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. 2021 Jan 26;143(4):310-321.
doi: 10.1161/CIRCULATIONAHA.120.051685. Epub 2020 Oct 23.

Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced

Faiez Zannad  1 , João Pedro Ferreira  1 , Stuart J Pocock  2 , Cordula Zeller  3 , Stefan D Anker  4 , Javed Butler  5 , Gerasimos Filippatos  6 , Sibylle Jenny Hauske  7   8 , Martina Brueckmann  7   9 , Egon Pfarr  10 , Janet Schnee  11   12 , Christoph Wanner, Milton Packer  13   14
Affiliations

Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced

Faiez Zannad et al. Circulation. .

Erratum in

Abstract

Background: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin reduced cardiovascular death or heart failure (HF) hospitalization and total HF hospitalizations, and slowed the progressive decline in kidney function in patients with HF and a reduced ejection fraction, with and without diabetes. We aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.

Methods: In this prespecified analysis, patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 or albumin-to-creatine ratio >300 mg/g). The primary and key secondary outcomes were: (1) a composite of cardiovascular death or HF hospitalization (primary outcome); (2) total HF hospitalizations; and (3) eGFR slope. The direct impact on kidney events was investigated by a prespecified composite kidney outcome (defined as a sustained profound decline in eGFR, chronic dialysis, or transplant). The median follow-up was 16 months.

Results: Of 3730 patients who were randomized to empagliflozin or placebo, 1978 (53%) had CKD. Empagliflozin reduced the primary outcome and total HF hospitalizations in patients with and without CKD: hazard ratio (HR)=0.78 (95% CI, 0.65-0.93) and HR=0.72 (95% CI, 0.58-0.90), respectively (interaction P=0.63). Empagliflozin slowed the slope of eGFR decline by 1.11 (0.23-1.98) ml/min/1.73 m2/yr in patients with CKD and by 2.41 (1.49-3.32) ml/min/1.73 m2/yr in patients without CKD. The risk of the composite kidney outcome was reduced similarly in patients with and without CKD: HR=0.53 (95% CI, 0.31-0.91) and HR=0.46 (95% CI, 0.22-0.99), respectively. The effect of empagliflozin on the primary composite outcome and key secondary outcomes was consistent across a broad range of baseline kidney function, measured by clinically relevant eGFR subgroups or by albuminuria, including patients with eGFR as low as 20 ml/min/1.73 m2. Empagliflozin was well tolerated in CKD patients.

Conclusions: In EMPEROR-Reduced, empagliflozin had a beneficial effect on the key efficacy outcomes and slowed the rate of kidney function decline in patients with and without CKD, and regardless of the severity of kidney impairment at baseline. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Keywords: empagliflozin; glomerular filtration rate; heart failure; renal insufficiency, chronic.

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Conflict of interest statement

Dr Zannad reports personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera outside of the submitted work; and other support from cardiovascular clinical trialists and Cardiorenal, outside of the submitted work. Dr Ferreira reports consulting fees from Boehringer Ingelheim during the conduct of the study. Dr Pocock reports personal fees from Boehringer Ingelheim during the conduct of the study. Dr Anker reports grants from Vifor; personal fees from Vifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Thermo Fisher Scientific; and grants and personal fees from Abbott Vascular, outside of the submitted work. Dr Butler reports consultancy fees from Boehringer Ingelheim during the conduct of the study; and consultancy fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave, and Vifor, outside of the submitted work. Dr Filippatos reports receiving payment from Boehringer Ingelheim for being a trial committee member during the conduct of the study and from Medtronic, Vifor, Servier, and Novartis for being a trial committee member outside of the submitted work. Dr Wanner reports personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Gilead, Merck Sharp & Dohme, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside of the submitted work. Dr Packer reports personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and NovoNordisk outside of the submitted work. Drs Hauske, Brueckmann, and Schnee, C. Zeller, and E. Pfarr are employees of Boehringer Ingelheim.

Figures

Figure 1.
Figure 1.
Clinical outcomes in patients by CKD status, eGFR and UACR categories at baseline. Data for randomized patients; HR and 95% CI from Cox proportional hazards model unless otherwise noted. CKD-EPI indicates Chronic Kidney Disease Epidemiology Collaboration equation; CV, cardiovascular; eGFR, estimated glomerular filtration rate (CKD-EPI; ml/min/1.73 m2); HHF, hospitalization for heart failure; HR, hazard ratio; and UACR, urinary albumin-to-creatinine ratio (mg/g). *Prevalent CKD defined as eGFR (CKD-EPI) <60 ml/min/1.73 m2 or UACR >300 mg/g. †Evaluated using a joint frailty model together with CV death. ‡Composite exploratory endpoint included chronic dialysis or kidney transplant or sustained reduction of ≥40% in eGFR or sustained eGFR (CKD-EPI) <15 ml/min/1.73 m2 (for patients with baseline eGFR ≥30) or sustained eGFR <10 (for patients with baseline eGFR <30). §Not calculated as less than 14 events in this subgroup. **P value for interaction shown for CKD subgroups; P value for trend test shown for eGFR and UACR subgroups.
Figure 2.
Figure 2.
eGFR over time by CKD status at baseline. Data for treated patients from a mixed model for repeated measures based on on-treatment data. Prevalent CKD defined as eGFR (CKD-EPI) <60 ml/min/1.73 m2 or UACR >300 mg/g. CKD indicates chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; eGFR, estimated glomerular filtration rate; and UACR, urinary albumin-to-creatinine ratio.
Figure 3.
Figure 3.
Additional clinical outcomes by CKD status at baseline. Data for randomized patients; HR and 95% CI from Cox proportional hazards model. CKD indicates chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalization for heart failure; HR, hazard ratio; MedDRA, Medical Dictionary for Regulatory Activities; and UACR, urinary albumin-to-creatinine ratio. *Prevalent CKD defined as eGFR (CKD-EPI) <60 ml/min/1.73 m2 or UACR >300 mg/g. †Composite exploratory endpoint included chronic dialysis or kidney transplant or sustained reduction of ≥40% in eGFR or sustained eGFR (CKD-EPI) <15 ml/min/1.73 m2 (for patients with baseline eGFR ≥30) or sustained eGFR <10 (for patients with baseline eGFR <30). ‡Acute kidney injury based on MedDRA preferred term based on investigator-reported adverse events.
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