2017; 8. Zinman B, et al. N Engl J Med. 2015;373:2117-2128; 9. ClinicalTrials.gov. Identifier: NCT01032629. Available at: https://www.clinicaltrials.gov/ct2/show/nct01032629. Accessed Mar 13, 2017; 10. ClinicalTrials.gov. Identifier: NCT01730534. Available at: https://www.clinicaltrials.gov/ct2/show/nct01730534. Accessed Mar 13, 2017; 11. ClinicalTrials.gov. Identifier: NCT01986881. Available at: https://www.clinicaltrials.gov/ct2/show/nct01986881. Accessed Mar 13, 2017.

Superiority CVOT STUDIES: Similarities/Differences in Study Populations SGLT2 Inhibitors GLP-1 Receptor Agonists LEADER[g] SUSTAIN-6 10,142 9,340 3,297 63 63 64.3 64.6 Diabetes, y 57%>10y 13.5 12.8 13.9 BMI, kg/m2 30.6 32 32.5 32.8 HbA1c, % 8.1 8.2 8.7 8.7 Prior CVD, % 99 65.6 ~81 ~83 Hypertension,% 94 92 92.8 Insulin, % 48 44 58 Baseline Features n Age, y EMPA-REG OUTCOME CANVAS PROGRAM (empagliflozin) (canagliflozin) 7,034 90 50 (liraglutide) (semaglutide) a. Scirica BM, et al. N Engl J Med. 2013;369:1317-1326; b. White WB, et al. N Engl J Med. 2013;369:1327-1335; c. Green JB, et al. N Engl J Med. 2015;373:232242; d. Zinman B et al. N Engl J Med. 2015;373:2117-2128; e. Neal B, et al. N Engl J Med. 2017 Jun 12; f. Pfeffer MA, et al. N Engl J Med, 2015;373:2247-2257; g. Marso SP, et al. N Engl J Med. 2016;375:311-322; h. Marso SP et al. N Engl J Med. 2016;375:1834-1844.

EMPA-REG: CardioRenal Outcomes

EMPA-REG Baseline Characteristics: HbA1c, % Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) 8.08 (0.84) 8.07 (0.86) 8.06 (0.84) Time since diagnosis of type 2 diabetes, years 5 423 (18.1) 406 (17.3) 434 (18.6) >5 to 10 571 (24.5) 585 (24.9) 590 (25.2) >10 1339 (57.4) 1354 (57.7) 1318 (56.3) Metformin 1734 (74.3) 1729 (73.7) 1730 (73.9) Sulphonylurea 992 (42.5) 985 (42.0) 1029 (43.9) Thiazolidinedione 101 (4.3) 96 (4.1) 102 (4.4) 1135 (48.6) 1132 (48.3) 1120 (47.8) 65 (50.6) 65 (47.9) 66 (48.9) Glucose-lowering medication* Insulin Mean daily dose, U** Data are n (%) or mean (SD) in patients treated with 1 dose of study drug *Medication taken alone or in combination **Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg, n=1120

Results From EMPA-REG CVOT Treatment Duration 2.6 years 3-point MACE Zinman B, et al. N Engl J Med. 2015;373:2117-2128.

EMPA-REG Primary Composite: MACE CV Death, Non-Fatal MI and Non-Fatal Stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 1) CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 2) Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 3) Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 0.25 0.50 Favours empagliflozin Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI 1.00 2.00 Favours placebo

CANVAS: CardioRenal Outcomes

CANVAS PROGRAM Study Populations CANVAS PROGRAM combined 2 studies: (CANVAS and CANVAS-R) looked at a mixture of ~2/3 Secondary and ~1/3 Primary Intervention subjects (with CV risk factors but without evidence of serious cardiovascular events) Neal B, et al. N Engl J Med. 2017 Jun 12.

1 4 CANVAS PROGRAM Follow-up CANVAS-R 2.1 years (108 weeks) CANVAS 5.7 years (296 weeks) 2009 2010 2011 2012 2013 2014 2015 2016 CANVAS Program mean follow-up 3.6 years (188 weeks) Patients remaining on randomized treatment: Canagliflozin 71% Placebo 70% Mean age-63 years; 65% male; duration of diabetes- 14 years 2017

1 5 CANVAS Baseline Therapies Antihyperglycemic agents Metformin Insulin Sulfonylurea DPP-4 inhibitor GLP-1 receptor agonist Cardioprotective agents ACE inhibitor/arb Statin Antithrombotic Beta blocker Diuretic Canagliflozin (n = 5795) Placebo (n = 4347) % % 77 50 44 12 4 78 51 42 13 4 80 75 73 52 44 80 75 74 55 45

CANVAS PROGRAM : Primary Composite (MACE) by Individual Study Components and Combined Hazard ratio (95% CI) CANVAS 0.88 (0.75-1.03) CANVAS-R 0.82 (0.66-1.01) CANVAS Program 0.86 (0.75-0.97) 0.5 Favors Canagliflozin Intent-to-treat analysis 2.0 1.0 Favors Placebo

CANVAS Program Primary Composite: MACE Patients with an event (%) CV Death, Nonfatal Myocardial Infarction, or Nonfatal Stroke 20 Hazard ratio 0.86 (95% CI, 0.75-0.97) p <0.0001 for noninferiority p = 0.0158 for superiority 18 16 14 12 10 8 6 4 Placebo Canagliflozin 2 0 0 1 Intent-to-treat analysis 3 4 5 6 Years since randomization No. of patients 4347 Placebo Canagliflozin 5795 2 4153 2942 1240 1187 1120 789 5566 4343 2555 2460 2363 1661

CANVAS PROGRAM SUMMARY Hazard ratio (95% CI) CV death, nonfatal myocardial infarction, or nonfatal stroke ( 3 point MACE) CV death 0.86 (0.75-0.97) 0.87 (0.72-1.06) Nonfatal myocardial infarction 0.85 (0.69-1.05) Nonfatal stroke 0.90 (0.71-1.15) All-cause mortality 0.87 (0.74-1.01) Hospitalization for heart failure 0.67 (0.52-0.87) CV death or hospitalization for heart failure 0.78 (0.67-0.91) 0.5 Favors Canagliflozin Intent-to-treat analysis 1.0 Favors Placebo

Patients with an event (%) All-Cause Mortality Placebo Canagliflozin Hazard ratio 0.87 (95% CI, 0.74-1.01) 20 18 16 14 12 10 8 6 4 2 0 0 1 Intent-to-treat analysis 3 4 5 6 Years since randomization No. of patients 4347 Placebo Canagliflozin 5795 2 4279 3119 1356 1328 1292 924 5723 4576 2761 2710 2651 1904

Hospitalization for Heart Failure Patients with an event (%) Placebo Canagliflozin Hazard ratio 0.67 (95% CI, 0.52-0.87) 20 18 16 14 12 10 8 6 4 2 0 0 1 Intent-to-treat analysis 3 4 5 6 Years since randomization No. of patients 4347 Placebo Canagliflozin 5795 2 4198 3011 1274 1236 1180 829 5653 4437 2643 2572 2498 1782

CV Death or Hospitalization for Heart Failure Patients with an event (%) Placebo Canagliflozin Hazard ratio 0.78 (95% CI, 0.67-0.91) 20 18 16 14 12 10 8 6 4 2 0 0 1 Intent-to-treat analysis 3 4 5 6 Years since randomization No. of patients 4347 Placebo Canagliflozin 5795 2 4202 3015 1281 1242 1184 831 5655 4442 2647 2577 2503 1782

EMPA-REG OUTCOME and CANVAS CVOTs: Comparison of CV Results CV STUDY ENDPOINTS EMPA-REG OUTCOME[a] (empagliflozin) N=7034 CANVAS[b] (canagliflozin) N=10,142 CV death, nonfatal MI, or nonfatal stroke 0.86 (0.74, 0.99) P<.001 for noninferiority P=.04 for superiority CV death, nonfatal MI, or nonfatal stroke 0.86 (0.75, 0.97) P<.001 for noninferiority P=.02 for superiority CV death 0.62 (0.49, 0.77) P<.001 0.87 (0.72, 1.06) Nonfatal MI 0.87 (0.70, 1.09) P=.23 0.85 (0.69, 1.05) Nonfatal stroke 1.18 (0.89, 1.56) P=.26 0.90 (0.71, 1.15) Hospitalization for UA 0.99 (0.74, 1.34) P=.97 Hospitalization for HF 0.65 (0.50, 0.85) P=.002 Primary composite endpoint (MACE) 0.67 (0.52, 0.87) a. Zinman B, et al. N Engl J Med. 2015;373:2117-28; b. Neal B, et al. N Engl J Med. 2017 Jun 12.

Superiority CVOT STUDIES: Similarities/Differences in Study Populations SGLT2 Inhibitors GLP-1 Receptor Agonists LEADER[g] SUSTAIN-6 10,142 9,340 3,297 63 63 64.3 64.6 Diabetes, y 57%>10y 13.5 12.8 13.9 BMI, kg/m2 30.6 32 32.5 32.8 HbA1c, % 8.1 8.2 8.7 8.7 Prior CVD, % 99 65.6 ~81 ~83 Hypertension,% 94 92 92.8 Insulin, % 48 44 58 Baseline Features n Age, y EMPA-REG OUTCOME CANVAS PROGRAM (empagliflozin) (canagliflozin) 7,034 90 50 (liraglutide) (semaglutide) a. Scirica BM, et al. N Engl J Med. 2013;369:1317-1326; b. White WB, et al. N Engl J Med. 2013;369:1327-1335; c. Green JB, et al. N Engl J Med. 2015;373:232242; d. Zinman B et al. N Engl J Med. 2015;373:2117-2128; e. Neal B, et al. N Engl J Med. 2017 Jun 12; f. Pfeffer MA, et al. N Engl J Med, 2015;373:2247-2257; g. Marso SP, et al. N Engl J Med. 2016;375:311-322; h. Marso SP et al. N Engl J Med. 2016;375:1834-1844.

LEADER TRIAL Primary Endpoint -3 Point MACE Key inclusion criteria T2DM, HbA1C 7.0% Antidiabetic drug naïve, OADs and/or basal/premix insulin Aged 50 y with established CV disease or chronic renal failure (Secondary Prevention) -81% OR Aged 60 y with risk factors for CV disease (Primary Prevention)-19% Patients were randomized 1:1 to: Liraglutide 1.8 mg (or the maximum tolerated dose) or matching placebo as a once-daily, subcutaneous injection All received standard care Marso SP, et al. N Engl J Med. 2016;375(4):311-322

LEADER: Baseline Characteristics Liraglutide (N=4668) Placebo (N=4672) 3011 (64.5) 2992 (64.0) Age, years 64.2 ± 7.2 64.4 ± 7.2 Diabetes duration, years 12.8 ± 8.0 12.9 ± 8.1 HbA1c, % 8.7 ± 1.6 8.7 ± 1.5 BMI, kg/m2 32.5 ±6.3 32.5 ± 6.3 91.9 ±21.2 91.6 ± 20.8 Systolic blood pressure, mmhg 135.9 ± 17.8 135.9 ± 17.7 Diastolic blood pressure, mmhg 77.2 ± 10.3 77.0 ± 10.1 835 (17.9) 832 (17.8) Male sex, N (%) Body weight, kg Heart failure*, N (%) (mean ± SD unless stated) *Heart failure includes New York Heart Association class I, II, and III. BMI: body mass index; HbA 1c: glycated haemoglobin; SD: standard deviation Marso SP et al. N Engl J Med 2016;375:311 322

LEADER: Primary and Secondary Outcomes with Liraglutide Primary Outcomea Patients With Event, % 20 Hazard ratio, 0.87 (95% CI, 0.78 0.97) P<0.001 for noninferiority P=0.01 for superiority 15 10 5 20 CardiovascularRelated Death 15 Placebo Liraglutide 10 Death From Any Cause 20 15 Hazard ratio, 0.78 (95% CI, 0.66 0.93) P=0.007 Placebo 5 Hazard ratio, 0.85 (95% CI, 0.74 0.97) P=0.02 10 Placebo 5 Liraglutide Liraglutide 0 0 6 12 18 24 30 36 42 48 54 0 0 0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 Months Since Randomization acomposite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. N=9340 patients with T2DM and high cardiovascular risk. Marso SP, et al. N Engl J Med. 2016 June 13 [Epub ahead of print].

Primary Outcomes-MACE LEADER EMPA-REG CV death, non-fatal MI, or non-fatal stroke Median follow-up= 3.1 yrs CV death, non-fatal MI, or non-fatal stroke Median follow-up= 3.8 yrs c v Marso SP et al. N Engl J Med 2016;375:1834-44; Zinman B et al. N Engl J Med 2015;373:2117-28.

CV Death EMPA REG Pfeffer MA, et al. N Engl J Med 2015;373:2247-57; Marso SP et al. N Engl J Med 2016;375:311-22. LEADER

All Cause Mortality EMPA REG LEADER LEADER Marso SP, et al. N Engl J Med. 2016;375(4):311-322

Hospitalization for Heart Failure EMPA REG Pfeffer MA, et al. N Engl J Med 2015;373:2247-57; Marso SP et al. N Engl J Med 2016;375:311-22. LEADER

LEADER Summary Liraglutide reduced the risk of major CV events in patients with T2DM at high CV risk. MACE superiority driven by reduced CV DEATH like EMPA REG Time to separation of curves was early (days to months) with SGLT2i and separation was much slower separation (months to years) with GLP-1 RA (MACE and All-Cause Mortality). It appears unlikely that the CV risk reduction with liraglutide can be fully explained by the observed differences in HbA1c, body weight, SBP and lipids

SUSTAIN TRIAL Multicenter, randomized, double-blinded, placebo-controlled, parallel-group trial of semaglutide (Ozempic) Age 50 years with clinical evidence of CVD or 60 years with subclinical evidence of CVD Previously on 0 2 OADs, basal or premix insulin, HbA1C 7.0% Patients were randomized1:1:1:1 to: Semaglutide 0.5 mg or 1.0 mg or matching placebo as a once-weekly, subcutaneous injection for 104 weeks (2 Years) Fixed dose-escalation procedure, with starting dose of 0.25 mg for 4 weeks, then to 0.5 mg for 4 weeks until maintenance dose reached Non-inferiority was confirmed if two-sided upper bound of 95% CI was <1.8. Test of superiority was not pre-specified. Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.

SUSTAIN: Semaglutide in Patients With T2DM and High Cardiovascular Risk Baseline Characteristics Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.

SUSTAIN: Semaglutide in Patients With T2DM and High Cardiovascular Risk Baseline Characteristics - Antihyperglycemic Medications Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.

SUSTAIN 6: CV Outcomes Marso SP, et al. N Engl J Med. 2016;375:1834-1844s Note: Comparison of the studies is not intended to compare study outcomes.

LEADER TRIAL Nonfatal Stroke Marso SP, et al. N Engl J Med. 2016;375(4):311-322

CV Death EMPA-REG. Marso SP et al. N Engl J Med 2016;375:1834-44; Zinman B et al. N Engl J Med 2015;373:2117-28. SUSTAIN

Total All Cause Mortality EMPA-REG Marso SP et al. N Engl J Med 2016;375:1834-44; Zinman B et al. N Engl J Med 2015;373:2117-28. SUSTAIN

Primary Outcomes-MACE SUSTAIN EMPA-REG CV death, non-fatal MI, or non-fatal stroke Median follow-up= 3.1 yrs CV death, non-fatal MI, or non-fatal stroke Median follow-up= 2.1 yrs Marso SP et al. N Engl J Med 2016;375:1834-44; Zinman B et al. N Engl J Med 2015;373:2117-28.

Hospitalization for Heart Failure EMPA-REG Marso SP et al. N Engl J Med 2016;375:1834-44; Zinman B et al. N Engl J Med 2015;373:2117-28. SUSTAIN

SUSTAIN-6: Diabetic Retinopathy Complications Semaglutide Placebo N (%) N (%) Diabetic retinopathy complications 50 (3.0) 29 (1.8) Need for retinal photocoagulation 38 (2.3) 20 (1.2) Vitreous hemorrhage 16 (1.0) 7 (0.4) Need for treatment with intravitreal agents 16 (1.0) 13 (0.8) Onset of diabetes-related blindness 5 (0.3) 1 (0.1) The majority of these subjects (66 of 79) had pre-existing retinopathy at baseline in both groups (42, [84%] for semaglutide vs 24, [83%] fro placebo) In-tiral adjudicated events. Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.

Summary: GLP-1 Receptor Agonist Cardiovascular Outcomes Trials = MACE (3-Point) superiority: = In LEADER (liraglutide) was driven mainly by CV Death like in EMPA REG (empagliflozin) = In SUSTAIN 6 (semaglutide) was driven by Non-Fatal Stroke not seen with liraglutide. Also increased retinopathy (? Related to rapid glucose control)

Reconciling the Differing Results of GLP-1RA Trials Differences in study design (safety vs CV beefits), populations (I/E), duration of Rx Proportions of primary and secondary CVD prevention enrolled Concomitant medical therapies at baseline and during follow up Differences between chemical nature and metabolism of molecules Location (region of study conduct) of patients -- Efficacy on A1c, weight, BP, CV risk factors

New FDA Indication for Diabetes Medications Diabetes medications FDA approved for CV risk reduction 1. Empagliflozin (based on EMPA-REG data) Reduction in risk of CV death in patients with type 2 diabetes and established CV disease 2. Liraglutide (based on LEADER data) Reduction in risk of major CV events in patients with type 2 diabetes and established CV disease

Closing Comments 4 FDA-approved antihyperglycemic agents have now demonstrated CV benefits Risks vs benefits need to be weighed with all antihyperglycemic agents ADA 2017 and 2017 AACE/ACE guidelines now include recommendation for consideration of empagliflozin or liraglutide in patients with type 2 diabetes not at goal and with established atherosclerotic CV disease