New heart failure data for SGLT2 inhibitors · 2020. 10. 5. · SGLT2 Inhibition Improves Hemodynamic Parameters in Patients With T2D, Leading to Cardiorenal Protection ↓CV outcomes

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



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


Placebo

EmpagliflozinEstim

ated

cum

ulat

ive

inci

denc

efu

nctio

n(%

)6

4

2

0

90 180 270 360 450 540 630 720 8100


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



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)


All-cause mortality


38

0.50 1.251.000.75


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


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


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



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)


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


Favoursplacebo



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)


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)


Meta-analysis of DAPA-HF and EMPEROR-ReducedFirst hospitalisation for HF or CV death - subgroup

45



Favoursplacebo



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)


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)


Diabetes status

46



Favoursplacebo




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)


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)


Use of ARNi

47

Test for treatment by subgroup interaction, p=0.50 0.50 1.251.000.750.25


Favoursplacebo




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)


Meta-analysis of DAPA-HF and EMPEROR-ReducedFirst kidney composite*

48

0.50 1.251.000.750.25


Favoursplacebo



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)


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)


Age (≤65 and >65 years)

49



Favoursplacebo




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)


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)


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)


Race

50



Favoursplacebo


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



Favoursplacebo




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)


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)


BMI

52



Favoursplacebo


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:

https://www.boehringer-ingelheim.com/press-release/dcri-collaboration-empact-mi

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

Documents

New heart failure data for SGLT2 inhibitors · 2020. 10. 5. · SGLT2 Inhibition Improves Hemodynamic Parameters in Patients With T2D, Leading to Cardiorenal Protection ↓CV outcomes