Post on 22-Jan-2021
transcript
New heart failure data for SGLT2 inhibitors Results of the EMPEROR Reduced Trial
Javed Butler, MD MPH MBAProfessor and ChairmanDepartment of MedicineUniversity 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
5
Outcomes for HF Compared With the General US Population
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.
Median Survival Stratified by Age
18.7
15.1
11.9
9.1
6.8
5.0
3.62.9
2.31.7 1.2 0.8
3.3 2.8 2.61.8 1.3 1.0
4.03.4
2.6 2.21.5
0.9
0
2
4
6
8
10
12
14
16
18
20
65-69 70-74 75-79 80-84 85-89 ≥90
Med
ian
Surv
ival
in Y
ears
Age in Years
Life Expectancy in US HFrEF HFbEF HFpEF
HF Predicts Higher Mortality in DM Patients
Bertoni et al, Diab Care 2004
surv
ivin
g (%
)
100
75
50
25
0
O 1 2 3 4 5
years
DM without HF
DM + HF
Mortality
3.7 /100 Pat-Y
32.7 /100 Pat-y
Population based studyPatients with DM: N=151,738Age >65 years
Prevention and Treatment !
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.
• In this analysis the risk of hHF in patients with T2D (n=271,174) was compared to those without T2D (n=1,355,870)
• The following risk factors were either not present or within guideline range: elevated HbA1c, systolic/diastolic BP, or LDL-C, or albuminuria or tobacco use
• A substantial risk for hHF remained among patients who had all the variables within target range
Risk of event in patients with T2D and no risk factors out of target range compared to patients without diabetes
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
0 0.5 1 1.5 2
Death
MI
hHF
Stroke
HR (95% CI)
1.06 (1.00, 1.12)
0.84 (0.75, 0.93)
0.95 (0.84, 1.07)
1.45 (1.34, 1.57)
Despite control of known CV risk factors, patients with T2D remain at elevated risk of developing HF
T2DM
Obesity
Traditional focus
Novel Insights
�Lipids�Glucose�BP�Thrombotic
tendency
�Insulin�Renal SGLT2 �Glomerular
hyperfiltration�TGF
other mechanisms?
Na+ & glucoseretentionIntravascularvolume increase
AcceleratedAtherogenesis
�Volume Status/Hemodynamic& Glomerular stress
MI, CVA, PAD
Heart Failure
Kidney disease
Sattar N, McGuire D. Circulation 2018
SGLT2i trial - a rethink on diabetes to CVD pathways
Major CV outcome trials in type 2 diabetes
2015 20172016 2018 201920132012 2014
CAROLINAN = 6041MACE4
ELIXA(n = 6000)
805 MACE4
: SGLT2i
: DPP4i
: GLP1
TECOS(n = 14,723)
1400 MACE4
CANVAS(n = 4339)
MACE3
DECLARE-TIMI 58
(n = 27,000)MACE3
SAVOR-TIMI 53
(n = 16,492)1222 MACE3
SUSTAIN-6(n = 3260)
MACE3
EXAMINE(n = 5380)621 MACE3
LEADER(n = 9341)611 MACE3
CANVAS-R(n = 5700)Alb.uria
CREDENCE(n = 3627)
Cardiorenal
EXSCEL(n = 14000)
MACE3
REWIND(n = 9622)
MACE3
ErtugliflozinCVOT
(n = 3900)MACE3
CARMELINA N = 8300MACE4
EMPA-REG OUTCOMEN = 7034MACE3
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.
Favors DPP-4 inhibitor
EXAMINE2,3
TECOS4,c
CARMELINA5
HR (95% CI) HR (95% CI)
SAVOR-TIMI 531
HR (95% CI)
0.96 (≤1.16)b
0.99 (0.89, 1.10)
1.02 (0.89, 1.17)
1.00 (0.89, 1.12)
P value
0.32
0.84
0.74
0.99
HR (95% CI)
1.19 (0.90, 1.58)
1.00 (0.83, 1.20)
0.90 (0.74, 1.08)
1.27 (1.07, 1.51)
P value
0.007
0.22
0.98
0.26
0.5 1.0 2.0 0.5 1.0 2.0
hHFMACEa
Favors DPP-4 inhibitorFavors placebo Favors placebo
DPP-4 inhibitors on MACE and HF outcomes
12
EMPA-REG OUTCOME:Population with Established Cardiovascular Disease
Zinman B et al. N Engl M Med. 2015;373: 2117-28.
Zinman B et al. N Engl M Med. 2015;373: 2117-28.
EMPA-REG OUTCOME
3 questions
• Luck – Replication
• Prevention or Treatment– If treatment – HFrEF or HFpEF
• Mechanism of action
HHF outcomes in SGLT2 inhibitor CV outcomes trials
16
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).
Patie
nts
with
eve
nt (%
)
Month0 6 12 18 24 30 36 42 48
0
1
2
3
4
5
6
7
PlaceboEmpagliflozin
Patie
nts
with
eve
nt (%
)
0Week
52 104 156 208 260 31201
234
8
567
33826
0
Patie
nts
with
eve
nt (%
)
Day540 720 1080
0
1
2
4
3
180 360 1260 1440900
EMPA-REG OUTCOME1
DECLARE-TIMI 583 VERTIS CV
CANVAS Program2
PlaceboDapagliflozin
PlaceboCanagliflozin
0
1
3
5
HR, 0.70 (95% CI, 0.54, 0.90)
2
4
Month
Patie
nts
with
eve
nt (%
)
0 6 12 24 36 48 60
PlaceboErtugliflozin
HR, 0.67 (95% CI, 0.52, 0.87)
HR, 0.73 (95% CI, 0.61, 0.88)
HR, 0.65 (95% CI, 0.50, 0.85)
HHF by Prior HF (approx. 90% without HF)
Data are not from head-to-head trials and should not be directly compared
Adapted from Zelniker TA et al. Lancet. 2019;393:31-39.
Events per 1000 patient years Hazard Ratio (95% CI)
SGLT2i PlaceboHistory of HFEMPA-REG OUTCOME 40.7 52.4 0.75 (0.48–1.19)
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)Heterogeneity Q=2.14, P=0.34; I2=6.6% 0.68 (0.55–0.83)
No History of HFEMPA-REG OUTCOME 6.4 10.8 0.59 (0.43-0.82)
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)Heterogeneity Q=1.73, P=0.42; I2=0.0%
0.71 (0.60–0.83)0.25 0.5 1 2Favors
study drugFavorsplacebo
18*Renal composite outcome definitions varied across trials. CI, confidence interval.
RENAL COMPOSITE*
Time to first renal composite outcome
19
SGLT2 Inhibition Improves Hemodynamic Parameters in Patients With T2D, Leading to Cardiorenal Protection
↓CV outcomes↓HF hospitalization
Stabilization of eGFR↓Albuminuria
IMPROVED CLINICAL OUTCOMES3,5
CIRCULATION1,2
↓Plasma volume↓Arterial stiffness↓Systolic blood pressure↑Hematocrit
HEART2
↓Glucose/sodium reabsorption1↓Intraglomerular pressure2↓Intrarenal RAAS activity4
↓Hyperfiltration2↓Inflammation/hypoxia3
↓Cardiac preload/afterload ↓Cardiac wall stress↑Cardiac efficiency/output
KIDNEY
CARDIORENAL PROTECTION2,3
↑Cardiac function↑Renal function
Glycosuria2
Diuresis3
Natriuresis2,3
SGLT2 INHIBITION
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.
20
Assessing Dapagliflozin in Patients With Chronic HFrEF With or Without T2D1-4
Target primary endpoint events: 8441Median follow-up: 18.2 months2
Completion: July 20193
Placebo + standard of care
Dapagliflozin 10 mg + standard of care
1:1
Doub
le-b
lind
4744 patients• ≥18 years of age • With or without T2D• Diagnosis of symptomatic HFrEF
(NYHA class II-IV) for ≥ 2 months• LVEF ≤40% within last 12 months• Elevated NT-proBNP • eGFR ≥30 mL/min/1.73 m2
• Stable SoC HFrEF treatment
Visit 1 (enrollment)Day -14
Visit 2 (randomization)Day 0
Visit 6, etc.Every 120 days
Visit 5Day 120
Visit 3Day 14
Visit 4Day 60
Secondary Endpoints• Time to first occurrence of either of the components of the composite: CV death or hHF• 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
Primary Endpoint• Time to first occurrence of any of the components of
the composite: CV death or hHF or an urgent HF visit
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.
Primary Endpoint: CV Death or hHF or an Urgent HF Visit1,2
Months From Randomization
Cum
ulat
ive
Inci
denc
e (%
)
26% RRR
DAPA
Placebo
HR 0.74 (0.65, 0.85)P=0.00001
NNT = 21
2105931096147819172075216322582371Placebo2106121146156020022147222123052373DAPA
No. at Risk
32
28
24
20
16
12
8
4
0
36
242115 18129630
21
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.
*Guideline-directed medical therapyCV, 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 diabetes1. ClinicalTrials.gov. NCT03057977 (accessed Aug 2020); 2. Packer M et al. Eur J Heart Fail 2019;21:1270; 3. Date on file
EMPEROR-ReducedPhase 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 fractionPopulation: T2D and non-T2D, aged ≥18 years, chronic HF (NYHA class II–IV)
EMPEROR-ReducedLVEF ≤40%
3730 patients
Median follow-up = 16 months (event-driven)
Placebo qd + SOC*
Empagliflozin 10 mg qd + SOC* COMPOSITE PRIMARY ENDPOINT Time to first event of adjudicated CV death or adjudicated HHF
SECONDARY ENDPOINTS• First and recurrent adjudicated HHF
events• Slope of change in eGFR (CKD-EPI) from
baseline
Confirmatory endpoints1,2Study design1-3
Trial inclusion and exclusion criteria
EMPEROR-Reduced1,2 DAPA-HF3Age ≥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
NT-proBNP ≥600 pg/ml or NT-proBNP ≥400 pg/ml in patients with HHF within 12 months
Patients without AF†
EF (%) NT-proBNP (pg/ml)Patients without AF*
≥36 to ≤40≥31 to ≤35
≤30≤40% + HHF within 12 months
≥2500≥1000≥600≥600
Further inclusion criteria apply Further inclusion criteria apply
*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 HHFSee slides notes for abbreviations1. 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
Inclusion criteria
EMPEROR-ReducedeGFR <20 ml/min/1.73 m2
or requiring dialysis
DAPA-HFeGFR <30 ml/min/1.73 m2
or rapidly declining renal function
7220 patients screened for eligibilityNot randomized
Not eligible (3314)Withdrawal of consent (80)
Adverse event (21)Lost to follow-up (19)Other reasons (56)
3730 were randomized
1867 assignedto placebo
1863 assigned to empagliflozin
Final vital status known in 1852Final vital status unknown in 11
Final vital status known in 1857Final vital status unknown in 10
Drug discontinued Non-fatal AE (158)
Request by patient (92)Other reasons (53)
Drug discontinuedNon-fatal AE (167)
Request by patient (124)Other reasons (44)
Disposition: Overview
Median follow-up16 months
Final vital statusknown in 99.4%
Baseline Characteristics in EMPEROR-Reduced and DAPA-HF
EMPEROR-Reduced DAPA-HF
Empagliflozin Placebo Dapagliflozin Placebo
Number of participants 1863 1867 2373 2371Mean±SD age, years 67.2±10.8 66.5±11.2 66.2 ± 11.0 66.5 ± 10.8Females 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
NT-proBNP, pg/ml, median (IQR) 1887.0 (1077.0−3429.0)
1926.0 (1153.0−3525.0)
1428 (857-2655)
1446 (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 ± 19.3Heart 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 Endpointsin the Hierarchical Testing Procedure
Time to 1st event of CV death or HHF
Recurrent HHF
Time to 1st event of CV death or HHF
Total (first andrecurrent HF
hospitalizations
eGFR SlopeeGFR Slope
Meta-analyses
EMPEROR-Preserved EMPEROR-Reduced
α=0.0496
αp2= α
p_final - αp1
α=0.0010 α=0.0010
α=0.0010α=0.0010
α= 0.0486
αp_final
Primary endpoint
Secondary endpoints
Primary endpoint: First adjudicated CV death or hospitalisation for heart failure
Placebo
Empagliflozin
Days after randomisation
Estim
ated
cum
ulat
ive
inci
denc
efu
nctio
n(%
)
HR 0.75(95% CI 0.65, 0.86)
p<0.001
Empagliflozin: 361 patients with eventRate: 15.8/100 patient-yearsPlacebo: 462 patients with eventRate: 21.0/100 patient-years
40
30
20
10
0
90 180 270 360 450 540 630 720 8100
Patients at riskPlaceboEmpagliflozin
1867 1715 1612 1345 1108 854 611 410 224 1091863 1763 1677 1424 1172 909 645 423 231 101
NNT = 19RRR25%
ARR5.2
ARR, absolute risk reduction; Cox regression model including covariates age, baseline eGFR, geographic region, baseline diabetes status, sex, LVEF and treatmentCV, cardiovascular; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; RRR, relative risk reductionData on file
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)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)
Primary endpointSubgroups
Favours empagliflozin Favours placebo
0.25 0.5 1 228 BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration;
eGFR, estimated glomerular filtration rate.
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 <median 80/699 115/724 0.70 (0.53, 0.93)LVEF ≤30% and NTproBNP ≥median 169/631 249/661 0.65 (0.53, 0.79)LVEF >30% 108/526 97/475 0.99 (0.76, 1.31)
Baseline use of MRA
No 118/557 132/512 0.76 (0.59, 0.97)Yes 243/1306 330/1355 0.75 (0.63, 0.88)
Baseline use of ARNI
No 310/1523 369/1480 0.77 (0.66, 0.90)Yes 51/340 93/387 0.64 (0.45, 0.89)
Subgroups: Primary endpoint
Favours empagliflozin Favours placebo
0.25 0.5 1 229
ARNI, angiotensin receptor-neprilysin inhibitor; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonists; NTproBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association.
Key secondary: Adjudicated total hospitalisations for heart failure (first and recurrent)
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 fractionData on file
Placebo
Empagliflozin
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0 90 180 270 360 450 540 630 720 810 900
1867 1820 1762 1526 1285 1017 732 497 275 1351863 1826 1768 1532 1283 1008 732 495 272 118
Patients at riskPlaceboEmpagliflozin
Days after randomisation
Mea
nnu
mbe
rofe
vent
sper
pat
ient
HR 0.70(95% CI 0.58, 0.85)
p<0.001
Emagliflozin: 388 eventsPlacebo: 553 events
RRR30%
EMPEROR-Reduced: Total Emergency Department andUrgent Care Visits for Heart Failure Requiring IV Therapy
Placebo
Empagliflozin
0 90 180 270 360 450 540 630 720
Days After Randomization
Mea
n nu
mbe
r of e
vent
s pe
r pat
ient
0.00
0.05
0.10
0.15
0.20
0.25
HR 0.63(95% CI 0.49, 0.81)
P = 0.0004
261 events
184 events
Placebo
-10
-8
-6
-4
-2
0
Mea
n ch
ange
from
bas
elin
e (S
E)in
eGF
R (m
L/m
in/1
.73m
²)
Weeks after randomization
Placebo
Baseline Last value ondouble-blind
treatment
Off treatment for23-45 days
32
Change in eGFR (CKD-EPI) from baseline (MMRM)
479 479487 487
Empagliflozin
Empagliflozin
During double-blind treatment Withdrawal after end of study
P < 0.001
Difference off treatmentof 3.3 ml/min/1.73m2
(95% CI: 1.8 – 4.8)
Number of patientsPlacebo 1792 1765 1683 1500 1146 745 343 76Empagliflozin 1799 1782 1720 1554 1166 753 356 80
-7
-6
-5
-4
-3
-2
-1
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Placebo SlopeEmpa Slope
Key secondary endpoint: eGFR slope
33
eGFR (CKD−EPI)cr [mL/min/1.73m²] change from baseline slope from random intercept random coefficient model)
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.
eGFR Slope = rate of decline
eGFR slope is a measure forlong-term renal function
Early difference due to the well-knowninitial drop with Empa
eGFR
[mL/
min
/1.7
3m2 ]
chan
gefro
mba
selin
e
Weeks
Empa: Yearly decline of-0.5 ml/min/1.73m2 per year
Placebo: Yearly decline of-2.3 ml/min/1.73m2 per year + 1.73 ml/min/1.73m2 per year
(95% CI: 1.1 – 2.4)P < 0.0001
1-year 2-year 3-year
Composite renal endpoint (end-stage kidney disease and sustained profound decrease in eGFR)
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<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 LVEFCKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PY, patient years.Data on file
Empagliflozin: 30 patients with eventRate: 1.6/100 patient-yearsPlacebo: 58 patients with eventRate: 3.1/100 patient-years
Days after randomisation
Placebo
EmpagliflozinEstim
ated
cum
ulat
ive
inci
denc
efu
nctio
n(%
)6
4
2
0
90 180 270 360 450 540 630 720 8100
Patients at riskPlaceboEmpagliflozin
18671863
15921599
15011532
11361155
10581062
681687
357391
259276
HR 0.50(95% CI 0.32, 0.77)
RRR50%
ARR1.5
Primary EndpointComposite of cardiovascular deathor heart failure hospitalization
25% in risk P < 0.001
First Secondary EndpointTotal (first and recurrentheart failure hospitalizations)
30% in riskP < 0.001
Second Secondary EndpointSlope of decline in glomerular filtration rate over time
P < 0.001(50% in renal
events)
The picture can't be displayed.
SGLT2 Inhibition With Empagliflozin Is Effective in Heart FailureWith a Reduced Ejection Fraction With or Without Diabetes
Empagliflozin(n=1863)
Placebo(n=1867)
Hazard ratio (95% CI)
p-value
Number of events (%)
Events/100 patient-yr
Number of events (%)
Events/100 patient-yr
Primary composite outcome 361 (19.4) 15.8 462 (24.7) 21.0 0.75
(0.65, 0.86) <0.001
First hospitalisation for heart failure 246 (13.2) 10.7 342 (18.3) 15.5 0.69
(0.59, 0.81)Cardiovascular death 187 (10.0) 7.6 202 (10.8) 8.1 0.92
(0.75, 1.12)
EMPEROR-Reduced: Effect on individual components of the primary endpoint
yr, year1. Data on file
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=0.027Test for heterogeneity of effect, p=0.40
Cardiovascular death
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
37
0.50 1.251.000.75
Favours SGLT2 inhibitor
Favoursplacebo
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=0.018Test for heterogeneity of effect, p=0.39
All-cause mortality
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
38
0.50 1.251.000.75
Favours SGLT2 inhibitor
Favoursplacebo
Meta-analysis of DAPA-HF and EMPEROR-Reduced
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)
0 0.5 1 1.5
Favours drug Favours placebo
Test for overall treatment effect, p=0.027Test for heterogeneity of effect, p=0.40
CV death
HF, heart failure; SGLT2i, sodium-glucose co-transporter-2 inhibitorData on file
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)
0 0.5 1 1.5
Favours drug Favours placebo
Test for overall treatment effect, p=0.018Test for heterogeneity of effect, p=0.39
All-cause death
Quality of life: KCCQ-CSS at 52 weeks
All models include covariates age, baseline eGFR, region, baseline diabetes status, sex and baseline LVEF*No imputation for deathCV, cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalisation for heart failure, KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire clinical summary score;LVEF, left ventricular ejection fraction1. Data on file
Adj
uste
d m
ean
(SE)
0
1
2
3
4
5
6
7
-8 2 12 22 32 42 52Planned study week
0
N with data at visit17011734
16881720
15051561
11511176
Adjusted mean (95% CI) change from baseline at Week 52
Empagliflozin: 5.83 (4.96, 6.70)Placebo, 4.09 (3.20, 4.97)
Comparison vs placebo Adjusted mean ratio 1.75
(95% CI 0.51, 2.99), p=0.0058
PlaceboEMPA 10 mg
On treatment*
Empagliflozin
Empagliflozin 10 mg Placebo Adjusted mean difference Adjusted mean difference p-value
N analysed
KCCQ clinical summary score 1734 1701 1.75 (0.51, 2.99) 0.0058
KCCQ total symptom score 1734 1701 1.76 (0.45, 3.06) 0.0083
KCCQ overall summary score 1734 1701 1.55 (0.31, 2.79) 0.0143
-2 -1 0 1 2 3 4 5
MMRM results of KCCQ-CSS
CSS
TSS
OSS
Favours placebo Favours empagliflozinForest plot of KCCQ individual domains change from baseline at Week 52 – TS (OC-OT).
Changes in vital signs and laboratory findingsEmpagliflozin Placebo Treatment
Difference
Glycated hemoglobin (%) in patients with diabetes– mean (SE) – 0.28 ± 0.03 – 0.12 ± 0.03 – 0.16
(–0.25 to – 0.08)
Hematocrit (%) – mean (SE) 1.98 ± 0.10 – 0.38 ± 0.10 2.36 (2.08 to 2.63)
NT-proBNP (pg/ml) –median (IQR)
–244 (-890, 260)
–141(-784, 585)
0.87(0.82 to 0.93)
Body weight (kg) – mean (SE) – 0.73 ± 0.13 0.08 ± 0.13 – 0.82(–1.18 to –0.45)
Systolic blood pressure (mm Hg) –mean (SE) – 2.4 ± 0.4 – 1.7 ± 0.4 – 0.7
(–1.8 to 0.4)
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)
Serious adverse events and prespecified adverse events of interest
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
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<0.0001Test 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=0.0638Test for heterogeneity of effect, p=0.60
Meta-analysis of DAPA-HF and EMPEROR-ReducedFirst hospitalisation for HF or CV death - subgroup
44
Test for treatment by subgroup interaction, p=0.0087 0.50 1.251.000.75
Favours SGLT2 inhibitor
Favoursplacebo
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=0.0001Test 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<0.0001Test for heterogeneity of effect, p=0.38
Meta-analysis of DAPA-HF and EMPEROR-ReducedFirst hospitalisation for HF or CV death - subgroup
45
Test for treatment by subgroup interaction, p=0.44 0.50 1.251.000.75
Favours SGLT2 inhibitor
Favoursplacebo
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<0.0001Test 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<0.0001Test for heterogeneity of effect, p=0.65
Diabetes status
46
Test for treatment by subgroup interaction, p=0.81 0.50 1.251.000.75
Favours SGLT2 inhibitor
Favoursplacebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
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=0.0043Test 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<0.0001Test for heterogeneity of effect, p=0.71
Use of ARNi
47
Test for treatment by subgroup interaction, p=0.50 0.50 1.251.000.750.25
Favours SGLT2 inhibitor
Favoursplacebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
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=0.0128Test for heterogeneity of effect, p=0.42
Meta-analysis of DAPA-HF and EMPEROR-ReducedFirst kidney composite*
48
0.50 1.251.000.750.25
Favours SGLT2 inhibitor
Favoursplacebo
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=0.0002Test 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<0.0001Test for heterogeneity of effect, p=0.52
Age (≤65 and >65 years)
49
Test for treatment by subgroup interaction, p=0.96 0.50 1.251.000.75
Favours SGLT2 inhibitor
Favoursplacebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
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=0.0012Test 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=0.0005Test 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<0.0001Test for heterogeneity of effect, p=0.60
Race
50
Test for treatment by subgroup interaction, p=0.0063 0.50 1.251.000.750.25
Favours SGLT2 inhibitor
Favoursplacebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
SGLT2 inhibitor Placebon with event/N analysed (%) HR (95% CI)
North AmericaEMPEROR-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=0.0088Test for heterogeneity of effect, p=0.83
Latin AmericaEMPEROR-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=0.0002Test for heterogeneity of effect, p=0.51
EuropeEMPEROR-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=0.0858Test for heterogeneity of effect, p=0.46
AsiaEMPEROR-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<0.0001Test for heterogeneity of effect, p=0.48
Region
51
Test for treatment by subgroup interaction, p=0.04 0.50 1.251.000.750.25
Favours SGLT2 inhibitor
Favoursplacebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
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<0.0001Test 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=0.001Test for heterogeneity of effect, p=0.21
BMI
52
Test for treatment by subgroup interaction, p=0.79 0.50 1.251.000.75
Favours SGLT2 inhibitor
Favoursplacebo
Zannad et al. The Lancet 2020. DOI:10.1016/S0140-6736(20)31824-9.
Primary Endpoint in Context: Absolute risk reduction (ARR) and Number Needed to Treat (NNT)
53
EMPEROR-Reduced DAPA-HF
Victoria(vericiguat,
sGC-stimulator)
Adj. CV death or HHF (time to first event)Over total trial duration
ARR: 5.2%
NNT: 19Over 16mos
ARR: 3.9%
NNT: 21Over 18 mos
ARR: 4.2%
NNT: 36Over 11 mos
Adj. CV death or HHF (time to first event)Comparable durations across trials
ARR: 5.2%
NNT: 23Over 1 year
ARR: 3.9%
NNT: 29Over 1 year
ARR: 4.2%
NNT: 34Over 1 year
Trials in Heart Failure and a Reduced Ejection Fraction (With or Without Diabetes)DAPA-HF
(dapagliflozin)EMPEROR-Reduced
(empagliflozin)
Cardiovascular death or hospitalization for heart failure
0.75 (0.65 – 0.85)[877 events]
0.75 (0.65 – 0.86)[823 events]
First hospitalization for heart failure
0.70 (0.59 – 0.83)[549 events]
0.69 (0.59 – 0.81)[588 events]
Renal composite endpoint 0.71 (0.44 – 1.16)[67 events]
0.50 (0.32 – 0.77)[88 events]
Cardiovascular death 0.82 (0.69 – 0.98)[500 events]
0.92 (0.75 – 1.12)[389 events]
Trials in Type 2 Diabetes (With or Without Heart Failure)DECLARE-TIMI58
(dapagliflozin)EMPA-REG OUTCOME
(empagliflozin)Cardiovascular death or hospitalization for heart failure
0.83 (0.73 – 0.95)[913 events]
0.66 (0.55 – 0.79)[463 events]
First hospitalization for heart failure
0.73 (0.61 – 0.88)[498 events]
0·65 (0·50 – 0·85)[221 events]
Renal composite endpoint 0.53 (0·43 – 0·66)[365 events]
0·54 (0·40 – 0·75)[152 events]
Cardiovascular death in patients with prior myocardial infarction
0.92 (0.69 – 1.23)[183 events]
0.59 (0.44 – 0.79)[183 events]
55
Looking into the future …
EMPEROR-R Main Data/Publications
Aug 29
Q3 2020 Q4 2020
TC TC
ARNI
TC
T2D/Non-T2D
Sep 21–25
TC TC
Renal Data KCCQ
EMPEROR-Preserved
EMPULSE
2021 2022 2023
EMPACT-MI
*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 infarction1. 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)
EMPOWER is the largest cardio-renal-metabolic programs for an SGLT2 inhibitor to date, involving more than 257,000 patients*
EMPEROR-ReducedEffects on HHF and CV mortality in HFrEF1-2
EMPULSEEffects of in-hospital initiation in acute HF on HF-related events and patient-reported outcomes8
EMPA-VISIONEffects on cardiac Physiology and Metabolism in Patients With Heart Failure10
EMPACT-MIEffects on HHF and mortality in post-MI patients with high risk of Heart Failure9
EMPA-REG OUTCOME®Effects on CV morbidity and mortalityin patients with high CV risk and T2D12
EMPRISEReal world effectiveness in patients with T2Din the United States, Europe and Asia13-15
EMPA-KIDNEYEffects on kidney disease progression and CV death in patients with chronic kidney disease11
EMPEROR-PreservedEffects on HHF and CV mortality in HFpEF3-4
EMPERIAL-ReducedEffects on exercise capacity and patient-reported outcomes in HFrEF5-6
EMPERIAL-PreservedEffects on exercise capacity and patient-reported outcomes in HFpEF6-7
to explore the impact of empagliflozin on major clinical CV and renal outcomes in a spectrum of cardio-renal-metabolic conditions
3730 patients 5988 patients
500 patients
312 patients 315 patients
72 patients
3300 patients
6000 patients
7020 patients 230,000 patients
Aim:
Foundational therapies in heart failure use
Foundational therapy in HFrEF to reduce mortality
ARNI(Superior to ACEi)
MRA Beta-blocker SGLT2i?
(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 diabetesModified from Bhatt DL et al. Cell Metab. 2019;30:847
NEW