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. 2023 May 16;81(19):1902-1914.
doi: 10.1016/j.jacc.2023.03.390.

Efficacy of Empagliflozin in Patients With Heart Failure Across Kidney Risk Categories

Javed Butler  1 , Milton Packer  2 , Tariq Jamal Siddiqi  3 , Michael Böhm  4 , Martina Brueckmann  5 , James L Januzzi  6 , Subodh Verma  7 , Ingrid Gergei  8 , Tomoko Iwata  9 , Christoph Wanner  10 , João Pedro Ferreira  11 , Stuart J Pocock  12 , Gerasimos Filippatos  13 , Stefan D Anker  14 , Faiez Zannad  15
Affiliations

Efficacy of Empagliflozin in Patients With Heart Failure Across Kidney Risk Categories

Javed Butler et al. J Am Coll Cardiol. .

Abstract

Background: Empagliflozin reduces the risk of major heart failure outcomes in heart failure with reduced or preserved ejection fraction.

Objectives: The goal of this study was to evaluate the effect of empagliflozin across the spectrum of chronic kidney disease in a pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced or Preserved Ejection Fraction, respectively).

Methods: A total of 9,718 patients were grouped into Kidney Disease Improving Global Outcomes (KDIGO) categories based on estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio into low-, moderate-, high-, and very-high-risk categories, comprising 32.0%, 29.1%, 21.9%, and 17.0% of the participants, respectively.

Results: In the placebo arm, when compared with lower risk categories, patients at higher risk experienced a slower rate of decline in eGFR, but a higher risk of a composite kidney event. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalizations similarly in all KDIGO categories (HR: 0.81; 95% CI: 0.66-1.01 for low-; HR: 0.63; 95% CI: 0.52-0.76 for moderate-; HR: 0.82; 95% CI: 0.68-0.98 for high-; and HR: 0.84; 95% CI: 0.71-1.01 for very-high-risk groups; P trend = 0.30). Empagliflozin reduced the rate of decline in eGFR whether it was estimated by chronic slope, total slope, or unconfounded slope. When compared with the unconfounded slope, the magnitude of the effect on chronic slope was larger, and the effect on total slope was smaller. In EMPEROR-Reduced, patients at lowest risk experienced the largest effect of empagliflozin on eGFR slope; this pattern was not observed in EMPEROR-Preserved.

Conclusions: The benefit of empagliflozin on major heart failure events was not influenced by KDIGO categories. The magnitude of the renal effects of the drug depended on the approach used to calculate eGFR slopes.

Keywords: KDIGO category; SGLT2 inhibitor; cardiovascular disease; chronic kidney disease; congestive heart failure.

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Conflict of interest statement

Funding Support and Author Disclosures Boehringer Ingelheim and Eli Lilly and Company funded EMPEROR-Reduced and EMPEROR-Preserved. The manuscript was sponsored by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Butler has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, Occlutech, and Vifor; and is a Trial Executive Committee member of Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Packer has received consulting fees from AbbVie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Verma has received research and/or speaking honoraria from Amgen, Amarin, AstraZeneca, Bayer, CMS, Janssen, HLS, Sanofi, Novo Nordisk, Novartis, Merck, and PhaseBio; has received personal fees from Boehringer Ingelheim; is president of the Canadian Medical and Surgical Knowledge Translation Research Group; and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Dr Wanner has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly and Company, GSK, Gilead, MSD, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius. Dr Ferreira has received consulting fees from Boehringer Ingelheim; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Pocock has received consulting fees and payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Filippatos has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim, Medtronic, Vifor, Servier, and Novartis; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Anker has received grants from Abbott Vascular and Vifor (International) Ltd; has received consulting fees from Abbott Vascular, Bayer, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor (International) Ltd; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Zannad has recieved payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, and Bayer; other financial or nonfinancial interests in CVCT and Cardiorenal; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Drs Brueckmann and Gergei, and Tomoko Iwata are employees of Boehringer Ingelheim, the manufacturer of empagliflozin. Dr Siddiqi has reported that he has no relationships relevant to the contents of this paper to disclose.

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