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. 2023 Jul 1;8(7):640-649.
doi: 10.1001/jamacardio.2023.1090.

Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction: A Post Hoc Analysis of the EMPEROR-Preserved Trial

Javed Butler  1   2 , Muhammad Shariq Usman  1 , Gerasimos Filippatos  3 , João Pedro Ferreira  4 , Michael Böhm  5 , Martina Brueckmann  6   7 , James L Januzzi  8 , Sanjay Kaul  9 , Ileana L Piña  10 , Piotr Ponikowski  11 , Michele Senni  12 , Mikhail Sumin  6 , Subodh Verma  13 , Liliana Zaremba-Pechmann  14 , Stuart J Pocock  15 , Milton Packer  16   17 , Stefan Anker  18   19
Affiliations

Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction: A Post Hoc Analysis of the EMPEROR-Preserved Trial

Javed Butler et al. JAMA Cardiol. .

Abstract

Importance: The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved ejection fraction (HFpEF).

Objective: To assess the safety and efficacy of empagliflozin in combination with background diuretic therapy and the association of empagliflozin with the need for conventional diuretics.

Design, setting, and participants: This was a post hoc analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved). EMPEROR-Preserved was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from March 2017 to April 2021. Patients with class II to IV heart failure and left ventricular ejection fraction greater than 40% were included. Of 5988 patients enrolled, 5815 (97.1%) had baseline data on diuretic use and were included in this analysis, which was conducted from November 2021 to August 2022.

Interventions: Participants in EMPEROR-Preserved were randomized to empagliflozin or placebo. In this analysis, participants were divided into 4 subgroups: no diuretics and furosemide-equivalent diuretic dose of less than 40 mg, 40 mg, and greater than 40 mg at baseline.

Main outcomes and measures: The main outcomes of interest were first hospitalization for heart failure (HHF) or cardiovascular death (CV death) and its components. Association of empagliflozin vs placebo with outcomes by baseline diuretic status (no diuretic vs any dose) and dose (no diuretic, <40 mg, 40 mg, and > 40mg) was assessed. Association of empagliflozin use with changes in diuretic therapy was also studied.

Results: Among 5815 patients (mean [SD] age, 71.9 [9.4] years; 2594 [44.6%] female) with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking less than 40 mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking greater than 40 mg. In the placebo arm, patients with higher diuretic doses had worse outcomes. Empagliflozin decreased the risk of HHF or CV death, regardless of background diuretic status (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93] for the diuretic group vs HR, 0.72; 95% CI, 0.48-1.06 for the nondiuretic group; P for interaction = .58). Similarly, diuretic status was not associated with changes in improvements in first HHF, total HHF, rate of decline in estimated glomerular filtration rate, and Kansas City Cardiomyopathy Questionnaire 23 clinical summary score with empagliflozin. Findings were consistent when patients were categorized by diuretic dose. Empagliflozin was associated with a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65-0.84) and an increased likelihood of de-escalation (HR, 1.15; 95% CI, 1.02-1.30). Empagliflozin was associated with an increased risk of volume depletion in patients taking diuretics (HR, 1.34; 95% CI, 1.13-1.59).

Conclusion: In this study, treatment with empagliflozin was similar regardless of diuretic use or dose. Empagliflozin use was associated with decreased conventional diuretic dosing.

Trial registration: ClinicalTrials.gov Identifier: NCT03057951.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Butler reports consulting fees from Abbott, Adrenomed, American Regent, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Occlutech, Pfizer, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Filippatos reports lectures and/or committee member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, Bayer, Amgen, and Boehringer Ingelheim as well as grants from the European Union outside the submitted work. Dr Ferreira reports consulting fees from Boehringer Ingelheim during the conduct of the study. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Drs Brueckmann and Sumin are employees of Boehringer Ingelheim. Dr Januzzi reports grant support, consulting income, and participation in clinical end point committees/data safety monitoring boards from Janssen; participation in clinical end point committees/data safety monitoring boards from Boehringer Ingelheim; grant support from Novartis, Innolife, Applied Therapeutics, and Siemens Diagnostics; and consultancy fees from Novartis, Roche Diagnostics, and Abbott Diagnostics. Dr Kaul reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from Abbott, Amarin, AstraZeneca, Janssen Pharmaceuticals, Merck, Novo Nordisk, GSK and Novartis as well as stock equity in Johnson and Johnson outside the submitted work. Dr Piña reports personal fees from Boehringer Ingelheim and serving on an advisory board for AstraZeneca. Dr Ponikowski reports personal fees or other from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, Berlin Chemie, Cibiem, Bayer, RenalGuardSolution, and Respicardia as well as grants and personal fees from Vifor Pharma. Dr Senni reports consultancy fees from Abbotts, Bayer, Bayer Healthcare, Merck, Novartis, and Vifor Pharma. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; reports receiving research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio and Pfizer; honoraria from Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and personal fees from S & L Solutions, Canadian Medical and Surgical Knowledge Translation Research Group, and EOCI. He is a member of the scientific excellence committee of the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction) and served as a national lead investigator of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced trials. He is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Zaremba-Pechmann is a contractor at Elderbrook Solutions, contracted by Boehringer Ingelheim. Dr Pocock reports personal fees from Boehringer Ingelheim during the conduct of the study. Dr Packer reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from AbbVie, Actavis, Altimmune, Amgen, Amarin, Ardelyx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Caladrius, Casana, CSL Behring, Cytokinetics, Eli Lilly, Johnson & Johnson, Imara, Moderna, Novartis, ParatusRx, Pfizer, Reata, Regeneron, Relypsa, Salamandra, Synthetic Biologics, and Theravance outside the submitted work. Dr Anker has received grants from Vifor; has received personal fees from Vifor, Bayer, Boehringer Ingelheim, Brahms, Novartis, Occlutech, Servier, Impulse Dynamics, Cardiac Dimensions, SAB Biotherapeutics, Thermo Fisher Scientific, and V-Wave and has received grants and personal fees from Abbott Vascular outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Comparison of Empagliflozin vs Placebo on Clinical Outcomes by Baseline Diuretic Use
CV indicates cardiovascular; HHF, hospitalization for heart failure; HR, hazard ratio; NA, not applicable; py, patient-year.
Figure 2.
Figure 2.. Comparison of Empagliflozin vs Placebo on Kansas City Cardiomyopathy Questionnaire Subdomain Scores According to Baseline Diuretic Therapy
KCCQ-CSS indicates Kansas City Cardiomyopathy Questionnaire clinical summary score.
Figure 3.
Figure 3.. Cumulative Incidence Curves Showing Time to Initiation of Diuretics in Patients Not Receiving Diuretics at Baseline and Time to Permanent Discontinuation of Diuretics in Patients Receiving Diuretics at Baseline
Figure 4.
Figure 4.. Change in Diuretic Therapy in Empagliflozin vs Placebo Arms
HR indicates hazard ratio; py, patient-year. aP value for comparison of empagliflozin vs placebo. bP trend for comparison of baseline diuretic doses of <40mg, 40mg, and >40mg. cFor patients not receiving diuretic therapy at baseline. dFor patients receiving diuretic therapy at baseline.
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References

    1. Anker SD, Butler J, Filippatos G, et al. ; EMPEROR-Preserved Trial Investigators . Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038 - DOI - PubMed
    1. Tang J, Ye L, Yan Q, Zhang X, Wang L. Effects of sodium-glucose cotransporter 2 inhibitors on water and sodium metabolism. Front Pharmacol. 2022;13:800490. doi:10.3389/fphar.2022.800490 - DOI - PMC - PubMed
    1. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5(6):632-644. doi:10.1016/j.jacbts.2020.02.004 - DOI - PMC - PubMed
    1. Packer M. Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors. Eur J Heart Fail. 2020;22(4):618-628. doi:10.1002/ejhf.1732 - DOI - PubMed
    1. Verma A, Patel AB, Waikar SS. SGLT2 inhibitor: not a traditional diuretic for heart failure. Cell Metab. 2020;32(1):13-14. doi:10.1016/j.cmet.2020.06.014 - DOI - PubMed

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