New heart failure data for SGLT2 inhibitors Results of the EMPEROR Reduced Trial
Javed Butler, MD MPH MBA Professor and Chairman Department of Medicine University of Mississippi Disclosures
• Consultant - Adrenomed, Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmacautical, Innolife, Janssen, LinaNova, Luitpold, Medtronic, Merck, Novartis, Relypsa, Roche, Sanofi, Vifor Objectives
• Discuss heart failure epidemiology • Discuss mechanism of action of SGLT2i • Discuss the effects of SGLT2i in preventing heart failure • Discuss the effect of SGLT2i in the treatment of heart failure • Discuss future CV trials with SGLT2i
Outcomes for HF Compared With the General US Population
Median Survival Stratified by Age
20 18.7 Life Expectancy in US HFrEF HFbEF HFpEF 18
16 15.1
14 11.9 12
10 9.1
8
Median Survival in Years in Survival Median 6.8
6 5.0 4.0 4 3.6 3.3 3.4 2.9 2.8 2.6 2.6 2.3 2.2 1.7 1.8 2 1.2 1.3 1.5 0.8 1.0 0.9
0 65-69 70-74 75-79 80-84 85-89 ≥90 Age in Years Across various age groups, median survival is greater in the US population compared with patients with HF across the EF spectrum. Data from National Vital Statistics Report 2004. HFbEF=HF with borderline ejection fraction. Shah KS et al. J Am Coll Cardiol. 2017;70(20):2476-2486. 5 HF Predicts Higher Mortality in DM Patients
Population based study Patients with DM: N=151,738 100 Mortality Age >65 years DM without HF 3.7 /100 Pat-Y 75
50 surviving surviving (%) 25 DM + HF 32.7 /100 Pat-y 0 O 1 2 3 4 5 years
Bertoni et al, Diab Care 2004 Prevention and Treatment ! Despite control of known CV risk factors, patients with T2D remain at elevated risk of developing HF
Risk of event in patients with T2D and no risk factors out of target range compared to patients without diabetes • In this analysis the risk of hHF in patients with T2D HR (95% CI) (n=271,174) was compared to those without T2D (n=1,355,870) Death 1.06 (1.00, 1.12) • The following risk factors were either not present or MI 0.84 (0.75, 0.93) within guideline range: elevated HbA1c, systolic/diastolic BP, or LDL-C, or albuminuria or Stroke 0.95 (0.84, 1.07) tobacco use • A substantial risk for hHF remained among patients hHF 1.45 (1.34, 1.57) who had all the variables within target range
0 0.5 1 1.5 2
On average, the patients with T2D had a 45% increase in the risk of hHF, despite other major risk factors in guideline recommended range or absent
BP = blood pressure; CV = cardiovascular; HbA1c = glycated hemoglobin; HF = heart failure; hHF = hospitalization for heart failure; HR = hazard ratio; LDL-C = low density–lipoprotein cholesterol; MI = myocardial infarction; T2D = type 2 diabetes. Rawshani A et al. N Engl J Med. 2018;379:633-644. SGLT2i trial - a rethink on diabetes to CVD pathways
Lipids Traditional Glucose Accelerated MI, CVA, PAD focus BP Atherogenesis Thrombotic T2DM tendency
Insulin Na+ & glucose Obesity Renal SGLT2 retention Volume Status/ Glomerular Intravascular Heart Novel Hemodynamic hyperfiltration volume Failure Insights & Glomerular TGF increase Kidney stress other mechanisms? disease
Sattar N, McGuire D. Circulation 2018 Major CV outcome trials in type 2 diabetes
SAVOR- : DPP4i TIMI 53 (n = 16,492) : SGLT2i 1222 MACE3 : GLP1
EXAMINE CARMELINA TECOS (n = 5380) N = 8300 CAROLINA 621 MACE3 (n = 14,723) MACE4 N = 6041 1400 MACE4 MACE4
2012 2013 2014 2015 2016 2017 2018 2019
Ertugliflozin REWIND ELIXA LEADER CVOT EXSCEL (n = 9622) (n = 6000) (n = 3900) (n = 9341) (n = 14000) MACE3 805 MACE4 611 MACE3 MACE3 MACE3
CREDENCE DECLARE-TIMI (n = 3627) CANVAS-R 58 Cardiorenal SUSTAIN-6 (n = 5700) (n = 27,000) EMPA-REG OUTCOME (n = 3260) Alb.uria MACE3 N = 7034 MACE3 MACE3 CANVAS (n = 4339) MACE3
DPP-4 inhibitors on MACE and HF outcomes
MACEa hHF
HR (95% CI) HR (95% CI) P value HR (95% CI) HR (95% CI) P value
SAVOR-TIMI 531 1.00 (0.89, 1.12) 0.99 1.27 (1.07, 1.51) 0.007
EXAMINE2,3 0.96 (≤1.16)b 0.32 1.19 (0.90, 1.58) 0.22
TECOS4,c 0.99 (0.89, 1.10) 0.84 1.00 (0.83, 1.20) 0.98
CARMELINA5 1.02 (0.89, 1.17) 0.74 0.90 (0.74, 1.08) 0.26
0.5 1.0 2.0 0.5 1.0 2.0
Favors DPP-4 inhibitor Favors placebo Favors DPP-4 inhibitor Favors placebo
aComposite of CV death, nonfatal myocardial infarction, and nonfatal stroke for SAVOR-TIMI 53, EXAMINE, and CARMELINA, with the addition of hospitalization for unstable angina in TECOS; bParenthetical value is the upper boundary of one-sided repeated CI at an alpha level of 0.01; cMACE reported HR, 95% CI, and P-value were for the secondary composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. CI = confidence interval; CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; hHF = hospitalization for heart failure; HR = hazard ratio; MACE = major adverse cardiovascular events; T2D = Type 2 diabetes. 1. Scirica B, et al. N Engl J Med. 2013;369:1317–1326; 2. White W, et al. N Engl J Med. 2013;369:1327−1335; 3. Zannad P, et al. Lancet. 2015;385:2067–2076; 4. Green JB, et al. N Engl J Med. 2015;373:232–242; 5. Rosenstock J et al. JAMA. 2019;321:69-79. 12 EMPA-REG OUTCOME: Population with Established Cardiovascular Disease
Zinman B et al. N Engl M Med. 2015;373: 2117-28. EMPA-REG OUTCOME
Zinman B et al. N Engl M Med. 2015;373: 2117-28. 3 questions
• Luck – Replication • Prevention or Treatment – If treatment – HFrEF or HFpEF • Mechanism of action HHF outcomes in SGLT2 inhibitor CV outcomes trials
EMPA-REG OUTCOME1 CANVAS Program2 7 8 HR, 0.65 HR, 0.67 6 7 (95% CI, 0.50, 0.85) (95% CI, 0.52, 0.87) 5 6 5 4 4 3 3 2 2 Placebo Placebo Patients with event (%) event with Patients Patients with event (%) event with Patients 1 Empagliflozin 1 Canagliflozin 0 0 0 6 12 18 24 30 36 42 48 0 26 52 104 156 208 260 312 338 Month Week 4 DECLARE-TIMI 583 5 VERTIS CV
HR, 0.73 4 HR, 0.70 3 (95% CI, 0.61, 0.88) (95% CI, 0.54, 0.90) 3 2 2 1
Placebo (%) event with Patients 1 Patients with event (%) event with Patients Placebo Dapagliflozin Ertugliflozin 0 0 0 6 12 24 36 48 60 0 180 360 540 720 900 1080 1260 1440 Day Month CI, confidence interval; CV, cardiovascular; HHF, hospitalization for heart failure; HR, hazard ratio; SLGT2, sodium-glucose cotransporter 2. 1. Zinman B et al. N Engl J Med 2015;373:2117-2128; 2. Neal B et al. N Engl J Med 2017;377:644-657; 3. Wiviott SD et al. N Engl J Med 2019;380:347-357 (figure provided by D.K. McGuire, with permission).
16 HHF by Prior HF (approx. 90% without HF)
Events per 1000 patient years Hazard Ratio (95% CI) SGLT2i Placebo History of HF EMPA-REG 40.7 52.4 0.75 (0.48–1.19) OUTCOME CANVAS Program 14.1 28.1 0.51 (0.33–0.78) DECLARE-TIMI 58 27.7 37.2 0.73 (0.55–0.96) Fixed effects model for history of HF (P=0.0002) 0.68 (0.55–0.83) Heterogeneity Q=2.14, P=0.34; I2=6.6%
No History of HF EMPA-REG 6.4 10.8 0.59 (0.43-0.82) OUTCOME CANVAS Program 4.3 5.7 0.79 (0.57–1.09) DECLARE-TIMI 58 4.0 5.6 0.73 (0.58–0.92) Fixed effects model for no history of HF (P<0.0001) 0.25 0.5 1 0.712 (0.60–0.83) Heterogeneity Q=1.73, P=0.42; I2=0.0% Favors Favors Data are not from head-to-head trials and should not be directly compared study drug placebo
Adapted from Zelniker TA et al. Lancet. 2019;393:31-39. Time to first renal composite outcome
RENAL COMPOSITE*
*Renal composite outcome definitions varied across trials. 18CI, confidence interval. SGLT2 Inhibition Improves Hemodynamic Parameters in Patients With T2D, Leading to Cardiorenal Protection
HEART2
↓Cardiac preload/afterload ↓Cardiac wall stress ↑Cardiac efficiency/output
CIRCULATION1,2 CARDIORENAL PROTECTION2,3
↓Plasma volume ↑Cardiac function ↓Arterial stiffness SGLT2 INHIBITION ↑Renal function ↓Systolic blood pressure ↑Hematocrit
↓Glucose/sodium reabsorption1 IMPROVED CLINICAL 3,5 ↓Intraglomerular pressure2 OUTCOMES 2 Glycosuria ↓Intrarenal RAAS activity4 3 ↓CV outcomes Diuresis 2 2,3 ↓Hyperfiltration ↓HF hospitalization Natriuresis 3 ↓Inflammation/hypoxia Stabilization of eGFR KIDNEY ↓Albuminuria
1. Sattar N et al. Diabetologia. 2016;59(7):1333-1339; 2. Verma S et al. JAMA Cardiol. 2017;2(9)939-940; 3. Scheen AJ. Circ Res. 2018;122(10):1439-1459; 4. Shin SJ et al. PLoS One. 2016;11(11):e0165703; 5. Tamargo J. Eur Cardiol. 2019;14(1):23-32. 19 Assessing Dapagliflozin in Patients With Chronic HFrEF With or Without T2D1-4
4744 patients Dapagliflozin 10 mg • ≥18 years of age • With or without T2D + standard of care
• Diagnosis of symptomatic HFrEF blind - (NYHA class II-IV) for ≥ 2 months 1:1 • LVEF ≤40% within last 12 months • Elevated NT-proBNP Double Placebo • eGFR ≥30 mL/min/1.73 m2 + standard of care • Stable SoC HFrEF treatment
Visit 1 (enrollment) Visit 2 (randomization) Visit 3 Visit 4 Visit 5 Visit 6, etc. Target primary endpoint events: 8441 Day -14 Day 0 Day 14 Day 60 Day 120 Every 120 days Median follow-up: 18.2 months2 Completion: July 20193
Primary Endpoint Secondary Endpoints • Time to first occurrence of any of the components of • Time to first occurrence of either of the components of the composite: CV death or hHF the composite: CV death or hHF or an urgent HF visit • Total number of (first and recurrent) hHF and CV deaths • Change from baseline measured at 8 months in the total symptom score of the KCCQ • Time to first occurrence of any of the components of the composite: ≥50% sustained decline in eGFR or reaching ESRD or renal death • Time to death from any cause
ESRD=end-stage renal disease; LVEF=left ventricular ejection fraction; SoC=standard of care. 1. McMurray JJV et al. Article and supplementary appendix. Eur J Heart Fail. 2019;21(5):665-675; 2. McMurray JJV et al. N Engl J Med. 2019;381(21):1995-2008; 3. ClinicalTrials.gov website. Identifier NCT03036124; 4. McMurray JJV et al. Eur J Heart Fail. 2019;21(11):1402-1411. 20 Primary Endpoint: CV Death or hHF or an Urgent HF Visit1,2 36 26% RRR 32 HR 0.74 (0.65, 0.85) P=0.00001 28 NNT = 21 Placebo 24
20
16 DAPA 12
8 Cumulative Incidence (%) Incidence Cumulative
4
0 0 3 6 9 12 15 18 21 24 Months From Randomization No. at Risk DAPA 2373 2305 2221 2147 2002 1560 1146 612 210 Placebo 2371 2258 2163 2075 1917 1478 1096 593 210
NNT=number needed to treat; RRR=relative risk reduction. 1. McMurray JJV et al. N Engl J Med. 2019;381(21)1995-2008; 2. McMurray J. Presented at: European Society of Cardiology Congress; September 1, 2019; Paris, France. 21 EMPEROR-Reduced Phase III randomised double-blind placebo-controlled trial
Aim: To investigate the safety and efficacy of empagliflozin versus placebo on top of guideline- directed medical therapy in patients with heart failure with reduced ejection fraction Population: T2D and non-T2D, aged ≥18 years, chronic HF (NYHA class II–IV)
Study design1-3 Confirmatory endpoints1,2
COMPOSITE PRIMARY ENDPOINT Empagliflozin 10 mg qd + SOC* Time to first event of adjudicated CV death or adjudicated HHF EMPEROR-Reduced LVEF ≤40% SECONDARY ENDPOINTS Placebo qd + SOC* 3730 patients • First and recurrent adjudicated HHF events Median follow-up = 16 months • Slope of change in eGFR (CKD-EPI) from (event-driven) baseline
*Guideline-directed medical therapy CV, cardiovascular; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; HF, heart failure; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; qd, once daily; SOC, standard of care; T2D, type 2 diabetes 1. ClinicalTrials.gov. NCT03057977 (accessed Aug 2020); 2. Packer M et al. Eur J Heart Fail 2019;21:1270; 3. Date on file Trial inclusion and exclusion criteria
Inclusion criteria EMPEROR-Reduced1,2 DAPA-HF3 Age ≥18 years (Japan, age ≥20 years) at screening Age ≥18 years Chronic HF NYHA class II−IV Chronic HF NYHA class II−IV HFrEF (LVEF ≤40%) HFrEF (LVEF ≤40%) Elevated NT-proBNP EF (%) NT-proBNP (pg/ml) Patients without AF* NT-proBNP ≥600 pg/ml or NT-proBNP ≥400 pg/ml in ≥36 to ≤40 ≥2500 patients with HHF within 12 months ≥31 to ≤35 ≥1000 Patients without AF† ≤30 ≥600 ≤40% + HHF within 12 months ≥600 Further inclusion criteria apply Further inclusion criteria apply EMPEROR-Reduced DAPA-HF eGFR <20 ml/min/1.73 m2 eGFR <30 ml/min/1.73 m2 or requiring dialysis or rapidly declining renal function
*The cut off for patients with AF is doubled in EMPEROR-Reduced. †In DAPA-HF patients with AF or atrial flutter were required to have NT-proBNP ≥900 pg/ml regardless of history of HHF See slides notes for abbreviations 1. ClinicalTrials.gov. NCT03057977 (accessed Aug 2020); 2. Zannad F et al. ESC-HF 2018; poster P1755; 3. McMurray JJV et al. N Engl J Med. 2019;381(21):1995–2008 Disposition: Overview
7220 patients screened for eligibility Not randomized Not eligible (3314) Withdrawal of consent (80) Adverse event (21) Lost to follow-up (19) Other reasons (56) 3730 were randomized
1863 assigned 1867 assigned to empagliflozin to placebo Median follow-up 16 months Drug discontinued Drug discontinued Non-fatal AE (158) Non-fatal AE (167) Request by patient (92) Request by patient (124) Final vital status Other reasons (53) Other reasons (44) known in 99.4%
Final vital status known in 1852 Final vital status known in 1857 Final vital status unknown in 11 Final vital status unknown in 10 Baseline Characteristics in EMPEROR-Reduced and DAPA-HF
EMPEROR-Reduced DAPA-HF
Empagliflozin Placebo Dapagliflozin Placebo Number of participants 1863 1867 2373 2371 Mean±SD age, years 67.2±10.8 66.5±11.2 66.2 ± 11.0 66.5 ± 10.8 Females 437 (23.5%) 456 (24.4%) 564 (23.8%) 545 (23.0%) NYHA II 1399 (75.1%) 1401 (75.0%) 1606 (67.7%) 1597 (67.4%) NYHA III 455 (24.4%) 455 (24.4%) 747 (31.5%) 751 (31.7%) NYHA IV 9 (0.5%) 11 (0.6%) 20 (0.8%) 23 (1.0%) LVEF (%), mean ± SD 27.7 ± 6.0 27.2 ± 6.1 31.2±6.7 30.9±6.9 1887.0 1926.0 1428 1446 NT-proBNP, pg/ml, median (IQR) (1077.0−3429.0) (1153.0−3525.0) (857-2655) (857-2641) Hosp HF < 12 months 577 (31.0%) 574 (30.7%) 27.3% Diabetes 927 (49.8%) 929 (49.8%) 1075 (45.3%) 1064 (44.9%) eGFR, ml/min/1.73 m2 (CKD-EPI) 61.8±21.7 62.2 ±21.5 66.0 ± 19.6 65.5 ± 19.3 Heart failure medications /devices ACE inhibitor 867 (46.5%) 836 (44.8%) 1332 (56.1%) 1329 (56.1%) ARB 451 (24.2%) 457 (24.5%) 675 (28.4%) 632 (26.7%) MRA 1306 (70.1%) 1355 (72.6%) 1696 (71.5%) 1674 (70.6%) ARNI 340 (18.3%) 387 (20.7%) 250 (10.5%) 258 (10.9%) ICD or CRT-D 578 (31%) 593 (31.8%) 622 (26.2%) 620 (26.1%) CRT-D or CRT-P 220 (11.8%) 222 (11.9%) 190 (8.0%) 164 (6.9%) EMPEROR-Reduced Trial Had Only 3 Endpoints in the Hierarchical Testing Procedure
EMPEROR-Preserved EMPEROR-Reduced
Time to 1st event of Time to 1st event of Primary endpoint CV death or HHF CV death or HHF
αp_final α=0.0496
Recurrent HHF Secondary endpoints Total (first and recurrent HF α hospitalizations p2 = α p_final α=0.0010 - α α=0.0010 p1 0.0486 eGFR Slope α= eGFR Slope
Meta-analyses α=0.0010 α=0.0010 Primary endpoint: First adjudicated CV death or hospitalisation for heart failure
40
RRR ARR NNT = 19 (%) 30 25% 5.2 Placebo cumulative function 20
Empagliflozin HR 0.75 10 (95% CI 0.65, 0.86) Estimated
incidence p<0.001
0
0 90 180 270 360 450 540 630 720 810 Empagliflozin: 361 patients with event Days after randomisation Rate: 15.8/100 patient-years Patients at risk Placebo 1867 1715 1612 1345 1108 854 611 410 224 109 Placebo: Empagliflozin 1863 1763 1677 1424 1172 909 645 423 231 101 462 patients with event Rate: 21.0/100 patient-years
ARR, absolute risk reduction; Cox regression model including covariates age, baseline eGFR, geographic region, baseline diabetes status, sex, LVEF and treatment CV, cardiovascular; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; RRR, relative risk reduction Data on file Primary endpoint Empagliflozin 10 mg Placebo Subgroups n with event/N analysed HR (95% CI) HR (95% CI) Overall 361/1863 462/1867 0.75 (0.65, 0.86) Baseline diabetes status Diabetic 200/927 265/929 0.72 (0.60, 0.87) Non-diabetic 161/936 197/938 0.78 (0.64, 0.97) Age, years <65 128/675 193/740 0.71 (0.57, 0.89) ≥65 233/1188 269/1127 0.78 (0.66, 0.93) Sex Male 294/1426 353/1411 0.80 (0.68, 0.93) Female 67/437 109/456 0.59 (0.44, 0.80) Race White 264/1325 289/1304 0.88 (0.75, 1.04) Black/African-American 24/123 48/134 0.46 (0.28, 0.75) Asian 62/337 99/335 0.57 (0.41, 0.78) Other 5/51 14/63 0.41 (0.15, 1.14) Baseline BMI <30 226/1263 322/1300 0.70 (0.59, 0.83) ≥30 135/600 140/567 0.85 (0.67, 1.08) Baseline eGFR (CKD-EPI), ml/min/1.73 m2 ≥60 159/969 224/960 0.67 (0.55, 0.83) <60 202/893 237/906 0.83 (0.69, 1.00)
0.25 0.5 1 2 28 BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate. Favours empagliflozin Favours placebo Subgroups: Primary endpoint Empagliflozin 10 mg Placebo n with event/N analysed HR (95% CI) HR (95% CI) Overall 361/1863 462/1867 0.75 (0.65, 0.86) History of HF (in last 12 months) No 208/1286 285/1293 0.71 (0.60, 0.85) Yes 153/577 177/574 0.79 (0.64, 0.99) Cause of HF Ischaemic 207/983 236/946 0.82 (0.68, 0.99) Non-ischaemic 154/880 226/921 0.67 (0.55, 0.82) Baseline NYHA class II 220/1399 299/1401 0.71 (0.59, 0.84) III/IV 141/464 163/466 0.83 (0.66, 1.04) HF physiology LVEF ≤30% and NTproBNP
ARNI, angiotensin receptor-neprilysin inhibitor; HF, heart failure; LVEF, left ventricular ejection fraction; 0.25 0.5 1 2 29 MRA, mineralocorticoid receptor antagonists; NTproBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association. Favours empagliflozin Favours placebo Key secondary: Adjudicated total hospitalisations for heart failure (first and recurrent)
0.60
patient 0.50 RRR per 0.40 Placebo 30%
0.30 events of 0.20 HR 0.70 Empagliflozin (95% CI 0.58, 0.85) p<0.001 number 0.10
0.00 Mean 0 90 180 270 360 450 540 630 720 810 900 Emagliflozin: 388 events Days after randomisation Placebo: 553 events Patients at risk Placebo 1867 1820 1762 1526 1285 1017 732 497 275 135 Empagliflozin 1863 1826 1768 1532 1283 1008 732 495 272 118
Analysis of first and recurrent HHF accounting for CV death as terminal event using a joint frailty model. Model includes covariates age, baseline eGFR, treatment, region, baseline diabetes status, sex, and baseline LVEF, estimated dependence between adjudicated HHF and adjudicated CV death, and variance of frailty. CV, cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction Data on file EMPEROR-Reduced: Total Emergency Department and Urgent Care Visits for Heart Failure Requiring IV Therapy
0.25 261 events
0.20 184 events Placebo 0.15
0.10
Empagliflozin HR 0.63 0.05 (95% CI 0.49, 0.81)
Mean Mean number of events per patient P = 0.0004
0.00
0 90 180 270 360 450 540 630 720
Days After Randomization Change in eGFR (CKD-EPI) from baseline (MMRM)
During double-blind treatment Withdrawal after end of study 0 Empagliflozin
-2 P < 0.001 Empagliflozin Placebo -4
-6 Difference off treatment Placebo 2
in eGFR (mL/min/1.73m²) eGFR in of 3.3 ml/min/1.73m -8 (95% CI: 1.8 – 4.8) Mean change from baseline (SE) from change Mean
-10 Weeks after randomization Baseline Last value on Off treatment for double-blind 23-45 days Number of patients treatment Placebo32 1792 1765 1683 1500 1146 745 343 76 479 479 Empagliflozin 1799 1782 1720 1554 1166 753 356 80 487 487 Key secondary endpoint: eGFR slope
eGFR (CKD−EPI)cr [mL/min/1.73m²] change from baseline slope from random intercept random coefficient model)
0 Early difference due to the well-known -1
] initial drop with Empa 2
-2 Empa: Yearly decline of eGFR Slope = rate of decline 2 baseline -0.5 ml/min/1.73m per year -3 /min/1.73m
from eGFR slope is a measure for
mL -4 long-term renal function Placebo: Yearly decline of -5 2 change eGFR[ -2.3 ml/min/1.73m per year + 1.73 ml/min/1.73m2 per year -6 (95% CI: 1.1 – 2.4) Placebo Slope P < 0.0001 Em pa Slope -7 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Weeks 1-year 2-year 3-year
For the key secondary endpoint, the intercept and slope is estimated with random intercept random slope model. The key secondary endpoint is the estimated population average of individual patient’s slopes.
33 Composite renal endpoint (end-stage kidney disease and sustained profound decrease in eGFR)
6 (%)
RRR ARR 4 Placebo cumulative
function 50% 1.5
2 Estimated
incidence Empagliflozin HR 0.50 (95% CI 0.32, 0.77) 0
0 90 180 270 360 450 540 630 720 810 Days after randomisation Empagliflozin: Patients at risk 30 patients with event Placebo 1867 1592 1501 1136 1058 681 357 259 Rate: 1.6/100 patient-years Empagliflozin 1863 1599 1532 1155 1062 687 391 276 Placebo: 58 patients with event Composite renal endpoint is defined as chronic dialysis, renal transplant, sustained reduction of ≥40% eGFR or sustained eGFR <15 ml/min/1.73 m2 for patients with eGFR ≥30 ml/min/1.73 m2 at baseline (<10 ml/min/1.73 m2 for patients with eGFR Rate: 3.1/100 patient-years <30 ml/min/1.73 m2 at baseline). Dialysis is regarded as chronic if the frequency of dialysis is twice or more per week for at least 90 days. Cox regression model including covariates age, baseline eGFR (CKD-EPI), region, baseline diabetes status, sex, and baseline LVEF CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PY, patient years. Data on file SGLT2 Inhibition With Empagliflozin Is Effective in Heart Failure With a Reduced Ejection Fraction With or Without Diabetes
Primary Endpoint 25% in risk Composite of cardiovascular death P < 0.001 or heart failure hospitalization
First Secondary Endpoint 30% in risk Total (first and recurrent P < 0.001 heart failure hospitalizations)
The Second Secondary Endpoint P < 0.001 picture can't be Slope of decline in glomerular displaye (50% in renal d. filtration rate over time events) EMPEROR-Reduced: Effect on individual components of the primary endpoint
Empagliflozin Placebo Hazard ratio p-value (n=1863) (n=1867) (95% CI)
Number of Events/100 Number of Events/100 events (%) patient-yr events (%) patient-yr
Primary composite 0.75 361 (19.4) 15.8 462 (24.7) 21.0 <0.001 outcome (0.65, 0.86) First hospitalisation 0.69 246 (13.2) 10.7 342 (18.3) 15.5 for heart failure (0.59, 0.81) Cardiovascular 0.92 187 (10.0) 7.6 202 (10.8) 8.1 death (0.75, 1.12)
yr, year 1. Data on file Cardiovascular death
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
EMPEROR-Reduced 187/1863 (10.0) 202/1867 (10.8) 0.92 (0.75, 1.12)
DAPA-HF 227/2373 (9.6) 273/2371 (11.5) 0.82 (0.69, 0.98)
Total 0.86 (0.76, 0.98)
Test for overall treatment effect, p=0.027 Test for heterogeneity of effect, p=0.40
0.50 0.75 1.00 1.25
Favours SGLT2 Favours inhibitor placebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
37 All-cause mortality
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
EMPEROR-Reduced 249/1863 (13.4) 266/1867 (14.2) 0.92 (0.77, 1.10)
DAPA-HF 276/2373 (11.6) 329/2371 (13.9) 0.83 (0.71, 0.97)
Total 0.87 (0.77, 0.98)
Test for overall treatment effect, p=0.018 Test for heterogeneity of effect, p=0.39
0.50 0.75 1.00 1.25
Favours SGLT2 Favours inhibitor placebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
38 Meta-analysis of DAPA-HF and EMPEROR-Reduced
CV death Trial SGLT2i, n/N (%) Placebo, n/N (%) HR (95% CI) HR (95% CI) EMPEROR-Reduced 187/1863 (10.0) 202/1867 (10.8) 0.92 (0.75, 1.12) DAPA-HF 227/2373 (9.6) 273/2371 (11.5) 0.82 (0.69, 0.98) Total 0.86 (0.76, 0.98)
Test for overall treatment effect, p=0.027 0 0.5 1 1.5 Test for heterogeneity of effect, p=0.40 Favours drug Favours placebo
All-cause death Trial SGLT2i, n/N (%) Placebo, n/N (%) HR (95% CI) HR (95% CI) EMPEROR-Reduced 249/1863 (13.4) 266/1867 (14.2) 0.92 (0.77, 1.10) DAPA-HF 276/2373 (11.6) 329/2371 (13.9) 0.83 (0.71, 0.97) Total 0.87 (0.77, 0.98)
Test for overall treatment effect, p=0.018 Test for heterogeneity of effect, p=0.39 0 0.5 1 1.5
HF, heart failure; SGLT2i, sodium-glucose co-transporter-2 inhibitor Favours drug Favours placebo Data on file Quality of life: KCCQ-CSS at 52 weeks
7 On treatment* 6
5 Empagliflozin
4 Adjusted mean (95% CI) change from baseline at Week 52 3 Empagliflozin: 5.83 (4.96, 6.70) Placebo, 4.09 (3.20, 4.97)
Adjusted mean (SE) mean Adjusted 2 Comparison vs placebo 1 Adjusted mean ratio 1.75 (95% CI 0.51, 2.99), p=0.0058
0 -8 0 2 12 22 32 42 52 Planned study week N with data at visit Placebo 1701 1688 1505 1151 EMPA 10 mg 1734 1720 1561 1176 All models include covariates age, baseline eGFR, region, baseline diabetes status, sex and baseline LVEF *No imputation for death CV, cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalisation for heart failure, KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire clinical summary score; LVEF, left ventricular ejection fraction 1. Data on file MMRM results of KCCQ-CSS
Empagliflozin 10 mg Placebo Adjusted mean Adjusted mean difference p-value difference N analysed KCCQ clinical summary score 1734 1701 1.75 (0.51, 2.99) 0.0058 CSS
KCCQ total symptom score 1734 1701 1.76 (0.45, 3.06) 0.0083 TSS
KCCQ overall summary score 1734 1701 1.55 (0.31, 2.79) 0.0143 OSS
-2 -1 0 1 2 3 4 5
Favours placebo Favours empagliflozin Forest plot of KCCQ individual domains change from baseline at Week 52 – TS (OC-OT). Changes in vital signs and laboratory findings
Treatment Empagliflozin Placebo Difference
Glycated hemoglobin (%) in patients – 0.16 – 0.28 ± 0.03 – 0.12 ± 0.03 with diabetes– mean (SE) (–0.25 to – 0.08)
2.36 Hematocrit (%) – mean (SE) 1.98 ± 0.10 – 0.38 ± 0.10 (2.08 to 2.63)
NT-proBNP (pg/ml) – –244 –141 0.87 median (IQR) (-890, 260) (-784, 585) (0.82 to 0.93)
– 0.82 Body weight (kg) – mean (SE) – 0.73 ± 0.13 0.08 ± 0.13 (–1.18 to –0.45)
Systolic blood pressure (mm Hg) – – 0.7 – 2.4 ± 0.4 – 1.7 ± 0.4 mean (SE) (–1.8 to 0.4) Serious adverse events and prespecified adverse events of interest
Empagliflozin (n=1863) – N (%) Placebo (n=1863) – N (%) Patients with any AEs 1420 (76.2) 1463 (78.5) Serious AEs 772 (41.4) 896 (48.1) Serious AEs of special interest Volume depletion 197 (10.6) 184 (9.9) Hypotension 176 (9.4) 163 (8.7) Symptomatic hypotension 106 (5.7) 103 (5.5) Ketoacidosis 0 (0.0) 0 (0.0) Confirmed hypoglycaemic events‡ 27 (1.4) 28 (1.5) In patients with type 2 diabetes 20 (2.2) 22 (2.4) In patients without type 2 diabetes 7 (0.7) 6 (0.6) Urinary tract infections 91 (4.9) 83 (4.5) Complicated urinary tract infections 19 (1.0) 15 (0.8) Genital tract infections 31 (1.7) 12 (0.6) Complicated genital tract infections 6 (0.3) 5 (0.3) Bone fractures 45 (2.4) 42 (2.3) Events leading to lower limb amputation 13 (0.7) 10 (0.5)
Shown are adverse events up to 7 days following discontinuation of study medication, but lower limb amputations were shown up to the end of the trial ‡Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required treatment Meta-analysis of DAPA-HF and EMPEROR-Reduced First hospitalisation for HF or CV death - subgroup
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
NYHA class: II
EMPEROR-Reduced 220/1399 (15.7) 299/1401 (21.3) 0.71 (0.59, 0.84)
DAPA-HF 190/1606 (11.8) 289/1597 (18.1) 0.63 (0.52, 0.75)
Subtotal 0.67 (0.59, 0.76)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.36
NYHA class: III–IV
EMPEROR-Reduced 141/464 (30.4) 163/466 (35.0) 0.83 (0.66, 1.04)
DAPA-HF 196/767 (25.6) 213/774 (27.5) 0.90 (0.74, 1.09)
Subtotal 0.87 (0.75, 1.01)
Test for overall treatment effect, p=0.0638 Test for heterogeneity of effect, p=0.60
Test for treatment by subgroup interaction, p=0.0087 0.50 0.75 1.00 1.25
Favours SGLT2 Favours 44 inhibitor placebo Meta-analysis of DAPA-HF and EMPEROR-Reduced First hospitalisation for HF or CV death - subgroup
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
eGFR: <60 ml
EMPEROR-Reduced 202/893 (22.6) 237/906 (26.2) 0.83 (0.69, 1.00)
DAPA-HF 191/962 (19.9) 254/964 (26.3) 0.72 (0.59, 0.86)
Subtotal 0.77 (0.68, 0.88)
Test for overall treatment effect, p=0.0001 Test for heterogeneity of effect, p=0.29
eGFR: ≥60 ml
EMPEROR-Reduced 159/969 (16.4) 224/960 (23.3) 0.67 (0.55, 0.83)
DAPA-HF 195/1410 (13.8) 248/1406 (17.6) 0.76 (0.63, 0.92)
Subtotal 0.72 (0.62, 0.82)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.38
Test for treatment by subgroup interaction, p=0.44 0.50 0.75 1.00 1.25
Favours SGLT2 Favours 45 inhibitor placebo Diabetes status
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
With diabetes
EMPEROR-Reduced 200/927 (21.6) 265/929 (28.5) 0.72 (0.60, 0.87)
DAPA-HF 215/1075 (20.0) 271/1064 (25.5) 0.75 (0.63, 0.90)
Subtotal 0.74 (0.65, 0.84)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.76
Without diabetes
EMPEROR-Reduced 161/936 (17.2) 197/938 (21.0) 0.78 (0.64, 0.97)
DAPA-HF 171/1298 (13.2) 231/1307 (17.7) 0.73 (0.60, 0.88)
Subtotal 0.75 (0.65, 0.87)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.65
Test for treatment by subgroup interaction, p=0.81 0.50 0.75 1.00 1.25 Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9. Favours SGLT2 Favours 46 inhibitor placebo Use of ARNi
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
Receiving ARNI
EMPEROR-Reduced 51/340 (15.0) 93/387 (24.0) 0.64 (0.45, 0.89)
DAPA-HF 41/250 (16.4) 56/258 (21.7) 0.75 (0.50, 1.13)
Subtotal 0.68 (0.53, 0.89)
Test for overall treatment effect, p=0.0043 Test for heterogeneity of effect, p=0.56
Not receiving ARNI
EMPEROR-Reduced 310/1523 (20.4) 369/1480 (24.9) 0.77 (0.66, 0.90)
DAPA-HF 345/2123 (16.3) 446/2113 (21.1) 0.74 (0.65, 0.86)
Subtotal 0.75 (0.68, 0.84)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.71
Test for treatment by subgroup interaction, p=0.50 0.25 0.50 0.75 1.00 1.25 Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9. Favours SGLT2 Favours 47 inhibitor placebo Meta-analysis of DAPA-HF and EMPEROR-Reduced First kidney composite*
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
EMPEROR-Reduced 18/1863 (1.0) 33/1867 (1.8) 0.52 (0.29, 0.92)
DAPA-HF 28/2373 (1.2) 39/2371 (1.6) 0.71 (0.44, 1.16)
Total 0.62 (0.43, 0.90)
Test for overall treatment effect, p=0.0128 Test for heterogeneity of effect, p=0.42
0.25 0.50 0.75 1.00 1.25
Favours SGLT2 Favours inhibitor placebo
48 Age (≤65 and >65 years)
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
Age ≤65 years
EMPEROR-Reduced 128/675 (19.0) 193/740 (26.1) 0.71 (0.57, 0.89)
DAPA-HF 162/1032 (15.7) 196/998 (19.6) 0.78 (0.63, 0.96)
Subtotal 0.75 (0.64, 0.87)
Test for overall treatment effect, p=0.0002 Test for heterogeneity of effect, p=0.55
Age >65 years
EMPEROR-Reduced 233/1188 (19.6) 269/1127 (23.9) 0.78 (0.66, 0.93)
DAPA-HF 224/1341 (16.7) 306/1373 (22.3) 0.72 (0.60, 0.85)
Subtotal 0.75 (0.66, 0.85)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.52
Test for treatment by subgroup interaction, p=0.96 0.50 0.75 1.00 1.25 Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9. Favours SGLT2 Favours 49 inhibitor placebo Race
SGLT2 inhibitor Placebo n with event/N analysed (%) HR (95% CI) White
EMPEROR-Reduced 264/1325 (19.9) 289/1304 (22.2) 0.88 (0.75, 1.04) DAPA-HF 275/1662 (16.5) 348/1671 (20.8) 0.78 (0.66, 0.91)
Subtotal 0.83 (0.74, 0.93)
Test for overall treatment effect, p=0.0012 Test for heterogeneity of effect, p=0.30
Black
EMPEROR-Reduced 24/123 (19.5) 48/134 (35.8) 0.46 (0.28, 0.75) DAPA-HF 26/122 (21.3) 32/104 (30.8) 0.62 (0.37, 1.04) Subtotal 0.53 (0.37, 0.76)
Test for overall treatment effect, p=0.0005 Test for heterogeneity of effect, p=0.41
Asian EMPEROR-Reduced 62/337 (18.4) 99/335 (29.6) 0.57 (0.41, 0.78)
DAPA-HF 78/552 (14.1) 118/564 (20.9) 0.64 (0.48, 0.86)
Subtotal 0.61 (0.49, 0.75)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.60
Test for treatment by subgroup interaction, p=0.0063 0.25 0.50 0.75 1.00 1.25 Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9. Favours SGLT2 Favours 50 inhibitor placebo Region
SGLT2 inhibitor Placebo n with event/N analysed (%) HR (95% CI) North America EMPEROR-Reduced 48/212 (22.6) 64/213 (30.0) 0.69 (0.48, 1.01) DAPA-HF 54/335 (16.1) 73/342 (21.3) 0.73 (0.51, 1.03) Subtotal 0.71 (0.55, 0.92) Test for overall treatment effect, p=0.0088 Test for heterogeneity of effect, p=0.83 Latin America EMPEROR-Reduced 115/641 (17.9) 151/645 (23.4) 0.73 (0.58, 0.94) DAPA-HF 62/401 (15.5) 97/416 (23.3) 0.64 (0.47, 0.88) Subtotal 0.70 (0.57, 0.84) Test for overall treatment effect, p=0.0002 Test for heterogeneity of effect, p=0.51 Europe EMPEROR-Reduced 140/676 (20.7) 149/677 (22.0) 0.94 (0.74, 1.18) DAPA-HF 193/1094 (17.6) 218/1060 (20.6) 0.84 (0.69, 1.01) Subtotal 0.88 (0.76, 1.02) Test for overall treatment effect, p=0.0858 Test for heterogeneity of effect, p=0.46 Asia EMPEROR-Reduced 49/248 (19.8) 80/245 (32.7) 0.55 (0.38, 0.78) DAPA-HF 77/543 (14.2) 114/553 (20.6) 0.65 (0.49, 0.87) Subtotal 0.61 (0.49, 0.76) Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.48
Test for treatment by subgroup interaction, p=0.04 0.25 0.50 0.75 1.00 1.25 Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9. Favours SGLT2 Favours 51 inhibitor placebo BMI
SGLT2 inhibitor Placebo
n with event/N analysed (%) HR (95% CI)
BMI: <30 kg/m2
EMPEROR-Reduced 226/1263 (17.9) 322/1300 (24.8) 0.70 (0.59, 0.83)
DAPA-HF 259/1537 (16.9) 320/1533 (20.9) 0.78 (0.66, 0.92)
Subtotal 0.74 (0.66, 0.83)
Test for overall treatment effect, p<0.0001 Test for heterogeneity of effect, p=0.37
BMI: ≥30 kg/m2
EMPEROR-Reduced 135/600 (22.5) 140/567 (24.7) 0.85 (0.67, 1.08)
DAPA-HF 127/834 (15.2) 182/838 (21.7) 0.69 (0.55, 0.86)
Subtotal 0.76 (0.65, 0.90)
Test for overall treatment effect, p=0.001 Test for heterogeneity of effect, p=0.21
Test for treatment by subgroup interaction, p=0.79 0.50 0.75 1.00 1.25 Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9. Favours SGLT2 Favours 52 inhibitor placebo Primary Endpoint in Context: Absolute risk reduction (ARR) and Number Needed to Treat (NNT)
EMPEROR- Victoria DAPA-HF (vericiguat, Reduced sGC-stimulator) Adj. CV death or HHF (time to first ARR: 5.2% ARR: 3.9% ARR: 4.2% event) NNT: 19 NNT: 21 NNT: 36 Over total trial Over 16mos Over 18 mos Over 11 mos duration Adj. CV death or HHF (time to first ARR: 5.2% ARR: 3.9% ARR: 4.2% event) Comparable NNT: 23 NNT: 29 NNT: 34 durations across trials Over 1 year Over 1 year Over 1 year
53 Trials in Heart Failure and a Reduced Ejection Fraction (With or Without Diabetes) DAPA-HF EMPEROR-Reduced (dapagliflozin) (empagliflozin) Cardiovascular death or 0.75 (0.65 – 0.85) 0.75 (0.65 – 0.86) hospitalization for heart failure [877 events] [823 events] First hospitalization for heart 0.70 (0.59 – 0.83) 0.69 (0.59 – 0.81) failure [549 events] [588 events]
Renal composite endpoint 0.71 (0.44 – 1.16) 0.50 (0.32 – 0.77) [67 events] [88 events]
Cardiovascular death 0.82 (0.69 – 0.98) 0.92 (0.75 – 1.12) [500 events] [389 events] Trials in Type 2 Diabetes (With or Without Heart Failure) DECLARE-TIMI58 EMPA-REG OUTCOME (dapagliflozin) (empagliflozin) Cardiovascular death or 0.83 (0.73 – 0.95) 0.66 (0.55 – 0.79) hospitalization for heart failure [913 events] [463 events] First hospitalization for heart 0.73 (0.61 – 0.88) 0·65 (0·50 – 0·85) failure [498 events] [221 events] Renal composite endpoint 0.53 (0·43 – 0·66) 0·54 (0·40 – 0·75) [365 events] [152 events] Cardiovascular death in patients 0.92 (0.69 – 1.23) 0.59 (0.44 – 0.79) with prior myocardial infarction [183 events] [183 events] Looking into the future …
EMPEROR-Preserved
EMPULSE EMPACT-MI
Q3 2020 Q4 2020 2021 2022 2023
EMPEROR-R Main T2D/ Data/Publications Non-T2D ARNI Renal Data KCCQ Aug 29 Sep 21–25
TC TC TC TC TC
55 EMPOWER is the largest cardio-renal-metabolic programs for an SGLT2 inhibitor to date, involving more than 257,000 patients*
Aim: to explore the impact of empagliflozin on major clinical CV and renal outcomes in a spectrum of cardio-renal-metabolic conditions
EMPEROR-Reduced EMPEROR-Preserved 5988 patients 3730 patients 3-4 Effects on HHF and CV mortality in HFrEF1-2 Effects on HHF and CV mortality in HFpEF
EMPERIAL-Reduced EMPERIAL-Preserved Effects on exercise capacity and 315 patients Effects on exercise capacity and 312 patients patient-reported outcomes in HFpEF6-7 patient-reported outcomes in HFrEF5-6
EMPULSE EMPACT-MI Effects of in-hospital initiation in acute HF on 500 patients Effects on HHF and mortality in post-MI 3300 patients HF-related events and patient-reported outcomes8 patients with high risk of Heart Failure9
EMPA-VISION EMPA-KIDNEY Effects on cardiac Physiology and 72 patients Effects on kidney disease progression and CV 6000 patients Metabolism in Patients With Heart Failure10 death in patients with chronic kidney disease11
EMPA-REG OUTCOME® EMPRISE Effects on CV morbidity and mortality 7020 patients Real world effectiveness in patients with T2D 230,000 patients in patients with high CV risk and T2D12 in the United States, Europe and Asia13-15 *EMPRISE is an observational study and is, therefore, excluded from the total patient number. CV, cardiovascular; HHF, hospitalisation for heart failure; T2D, type 2 diabetes; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; MI, myocardial infarction 1. ClinicalTrials.gov. NCT03057977; 2. Packer M et al. Eur J Heart Fail 2019;21:1270; 3. Clinicaltrials.gov. NCT03057951; 4. Anker SD et al. Eur J Heart Fail 2019;21:1279; 5. ClinicalTrials.gov. NCT03448419; 6. Abraham WT et al. Eur J Heart Fail 2019;21:932; 7. ClinicalTrials.gov. NCT03448406; 8. ClinicalTrials.gov. NCT04157751; 9. Boehringer Ingelheim Pharmaceuticals, Inc. Press release. 2020. https://www.boehringer-ingelheim.com/press-release/dcri-collaboration-empact-mi ; 10. Clinicaltrials.gov. NCT03332212; 11. ClinicalTrials.gov. NCT03594110; 12. Zinman B et al. N Engl J Med 2015;373:2117; 13. ClinicalTrials.gov. NCT03363464; 14. ClinicalTrials.gov. NCT03817463; 15. Patorno E et al. Circulation 2019;139:2822 (all websites accessed Jul 2020) Foundational therapies in heart failure use
Foundational therapy in HFrEF to reduce mortality
NEW ARNI Beta- (Superior MRA blocker SGLT2i? to ACEi) (with or without T2D)
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; HFrEF, heart failure with reduced ejection fraction; MR, mineralocorticoid receptor; SGLT2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes Modified from Bhatt DL et al. Cell Metab. 2019;30:847