Heart Failure: What are the practical consequences of current and ongoing SGLT2i outcome trials?Faiez Zannad

Université de Lorraine, Inserm, CHRU Nancy

Centre d’Investigations Cliniques 1433 and Inserm U1116, France

Currently Eugene Braunwald Scholar, Visiting Professor

Harvard Medical School, Brigham and Women’s Hospital, Boston, USA

Disclosures

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• Consultant; DSMB; steering committee; speaker:• Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer, Boston Scientific, Cardior, Cereno

Scientific, CEVA, Cirius therapeutics, CVRx, G3 Pharmaceuticals, GE Healthcare, J&J, KBP biosciences, LivaNova, Merck, Mitsubishi, Mundipharma, Nestlé Health Science, Novartis, NovoNordisk, Pfizer, Quantum Genomics, Relypsa, ResMed, Vifor Fresenius, ZS Pharma

• Founder:• CardioRenal, CVCT, Eshmoun

DGOS

N patients ~7000 ~10,000 ~17,000

Median follow-up (years) 3.1 2.4 4.2

SGLT2 inhibitor CVOTs in T2D: consistent effect across all outcomes, including HF1–3

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Comparison of studies should be interpreted with caution due to differences in study design, populations and

methodologyACM, all-cause mortality; HHF, hospitalisation for heart failure;

PY, patient-years1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Neal B et al.

Empa Placebo

HR (95% CI)

Cana Placebo

HR (95% CI)

Dapa Placebo

HR (95% CI)Events/1000 PY Events/1000 PY Events/1000 PY

3P-MACE 37.4 43.9 0.86 (0.74, 0.99) 26.9 31.5 0.86 (0.75, 0.97) 22.6 24.2 0.93 (0.84, 1.03)

CV death 12.4 20.2 0.62 (0.49, 0.77) 11.6 12.8 0.87 (0.72, 1.06) 7.0 7.1 0.98 (0.82, 1.17)

MI 16.8 19.3 0.87 (0.70, 1.09) 11.2 12.6 0.89 (0.73, 1.09) 11.7 13.2 0.89 (0.77, 1.01)

Stroke 12.3 10.5 1.18 (0.89, 1.56) 7.9 9.6 0.87 (0.69, 1.09) 6.9 6.8 1.01 (0.84, 1.21)

HHF 9.4 14.5 0.65 (0.50, 0.85) 5.5 8.7 0.67 (0.52, 0.87) 6.2 8.5 0.73 (0.61, 0.88)

HHF/CV death 19.7 30.1 0.66 (0.55, 0.79) 16.3 20.8 0.78 (0.67, 0.91) 12.2 14.7 0.83 (0.73, 0.95)

ACM 19.4 28.6 0.68 (0.57, 0.82) 17.3 19.5 0.87 (0.74,1.01) 15.1 16.4 0.93 (0.82, 1.04)

Drug EMPAGLIFLOZIN DAPAGLIFLOZIN

TrialEMPEROR-Preserved1 EMPEROR-Reduced2 Dapa-HF3 DELIVER

Sample size 5500 3350 4500 4700

Key inclusion criteria

• Chronic HF†

• Elevated NT-proBNP

• eGFR ≥20 ml/min/1.73 m2

• Symptomatic HFrEF†

• Elevated NT-proBNP

• eGFR ≥30 ml/min/1.73 m2

• Symptomatic HFpEF†

• Elevated NT-proBNP

• eGFR ≥25 ml/min/1.73 m2

• ≥ 40 years of age

HFpEF (LVEF >40%) HFrEF (LVEF

≤40%) HFrEF (LVEF ≤40%) HFpEF (LVEF > 40%)

Primary endpoint

• Time to first event of adjudicated CV death

or adjudicated HHF

• Time to first occurrence of CV death, HHF or urgent HF visit

• Time to first occurrence of CV death, HHF or urgent HF visit

Key secondary endpoints

• Individual components of primary endpoint

• All-cause mortality

• All-cause hospitalisation

• Time to first occurrence of sustained reduction of eGFR

• Change from baseline in KCCQ

• Total number of CV death or HHF

• All-cause mortality

• Composite of ≥50% sustained eGFR decline, ESRD or renal death

• Change from baseline in KCCQ

• Total number of CV death or HHF

• Time to death from any cause

• Change from baseline in TSS (total symptom score) of KCCQ at 8 mos

• Proportion of patients with worsened NYHA class from baseline to 8 months

Randomised controlled (outcome) trials of SGLT2 inhibitors in HF

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Empagliflozin chronic HFpEF and HFrEF outcomes trials

Comparisons of studies should be interpreted with caution due to differences in study design, populations and methodology*NT-proBNP-based enrichment of the population: patients with a higher EF require a higher NT-proBNP level for inclusion

AF, atrial fibrillation; EF, ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro−B-type natriuretic peptide

1. ClinicalTrials.gov. NCT03057951 (accessed May 2019); 2. Butler J et al. ESC-HF 2018; poster P972; 3. ClinicalTrials.gov. NCT03057977 (accessed May 2019); 4. Zannad F et al. ESC-HF 2018; poster P1755 5

EMPEROR-Preserved1,2 EMPEROR-Reduced3,4

Study drug Empagliflozin 10 mg qd Empagliflozin 10 mg qd

Population

HFpEF (LVEF >40%) with or without T2D

Elevated NT-proBNP (pg/ml)

Patients without AF

>300

HFrEF (LVEF ≤40%) with or without T2D

Sample size ~5500 ~3350

Primary endpoint Time to first event of adjudicated CV death or adjudicated HHF

EF (%)NT-proBNP (pg/ml)

Patients without AF*≥36 to ≤40 ≥2500≥31 to ≤35 ≥1000

≤30 ≥600≤40% + HHF within 12 months ≥600

N

Dapagliflozin chronic HFpEF and HFrEF outcomes trials

Comparisons of studies should be interpreted with caution due to differences in study design, populations and

methodologyHFpEF, heart failure with preserved ejection fraction; HFrEF,

heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure;

LVEF, left ventricular ejection fraction1. ClinicalTrials.gov. NCT03619213 (accessed May 2019); 2.

DELIVER1 DAPA-HF2,3

Study drug Dapagliflozin 10 mg qd Dapagliflozin 5 mg or 10 mg qd

Population HFpEF (LVEF >40%) HFrEF (LVEF ≤40%)

Sample size 4700 4500

Primary endpointTime to first occurrence

of CV death, HHF or urgent HF visit

N

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SOLOIST-WHF trial in patients with worsening HF and T2D

Comparisons of trials should be interpreted with caution due to differences in study design, populations and methodology *Patient numbers differ between CT.gov and EU Clinical Trials Register

HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction

1. ClinicalTrials.gov. NCT03521934; 2. EU Clinical Trials Register 2017-003510-16. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003510-16/SE (all websites accessed May 2019) 7

SOLOIST-WHF1,2

Study drug Sotagliflozin

Population Worsening HFpEF or HFrEF in patients with T2D

Sample size 6667*

Primary endpointsTime to first occurrence of CV death or HHF in patients with LVEF <50%

Time to first occurrence of CV death or HHF in total patient population

N

Target patient populations

Diabetes

HFpEF HFrEF

PARADIGM(n = 8442)

ATMOSPHERE(n = 7063)

DAPAHF(n = 4744)

Mean age, years 64 63 66

Female sex, n (%) 22 22 23

NYHA II % 70 69 68

NYHA III % 24 28 32

Mean LVEF, % 29 28 31

Median NT-proBNP, pg/mL 1615 1198 1437

History of HF hospitalization, % 63 60 47

Ischaemic aetiology, % 60 56 56

Median BMI, kg/m2 28 27 27

Obese, % 32 27 35

Diabetes, % 34 28 42

Hypertension, % 71 62 74

MI, % 43 41 44

PCI, % 21 20 34

CABG, % 15 14 17

Stroke, % 9 7 10

Atrial fibrillation/ flutter, %History 37 34 40

ECG 25 23 24

eGFR, mL/min/1.73 m2 68 74 66

eGFR < 60 mL/ min/1.73 m2,% 37 27 41

PARADIGM-HF(n = 8442)

ATMOSPHERE(n = 7063)

DAPAHF(n = 4744)

Treatment (%)

Diuretic 80 80 93

ACEi 78 100 56

ARB 23 0 28

ACEi or ARB 100 100 94a

𝛽-blocker 93 92 96

MRA 60 37 71

Digitalis 30 32 19

Ivabradine 2 1 5

CRT 7 6 7

ICD 15 15 26

Drug Therapy in HFrEFTraffic Jam Expected

AHF, acute heart failure; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction; WHF, worsening heart failure. Zannad F. Personal communication.

20192019 2020 2021

• Failed WHF AHF trials • Suboptimal use of GDMT• Slow adoption of

Sacubutril Valsartan

DAPA-HFrEFEMPEROR rEF

Guidelines

VICTORIA

SOLOIST WHF

Omecamtiv Mecabril

Need for creative implementation solutions• Disease management programs? • Precision medicine?

HF-REF: The building blocks of therapy

Beta-blocker + ACEi/ARB/ARNI + MRA

ICD

CRT

VADTX

H-ISDN, Ivabradine, Digoxin, CABG

SGLT2 I

Vericiguat?

Disease Management ProgramsRemote monitoring

O Mecabril?

Many mechanisms may contribute to the beneficial effects on heart failure seen with empagliflozin

LV, left ventricular

Adapted from: Farkouh ME & Verma S. J Am Coll Cardiol

2018;71:2505

SGLT2i and prevention of chronic HF

Reduction in interstitial oedema

Reduction in preload, afterload and LV wall stress

Improved kidney function and cardio–renal physiology

Natriuresis

Improved cardiacbioenergetics

Inhibition of cardiac sodium–hydrogen exchange

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Univariable mediation analysis of risk of CV death with empagliflozin versus placebo: time-dependent covariate analysis adjusting for the change from baseline in each variable

Cox proportional hazards regression analysis in patients treated with one or more doses of study drug

Increase in hematocrit with empagliflozin

16Inzucchi SE et al. Diabetes Care (in press).

What is unique about the diuretic effect of SGLT2 inhibitors?

1. Verma S & McMurray J. Diabetologia 2018;61:2108; 2. Hallow KM et al. Diabetes Obes Metab 2018;20:479; 3. Heise T et al. Clin Ther 2016;38:2248; 4. Rehman A et al. Diabetes Spectrum 2011;24:234; 5. Zinman B et al. N Engl J Med 2015;373:2117; 6. Scheen AJ. Diabetes Metab 2016;42:224;

7. Wanner C et al. N Engl J Med 2016;375:323

✓ Selectively reduces interstitial volume with minimal change in blood volume1

✓ NO counter-regulatory stimulation of the RAAS2–4

✓ NO hypokalaemia (unlike loop diuretics)5,6

✓ NO effect on uric acid (unlike loop diuretics)6

✓ NO hyperglycaemic effect (unlike thiazides)4,5

✓ AND improved renal function!5,7

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Heart failure with preserved

ejection fraction(HFpEF)

LVEF >40%1

Heart failure with reduced

ejection fraction (HFrEF)

LVEF ≤40%4

The empagliflozin chronic heart failure program

LVEF, left ventricular ejection fraction

See slide notes for references

Outcomes trial with planned recruitment:

3350 patients3,4

Outcomes trial with planned

recruitment:

5500 patients1,2

Functional capacity study

300 patients5,6

Functional capacity study

300 patients7,8

Mechanistic study

86 patients9

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