Congestive Heart Failure: The Complication That Gets No Respect

Number of Americans with HF (millions) Projected cost of HF (billions of dollars) Congestive Heart Failure: The Complication That Gets No Respect 65th Advanced Postgraduate Course February 9-11, 18, San Francisco, CA Sanjay Kaul, MD, FACC, FAHA Division of Cardiology Cedars-Sinai Medical Center Los Angeles, California Faculty/Presenter Disclosure Faculty Name: Sanjay Kaul, MD Advisor/Consultant - United States FDA Consultant - Boehringer Ingelheim - Sanofi - Novo Nordisk - Johnson & Johnson Stocks/Equity - Johnson & Johnson Congestive Heart Failure (in TDM): The Complication That Gets No Respect Congestive Heart Failure (in TDM): The Complication That Gets No Respect Outline Impact of heart failure Classification, prognosis, and medical management Epidemiology of TDM and heart failure Pathophysiology of TDM and heart failure Glucose-lowering medications and heart failure Heart failure outcomes in recent CVOTs in TDM Possible mechanisms for cardiovascular benefits Current trials with SGLT inhibitors in heart failure Take-home points HF is a Global Health Problem with a Prevalence of Approximately 6 million Worldwide Proportion of the population living with heart failure (HF) in individual countries across the world North America 1 Canada 1.5% USA 1.9% Europe 1 France.% UK 1.3% Latin America and Africa 1 No population-based estimates Middle East 1 Oman*.5% Australasia 1 Australia 1.3% Asia 1 China* 1.3% Japan 1.% Malaysia* 6.7% Singapore* 4.5% *Estimates based on a single centre or hospital Ponikowski P et al. Heart failure: Preventing disease and death worldwide. European Society of Cardiology, 14. www.escardio.org/static_file/escardio/subspecialty/hfa/whfa-whitepaper-15-may-14.pdf (accessed Nov 15) The Prevalence and Cost of HF is Projected to Increase Further 9 8 7 6 5 4 3 1 Prevalence of HF (US) 5.8m 8.5m 1 3 8 7 6 5 4 3 1 $31b Cost of HF* (US) $7b 1 3 * 8% of costs are related to Heidenreich et al., AHA Policy Statement: Forecasting the Impact of Heart Failure in the United States. Circ Heart Fail. 13;6:66 619

Deaths (% patients) Risk-adjusted 1-year mortality (%) There Scientific are Two Evidence Categories Underlying of Heart The Failure ACC/AHA HF preserved Clinical EF Practice Guidelines 1 HF reduced EF 3 LVEF 5% Caveat *, (4 5 borderline) LVEF 4% Emptor, Caveat Lector Attributed to pro-inflammatory CV and non-cv coexisting conditions 1 Occurs due to loss of systolic function 4 There Scientific are Two Evidence Categories Underlying of Heart The Failure ACC/AHA Clinical Practice Guidelines Caveat Emptor, Caveat Lector Associated with: hypertension, obesity, diabetes, metabolic syndrome, lung disease, smoking, and iron deficiency 1 HFpEF is less well understood than HFrEF 1, Accounts for >5% of all HF cases; 1% per year increase in prevalence 3 Leading cause: coronary artery disease 4 Associated with: coronary artery disease risk factors, e.g. hypertension, diabetes, advanced age, smoking, dyslipidemia 4 Accounts for 5% of all HF cases Important classification for clinical management,4 1. Redfield MM et al. N Engl J Med 16;375:1868;. Bugger H et al. Diabetologia 14;57:66; 3. Borlaug BA. Heart failure with preserved ejection fraction. In: Springer Verlag; 15;13 3. 4. Mann DL et al. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Single Volume, 1th Edition. Elsevier Saunders, Philadelphia 15 HFpEF Preserved systolic LV function No LV dilation Concentric LV remodeling Diastolic LV dysfunction HFrEF Systolic LV dysfunction LV dilation Eccentric LV remodeling Diastolic LV dysfunction Classification of HF: ACCF/AHA stage vs NYHA classification ACCF/AHA Stage NYHA Classification Heart Failure Risk Factors The Framingham Heart Study Age and Risk-factor Adjusted HR A At high risk for HF but without structural heart disease or symptoms of HF None B Structural heart disease but without signs or symptoms of HF I I No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF. Same as above 6% (PAR) 1% (PAR) C Structural heart disease with prior or current symptoms of HF II III Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF. Marked limitation of physical activity. Comfortable at rest but less than ordinary activity causes symptoms of HF. 39% (PAR) 59% (PAR) 34% (PAR) 13% (PAR) IV Unable to carry on any physical activity without symptoms of HF or symptoms of HF at rest. D Refractory HF requiring specialized interventions IV Unable to carry on any physical activity without symptoms of HF or symptoms of HF at rest. NYHA: New York Heart Association, HF: heart failure Yancy CW, et al. Circulation. 13 ;18(16):e4 37. Hypertension and CAD are the most common risk factors for HF Levy D, et al. JAMA 1996;75:1557 156 Not all Heart Failure Patients have a History of CAD HFpEF Study CAD HFrEF Study CAD TOPCAT 1 (n=3445) 59% PARADIGM-HF 7 (n=844) 6% I-Preserve (n=4133) 48% RALES 8 (n=1663) 55% CHARM-Preserved 3 (n=33) 6% COPERNICUS 9 (n=89) 67% Mortality Rates after HHF Results from Two Population-Based Cohort Studies 6 4 Mortality rates after HHF (ARIC study) 1 4 4 3 Mortality rates after HHF (US Acute Care) * 31 31 3 8 3 DIG-PEF 4 (n=988) 56% MERIT-HF 1 (n=3991) 65% PEP-CHF 5 (n=85) 7% CHARM-ALT 11 (n=8) 68% 1 1 SENIORS 6 (n=75) 77% SOLVD 1 (n=569) 71% 1 Pitt, B. et al. N Engl J Med. 14;37:1383 139; Massie, B. et al. N Engl J Med 8;359:456 467; 3 Yusuf, S. et al. Lancet. 3 Sep 6; 36(9386):777 781; 4 Ahmed A, et al. Circulation 6;114:397 43; 5 Cleland, J, et al. Eur Heart J. 6 Oct;7(19):338 345; 6 Flather, M et al. Eur Heart J. 5 Feb;6(3):15 5; 7 McMurray, J. et al. N Engl J Med 14; 371:993 14; 8 Pitt, B. et al. N Engl J Med 1999:341:79 717; 9 Packer et al. N Engl J Med. 1; 344:1651 1658; 1 Merit HF Study Group. The Lancet. 1999;353:1-1; 11 Granger, C et al. Lancet 3; 36:77 776; 1 SOLVD Study Investigators N Engl J Med 1991;35:93 3. Day 3 Year 1 Year 5 4 6 8 Time after *Risk-adjusted rates relative to 1999 1-year mortality of 31.7% Prognosis after for HF (HHF) is poor 1. Loehr LR et al. Am J Cardiol 8;11:116;. Chen J et al. JAMA 11;36:1669

Prevalence of diabetes (%) Hazard ratio (mortality) Repeat Hospitalization Leads to Worse Patient Outcomes 4% of patients died after discharge from HF 16 14 Guidelines for Management of HFrEF (Stage C/D) 17 ACC/AHA/HFSA Focused Update Class I Benefit>>>Risk Class IIa Benefit >>Risk 1 1 8 6 4 Time since discharge (months) 3 rd HF Hospitalization 1 st HF Hospitalization nd HF Hospitalization -1 1-3 3-6 6-1 1+ Adapted from Solomon SD et al. Circulation. 7;116:148 1487 Yancy CW et al, Circulation. 17 ACC/AHA/HFSA HF Focused Update of the 1 ACCF/AHA Guidelines for the Management of Heart Failure. DOI: 1.1161/CIR.59. Magnitude of Benefit Demonstrated in RCTs Class I LOE A Recommended Therapy Guideline-directed therapy RR reduction in mortality 1, NNT for mortality reduction (over 1 year) 1 RR reduction in HHF ACE inhibitor or ARB 17% 77 31% Beta blocker 34% 8 41% Aldosterone antagonist 3% 18 35% Hydralazine/nitrate 43% 1 33% ARNI 16% 8 1% 3 Benefit of therapy evident on the background of standard of care (incremental treatment effects) 1 Fonarow,G. et al. JAMA Cardiol. 16;1(6):714-717; Yancy CW et al. Circulation. 13;18:e4 e37; 3 McMurray, J. et al. N Engl J Med 14; 371:993 14 15 Guidelines for Management of HFpEF 17 ACC/AHA/HFSA Focused Update Recommendations 3 COR LOE Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines Diuretics should be used for relief of symptoms due to volume overload I C Coronary revascularization for patients with CAD in whom angina or demonstrable myocardial ischemia is present despite GDMT Management of AF according to published clinical practice guidelines for HFpEF to improve symptomatic HF Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF IIa C ARBs might be considered to decrease s in HFpEF IIb B In appropriately selected patients* with HFpEF aldosterone receptor antagonists might be considered to decrease s4 IIb B-R *Appropriately selected patients: with EF 45%, elevated BNP levels or HF admission within 1 year, estimated glomerular filtration rate >3 ml/min, creatinine <.5 mg/dl, potassium <5. meq/l No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFpEF Yancy CW et al, Circulation. 17 ACC/AHA/HFSA HF Focused Update of the 1 ACCF/AHA Guidelines for the Management of Heart Failure. DOI: 1.1161/CIR.59. I IIa IIa B C C Therapies Successful in HFrEF Have Not Demonstrated Success in HFpEF Diabetes is Common Among Patients with HF 6 Intervention HFrEF HFpEF Beta blocker SENIORS 1 OPTIMIZE-HF14 ACEi/ARB CHARM I-PRESERVE15 PEP-CHF 16 Digoxin DIG 3 Dig-PEF17 PDE5 inhibitor RELAX-HF 4 RELAX-HF4 MRA Hydralazine/Ni CRT ICD Exercise RALES 5 TOPCAT 18 EMPHASIS 6 ALDO-HF 19 A-HeFT 7 Cohn 8 MADIT-CRT 9 COMPANION 1 IMPROVE-HF 9 MADIT-I 11 HF-ACTION 1 Thompson et al. 13 NEAT-HFpEF PROSPECT1 No studies available Pandey* Evidence of clinical efficacy No evidence of clinical efficacy Clinical efficacy uncertain 49 5 48 43 43 4 4 4 35 33 3 3 1 TOPCAT 1 RELAX SOCRATES -P 3 EPHESUS 4 PARADIGM 5 SOCRATES-R 6 GWTG HF 7 OPTIMIZE 8 ADHERE 9 (n=3345) (n=16) (n=477) (n=664) (n=8399) (n=456) (n=1,78) (n=46,61) (n=46,61) HFpEF RCTs HFrEF RCTs Registries Prevalence of DM in HF is 5-3% overall, 4-45% in those hospitalized for HF 1 Pitt B et al. N Engl J Med 14;39:1383; Redfield MM et al. JAMA 13;39:168; B et al. Eur Heart J 16;38:1119; 4 Pitt B et al. N Engl J Med 3;348:139; 5 McMurray JJV et al. N Engl J Med 14;371:993; 6 Gheorghiade M et al. JAMA 15;314:51; 7 Luo N et al. JACC Heart Fail 17;5:35; 8 Greenberg BH et al. Heart J 7;154:77.e177.e8; 9 Peacock F, et al. N Engl J Med 8; 358:117 16.

Cumulative incidence of CV death or HHF (%) Chest wall restriction, reduced vital capacity, impaired ventilation and diffusion Obstructive sleep apnea Pulmonary hypertension Direct and indirect myocardial lipotoxicity Worsened cardiac mechanics Diastolic dysfunction; increased filling pressures/ volume overload, increased afterload Non-alcoholic fatty liver disease Promotes generalized inflammatory state Inflammatory cytokines Adverse neurohormones Increased BNP clearance Direct toxic effects of perinephric fat Glomerulomegaly with glomerular dysfunction Increased adipose infiltration Impaired perfusion Decreased diffusive O transport Mitochondrial dysfunction Cumulative incidence (%) Cumulative incidence (%) There is a Strong Relationship Between Heart Failure and Diabetes 5 5 TDM Confers Higher Risk of CV death, Hospitalization for Heart Failure and All-cause Mortality CV death or due to heart failure CV death Low EF Low EF Diabetes 657/136 (5.3%) 413/136 (31.6%) No diabetes 114/37 (33.8%) 77/37 (1.6%) 6 4 CV death or due to heart failure a.5 1 1.5.5 3 3.5 Follow-up (years) Diabetes (Low EF) No Diabetes (Low EF) People with diabetes have a - to 5-fold higher risk of developing HF (independent of IHD or HTN) 1 Diabetes confers 6 8% greater probability of CV death and all-cause mortality in those with established HF,3 * Hospitalization due to heart failure All-cause mortality Low EF Low EF 449/136 (34.4%) 496/136 (38.%) 79/37 (1.7%) 854/37 (6.1%) 6 4 All-cause mortality Diabetes (Low EF) No Diabetes (Low EF) 1. Kannel WB et al. Am J Cardiol 1974;34:9. Cubbon RM et al. Diab Vasc Dis Res 13;1:33 3. MacDonald MR et al. Eur Heart J 8;9:1377 MacDonald MR, et al. Eur Heart J 8;9:1377 1385.5 1 1.5.5 3 3.5 Follow-up (years) Diabetes Increases Risk in HFpEF to Approximate Risk in HFrEF in Non-DM Patients with Heart Failure have Similar Pathophysiological Features as Patients with Diabetes Increased risk of or death due to HF with HFrEF vs HFpEF 6 1 HFrEF: adjusted HR 1.6 Non-Diabetes Diabetes 95% CI 1.4, 1.77; p<.1 HFrEF HFpEF: adjusted HR. 4 95% CI 1.7,.36; p<.1 HFpEF HFrEF 1 HFpEF Heart failure Impaired contractility Cardiomyocyte apoptosis/fibrosis Neurohormonal activation LV remodelling Shared pathological features Endothelial dysfunction Insulin resistance Mitochondrial dysfunction RAAS activation Inflammation Diabetes Hyperglycaemia Pancreatic beta-cell function Advanced glycated end-product toxicity Neuronal degeneration/ demyelination.5 1 1.5.5 3 3.5 Follow-up (years) MacDonald MR et al. Eur Heart J 8;9:1377 LV, left ventricular; RAAS, renin-angiotensin-aldosterone system Adapted from: Sena CM et al. BBA Mol Basis Dis 13;183:16; Aroor AR et al. Heart Fail Clin 1;8:69; Anker SD et al. Heart 4;9:464; Sivitz WI et al. Antioxid Redox Signal 1;1:557; Bauters C et al. Cardiovasc Diabetol 3;:1 Diabetes Contributes to the Progression of Heart Failure HFpEF in 18: Phenotypic Diversity Lung Heart Liver Visceral adiposity Kidney Skeletal muscle Obesity-related HFpEF is the most common phenotype of heart failure in TDM Perrone-Filardi P et al. Eur Heart J. 15;36(39):63 634 Kitzman D, Shah SJ. JACC 16 Borlaug B. Nat Rev Cardiol 14

TZDs* GLP-1 R DDP-4 inhibitors* Intensive Glycaemic Control* Has Not Been Shown to Significantly Impact the Risk of HF Previous CV Outcomes s with Glucose-Lowering Agents Have Not Shown a Benefit for HF Outcomes Number of events (yearly rate, %) DHbA1c HR (95% CI) (%) More intensive Less intensive Admission to hospital/fatal HF ACCORD 15 (.9) 14 (.75) 1.1 1.18 (.93, 1.49) ADVANCE (.83) 31 (.88).7.95 (.79, 1.14) UKPDS 8 (.6) 6 (.11).66.55 (.19, 1.6) VADT 79 (1.8) 85 (1.94) 1.16.9 (.68, 1.5) Overall 459 446.88 1. (.86, 1.16)..5 1. agonists* Insulin* Study drug Comparator n (%) n (%) HR (95% CI) ORIGIN (HHF) 31 (4.9) 343 (5.5).9 (.77, 1.5) SAVOR-TIMI 53 (HHF) 89 (3.5) 8 (.8) 1.7 (1.7, 1.51) EXAMINE (HHF) 16 (3.9) 89 (3.3) 1.19 (.9, 1.58) TECOS (HHF) 8 (3.1) 9 (3.1) 1. (.83, 1.) TECOS (HHF or CV death) 538 (7.3) 55 (7.) 1. (.9, 1.15) ELIXA (HHF) 1 (4.) 17 (4.).96 (.75, 1.3) ELIXA (HHF or 4P-MACE) 456 (15.) 469 (15.5).97 (.85, 1.1) *Versus less-intensive glycaemic control; p=.31 for heterogeneity from Q test with significance cut off of p=.1 Favours more intensive control Favours less intensive control PROactive (HHF or HF death) 149 (5.7) 18 (4.1) 1.41(1.1, 1.8) RECORD (HHF or CHF death) 61 (.7) 9 (1.3).1 (1.35, 3.7) Vildagliptin increased ventricular end-diastolic volume in pts with reduced LV fx (VIVIDD).3 1. 4. Liraglutide increased (ns) the rate of death or hhf in pts recently hospitalized for HF (FIGHT) Favours study drug Favours comparator Excess adverse cardiac events with Liraglutide in chronic HF with or without DM (LIVE) Turnbull FM et al. Diabetologia 9;5:88 Metformin in Heart Failure Compared With Other Treatments For All-cause Mortality Congestive Heart Failure (in TDM): The Complication That Gets No Respect Risk ratio Study or IV, random, 95% CI subgroup log[risk ratio] SE Weight Year Evans.518.5.6%.6 (.37,.98) 5 Eurich.4156. 4.1%.66 (.45,.98) 5 Masoudi.1393.6 9.%.87 (.77,.98) 5 Inzucchi.834.13 8.9%.9 (.71, 1.19) 5 Shah.357.4 1.1%.79 (.36, 1.73) 1 MacDonald.438.15 6.9%.65 (.48,.87) 1 Roussel.3711.13 8.9%.69 (.53,.89) 1 Andersson.165.68 4.6%.85 (.74,.97) 1 Aguilar.744.1 13.9%.76 (.6,.9) 11 Total (95% CI) 1.%.8 (.74,.87) Heterogeneity: Tau =.; Chi =9.45, df=8 (P=.31); I =15% Test for overall effect: Z=5.35 (P<.1) Eurich DT, et al. Circ Heart Fail 13;6:395 4 Favors Metformin Control.5.7 1 1.5 Impact of heart failure Classification, prognosis, and medical management Epidemiology of TDM and heart failure Pathophysiology of TDM and heart failure Glucose-lowering medications and heart failure Heart failure outcomes in recent CVOTs in TDM Possible mechanisms for cardiovascular benefits Current trials with SGLT inhibitors in heart failure Take-home points 8 FDA Diabetes Guidance Recommendations Primary evidence for regulatory approval: glycemic control Demonstrate that therapy will not result in an unacceptable increase in CV risk (noninferiority, rule out HR 1.3) Phase /3 design should permit a pre-specified meta-analysis of major cardiovascular events (3p-MACE: CV death, non-fatal MI, or non-fatal stroke; 4-p MACE = 3-p MACE + hosp. for UA or CR) (4p-MACE to r/o 1.8, 3p-MACE to r/o 1.3) Independent committee should prospectively and blindly adjudicate MACE s should include patients at increased risk for cardiovascular disease (advanced CVD, CKD, elderly) duration(s) should be longer than 3-6 months to obtain enough events and provide long-term data (~yrs) No mention of heart failure outcome assessment in Diabetes Guidance! http://www.fda.gov/newsevents/newsroom/pressannouncements/8/ucm116994.htm CVOTs in TDM: Evidentiary Landscape 5 s (9 Completed), N=, since 13 SAVOR-TIMI 53 n = 16,49 EXAMINE n = 5,38 13 DPP-4 inhibitors SGLT inhibitors GLP-1 receptor agonists Insulin TZD α-glucosidase inhibitor EMPA-REG OUTCOME n = 7, * ELIXA n = 6,68 TECOS n = 14,671 CARMELINA n = 8,3, renal composite REWIND n = 9,91 CAROLINA n = 6,115 15 16 17 18 19 * LEADER n = 9,34 SUSTAIN-6 n = 3,97 * CANVAS Program n = 1,14 * DEVOTE n = 7,637 IRIS n = 3,876 Fatal or nonfatal stroke or MI FREEDOM-CVO n = 4, EXSCEL n = 14,75 ACE n = 6,56 5-P MACE ( + for HF or unstable angina) VERTIS CV n = 8, Dapa-HF n = 4,5 CV death, HF, HF urgent visit PIONEER 6 n = 3,176 HARMONY Outcomes n = 9,4 CREDENCE n = 4, ESRD, doubling of creatinine, renal/cv death DECLARE-TIMI 58 n = 17,15, CVD EMPEROR- Preserved n = 4,16 CV death or HF EMPEROR- Reduced n =,85 CV death or HF Dapa-CKD n = 4, 5% sustained decline in egfr or reaching ESRD or CV death or renal death

Spectrum of CV Risk of Target Patient Population of Key CVOTs of Glucose-Lowering Therapies Select Therapeutic Effects of Glucose-Lowering Therapies on HF and CV Outcomes DECLARE-TIMI 58 EMPEROR-Reduced EMPEROR-Preserved HF Outcomes + (Benefit) CV Outcomes +/- (Null) - (Harm) Dapa-HF + (Benefit) Empaglifozin (EMPA-REG OUTCOME) Canagliflozin (CANVAS) +/- (Null) Liraglutide (LEADER) Semaglutide (SUSTAIN-6) Insulin Glargine (ORIGIN) Acarbose (ACE) Lixisenatide (ELIXA) Exanetide (EXSCEL) Alogliptin (EXAMINE) Sitagliptin (TECOS) - (Harm) Pioglitazone (PROactive) Rosiglitazone (RECORD) Saxagliptin (SAVOR-TIMI 53) Borrowed from Javed Butler, MD (Circulation 18, In Press) Prevalence of Heart Failure in Recent Diabetes CVOTs F/U, y (median) Age, y BMI Male (%) Duration of DM, y H/O of CVD Baseline H/O HF HbA1c, baseline (D) SAVOR.1 65.1 8.7 67 1.3 78% 13% 8. (-.3) EXAMINE 1.5 61 9.5 68 7.1 1% 8% 8. (-.3) TECOS 4 66 3. 71 11.6 74% 18% 7. (-.3) ELIXA 61 3 69 9.3 1% % 7.7 (-.3) LEADER 3.8 64.3 3.5 64 1.7 81% 18% 8.7 (-.4) SUSTAIN-6.1 64.6 31.3 61 13.9 59% 4% 8.7 (-.7, -1.) EXCSEL 3. 6 31.8 6 1 73% 16% 8. (-.5) EMPA-REG 3.1 63.1 3.6 7 >1y (57%) 99% 1% 8.1 (-.3) CANVAS.4 63.3 3 64 13.5 66% 14% 8. (-.6) Heart failure not specified as an inclusion criterion in any trial! Heart Failure Outcomes in Recent Diabetes CVOTs PEP SEP (prespecified) Yes Powered SAVOR No Yes No EXAMINE* No No No TECOS No Yes No ELIXA No Yes No LEADER No Yes No SUSTAIN-6 No Yes No EXCSEL No Yes No EMPA-REG No Yes No CANVAS Program No Yes No *post hoc Hospitalization for heart failure (HHF) not prespecified as a primary endpoint or as a powered secondary endpoint in any trial! Heart Failure Outcomes in Recent IGT/TDM CVOTs NAVIGATOR (NEJM 1) (Valsartan/nateglinide vs placebo in pts with impaired glucose tolerance and established CV disease or risk factors) ORIGIN (NEJM 1) (Insulin glargine vs standard of care in pts with CV risk factors plus impaired fasting glucose, impaired glucose tolerance TDM) ACE (Lancet 17) (Acarbose vs placebo in Chinese pts with coronary heart disease and impaired glucose tolerance) Primary endpoint Development of diabetes CV death, nonfatal MI, nonfatal stroke, arterial revascularization, for heart failure, or for unstable angina CV death, nonfatal MI, nonfatal stroke, for heart failure CV death, nonfatal MI, nonfatal stroke CV death, nonfatal MI, nonfatal stroke, revascularization, for heart failure CV death, nonfatal MI, nonfatal stroke, for heart failure, or for unstable angina Hospitalization for heart failure (HHF) prespecified as a component of primary composite endpoint in trials of IGT and 1 trial of IGT/TDM! CVOTs in TDM: HF Outcome as Primary Endpoint 5 s (9 Completed), N=, since 13 SAVOR-TIMI 53 n = 16,49 EXAMINE n = 5,38 13 DPP-4 inhibitors SGLT inhibitors GLP-1 receptor agonists Insulin TZD α-glucosidase inhibitor EMPA-REG OUTCOME n = 7, ELIXA n = 6,68 TECOS n = 14,671 CARMELINA n = 8,3, renal composite REWIND n = 9,91 CAROLINA n = 6,115 15 16 17 18 19 LEADER n = 9,34 SUSTAIN-6 n = 3,97 CANVAS Program n = 1,14 DEVOTE n = 7,637 IRIS n = 3,876 Fatal or nonfatal stroke or MI FREEDOM-CVO n = 4, EXSCEL n = 14,75 ACE n = 6,56 5-P MACE ( + for HF or unstable angina) VERTIS CV n = 8, Dapa-HF n = 4,5 CV death, HF, HF urgent visit PIONEER 6 n = 3,176 HARMONY Outcomes n = 9,4 CREDENCE n = 4, ESRD, doubling of creatinine, renal/cv death DECLARE-TIMI 58 n = 17,15, CVD EMPEROR- Preserved n = 4,16 CV death or HF EMPEROR- Reduced n =,85 CV death or HF Dapa-CKD n = 4, 5% sustained decline in egfr or reaching ESRD or CV death or renal death Co-primary endpoint in DECLARE-TIMI 58: CV death or HHF

Patients with event (%) Patients with event (%) Death or heart failure re - rate Heart Failure Outcomes in Recent Diabetes CVOTs PEP Hosp. CV death MI Stroke (MACE) for HF (HHF) SAVOR 1 59 543 98 517 EXAMINE* 61 36 61 195 TECOS 169 6 561 36 457 ELIXA 85 314 531 17 49 LEADER 13 453 374 74 466 SUSTAIN-6 54 9 111 71 113 EXCSEL 1744 487 95 33 45 EMPA-REG 77 39 334 1 16 CANVAS Program 111 453 374 74 43 *post hoc HHF as common as other nonfatal MACE endpoints Heart Failure Outcomes in Recent Diabetes CVOTs Drug %, IR/1PY Hospitalization for Heart Failure (HHF) Control %, IR/1PY HR (95%CI) SAVOR 89 (3.5%) 8 (.8%) 1.7 (1-7-1.51) EXAMINE 16 (3.9%) 89 (3.3%) 1.19 (.89-1.58) TECOS 8 (1.7) 9 (1.9) 1. (.83-1.) ELIXA 17 (4.) 1 (4.).96 (.75 1.3) LEADER 18 (1.) 48 (1.4).87 (.73 1.5) SUSTAIN-6 59 (3.6) 54 (3.3) 1.11 (.77 1.61) EXCSEL 19 (3.%) 31 (3.1%).94 (.78 1.13) EMPA-REG 95 (.94) 1 (1.45).65 (.5.85) CANVAS Program 13 (.55) 1 (.87).67 (.5.87) risk of HHF with DPP4i, null outcomes with GLP-1 RA, risk with SGLT inhibitors Hospitalisation for Heart Failure in DPP4i CVOTs Updated FDA Label DPP4i (saxagliptin) DPP4i (alogliptin) DPP4i (sitagliptin) DPP4i (linagliptin) SAVOR-TIMI EXAMINE TECOS CAROLINA CARMELINA Impact on HHF compared with placebo HR 1.7; (95%CI 1.7-1.51) p=.7 HR 1.19; (95%CI.9-1.58) 4 p=. HR 1.; (95%CI.83-1.) 5 p=.98 Not completed FDA Label FDA guidance: May increase the risk of heart failure, particularly in patients who already have heart or kidney disease (4/5/16). 3 FDA guidance: May increase the risk of heart failure, particularly in patients who already have heart or kidney disease (4/5/16). 3 Consider the risks and benefits prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and renal impairment (8/1/17) Consider the risks and benefits prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and renal impairment (8/1/17) 1. Pfeffer M A et al., N Engl J Med 15;373:47;. Scirica BM et al. N Engl J Med 13;369:1317; 3. FDA Drug Safety Communication, Available at: http://www.fda.gov/drugs/drugsafety/ucm48696.htm (accessed April 16). 4. Zannad F et al. Lancet 15;385:67; 5. Green JB et al. N Engl J Med 15;373:3;.5.4.3..1. Incretins in Heart Failure: Phase s FIGHT (Phase, LV EF <4%, n=3) Liraglutide vs placebo HR=1.96 (95% CI:.9, 1.83; P=.14) Days post-randomization Margulies, KB et al, JAMA. 16;316:5-8. Liraglutide Placebo 3 6 9 1 15 18 LIVE - Phase, chronic HF, EF <45% with or without DM, n= 41, 4 wks - Excess adverse cardiac events with Liraglutide (1 v 3) VIVIDD - Phase, Class I-III HF, EF <4% with DM, n= 54, 4 wks - No difference in HF events - increased ventricular end-diastolic volume with vildagliptin Eur J Heart Fail. 17;19:69-77 (LIVE) JACC Heart Fail. 17 (VIVIDD). EMPA-REG OUTCOME: Empagliflozin Improved CV Outcomes in TDM Outcome Patients with event / analyzed Hazard ratio Empagliflozin Placebo 95% CI P value 3-point MACE 49/4687 8/333.86.74,.99*.38 CV death 17/4687 137/333.6.49,.77 <.1 Nonfatal MI 13/4687 11/333.87.7, 1.9.189 EMPA-REG OUTCOME: Empagliflozin Improved CV Outcomes in TDM 15 1 5 Death from any cause HR=.68 (95% CI:.57,.8) P<.1 Placebo Empagliflozin 7 6 5 4 3 1 Hospitalization for heart failure HR=.65 (95% CI:.5,.85) P=. Placebo Empagliflozin Nonfatal stroke 15/4687 6/333 1.4.9, 1.67.1638 Hospitalization for 16/4687 95/333.65.5,.85.17 heart failure.3.5 1.. 6 1 18 4 3 36 4 48 No. at risk Month Empagliflozin 4687 4651 468 4556 418 379 617 17 414 Placebo 333 33 8 43 1 153 181 85 177 6 1 18 4 3 36 4 48 No. at risk Month Empagliflozin 4687 4614 453 447 3988 95 487 1634 395 Placebo 333 71 6 173 193 144 1 775 168 Zinman B, et al. N Engl J Med 15;373:117 18 Zinman B, et al. N Engl J Med 15;373:117 18

Patients with an event (%) Patients with event/analysed (%) EMPA-REG OUTCOME: Reductions in HHF, CV death and All-cause Mortality Were Consistent in Patients with and without HF at Baseline 16 ESC Guidelines Recognise Empagliflozin for the Prevention or Delay of Heart Failure in TD Empagliflozin Placebo HR (95% CI) HR (95% CI) HHF or CV death All treatment All patients 65/4687 (5.7) 198/333 (8.5).66 (.55,.79) by subgroup HF at baseline interaction p>.4 1 No 19/45 (4.5) 149/89 (7.1).63 (.51,.78) Yes 75/46 (16.) 49/44 (.1).7 (.5, 1.4) HHF All patients 16/4687 (.7) 95/333 (4.1).65 (.5,.85) HF at baseline No 78/45 (1.8) 65/89 (3.1).59 (.43,.8) Yes 48/46 (1.4) 3/44 (1.3).75 (.48, 1.19) CV death All patients 17/4687 (3.7) 137/333 (5.9).6 (.49,.77) HF at baseline No 134/45 (3.) 11/89 (5.3).6 (.47,.77) Yes 38/46 (8.) 7/44 (11.1).71 (.43, 1.16) All-cause mortality All patients 69/4687 (5.7) 194/333 (8.3).68 (.57,.8) HF at baseline No 13/45 (5.) 159/89 (7.6).66 (.51,.81) Yes 56/46 (1.1) 35/44 (14.3).79 (.5, 1.).5.5 1 Favours empagliflozin Favours placebo Fitchett D et al. Eur Heart J 16;37:156 Empagliflozin should be considered in patients with Class Level TD in order to delay the onset of heart failure and IIa B prolong life Empagliflozin is not indicated for the treatment of heart failure Ponikowski P et al. Eur Heart J 16;37:19 Heart Failure Outcome in EMPA-REG OUTCOME Issues for Discussion Exploratory endpoint with no control for Type 1 error Endpoints redefined during trial Intensification of oral diuretic regimen used as a qualifying criteria Study not designed to explore effect on heart failure - Baseline prevalence (1%) likely under-reported - Functional class, EF, biomarkers not assessed - Concomitant medications and doses not well captured Heart failure outcome data not pivotal for label change or claim Hypothesis-generating that requires validation in future studies CANVAS Program Canagliflozin Improved CV Outcomes in TDM Patients with event/analysed Canagliflozin Placebo HR (95% CI) p-value 3P-MACE 585/5795 46/4347 CV death 68/5795 185/4347 Non-fatal MI 15/5795 159/4347 Non-fatal stroke 158/5795 116/4347 *P values not reported because all-cause mortality endpoint not met in the hierarchical test strategy.86 (.75,.97).87 (.7, 1.6).85 (.69, 1.5).9 (.71, 1.15).5 1.. Favours canagliflozin Neal B et al. N Engl J Med 17; doi:1.156/nejmoa161195 <.1 (non-inferiority). (superiority) Favours placebo NR* NR* NR* Superiority for 3P-MACE not prespecified in the testing hierarchy CANVAS Program Hospitalization for Heart Failure 8 Heart Failure Outcome in CANVAS Issues for Discussion 7 6 5 4 3 HR.67 (95% CI.5,.87) Placebo Canagliflozin Exploratory endpoint with no control for Type 1 error Study not designed to explore effect on heart failure - Baseline prevalence (14%) likely under-reported - Functional class, EF, biomarkers not assessed 1 - Concomitant medications and doses not well captured 6 5 78 14 13 156 18 8 34 6 86 31 338 Weeks since randomisation No. at risk Canagliflozin 5795 573 5653 5564 4437 359 643 61 57 54 498 451 178 49 Placebo 4347 467 4198 413 311 1667 174 156 136 11 118 1158 89 33 Intention-to-treat analysis. Exploratory outcome, no p-value is reported, only nominal effect estimate is given Neal B et al. N Engl J Med 17; doi:1.156/nejmoa161195 Heart failure outcome data not pivotal for label change or claim Hypothesis-generating that requires validation in future studies

Kosiborod M et al. Circulation. 17;doi.org/1.1161/CIRCULATIONAHA.117.919 SGLTi in Real World Practice: CVD-Real Registry Primary Outcomes Potential Mechanistic Links Between Glucose- Lowering Therapies and Heart Failure Risk Hospitalization for Heart Failure (HR.61) (Cana 53%, Dapa 4%, Empa 5%) All-cause Death (HR.49) (Cana 4%, Dapa 51%, Empa 7%) P hetero.169 P hetero.89 P<.1 P<.1 Inconsistent results for all-cause mortality, but not for heart failure between CANVAS and CVD-Real! Borrowed from Javed Butler, MD (Circulation 18, In Press) Potential CV & Renal Function Preservation Mechanisms of SGLTi that May Benefit Heart Failure Randomised Controlled s of SGLT Inhibitors in HF SGLT inhibition 1, Na+ removal Glucose removal Mechanism1 4 Possible cardio renal effects5,6 CV/renal outcomes observed in EMPA-REG OUTCOME 7,8 Osmotic diuresis Metabolism Sodium Cardiac function Arrhythmia Preload Afterload Cardiometabolic efficiency Arterial wall structure/function Renal function 1. Heise T et al. Diabetes Obes Metab 13;15:613;. Heise T et al. Clin Ther 16;38:65; 3. Ferrannini G et al. Diabetes Care 15;38:173; 4. Briand F et al. Diabetes 16;65:3; 5. Heerspink HJ et al. Circulation 16;134:75; 6. Inzucchi S et al. Diab Vasc Dis Res 15;1:9; 7. Zinman B et al. N Engl J Med 15;373:117; 8. Wanner C et al. N Engl J Med 16;375:33 CV death Hospitalisation for heart failure Renal events 1 EMPEROR-Preserved1 EMPEROR-Reduced Dapa-HF3 Sample size 416 85* 45 Key inclusion Patients with chronic HF Elevated NT-proBNP Symptomatic HFrEF Elevated NT-proBNP criteria egfr ml/min/1.73 m egfr 3 ml/min/1.73 m Primary endpoint Key secondary endpoints Start date: Expected completion date: HFpEF (LVEF >4%) HFrEF (LVEF 4%) HFrEF (LVEF 4%) Time to first occurrence of CV Time to first event of adjudicated CV death or adjudicated HHF death, HHF or urgent HF visit Individual components of primary endpoint All-cause mortality All-cause hospitalisation Time to first occurrence of sustained reduction of egfr Change from baseline in KCCQ March 17 June March 17 June Total number of HHF or CV death All-cause mortality Composite of 5% sustained egfr decline ESRD or renal death Change from baseline in KCCQ February 17 December 19 1. Clinicals.gov NCT357951;. Clinicals.gov NCT357977; 3. Clinicals.gov NCT33614 Diabetes and Heart Failure Take Home Points Heart failure is a complex disease, with various etiologies and poor prognosis many treatments are available for HFrEF, but few are available for HFpEF TDM is a major risk factor for heart failure, and the prevalence of both is increasing Outcomes of patients with heart failure are poor, and worse with TDM, so there is a critical need for novel management strategies to improve outcomes in this high-risk group SGLT inhibitors have been shown to improve cardiovascular outcomes in patients with TDM, regardless of glycemic response Mechanisms of cardiovascular protection with SGLT inhibitors are likely to include increased natriuresis, increased hematopoiesis, and a possible shift in heart fuel metabolism Large trials of cardiovascular outcomes with SGLT inhibitors, as well as dedicated trials in patients with heart failure and a number of mechanistic studies, are ongoing. These trials will provide further insight into the cardiovascular and renal protective signals seen with this class of drugs