SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials

Muthiah Vaduganathan, Kieran F. Docherty, Brian L. Claggett, Pardeep S. Jhund, Rudolf A. de Boer, Adrian F. Hernandez, Silvio E. Inzucchi, Mikhail N. Kosiborod, Carolyn S.P. Lam, Felipe Martinez, Sanjiv J. Shah, Akshay S. Desai, John J.V. McMurray, Scott D. Solomon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

104 Citations (Scopus)

Abstract

Background: SGLT2 inhibitors are strongly recommended in guidelines to treat patients with heart failure with reduced ejection fraction, but their clinical benefits at higher ejection fractions are less well established. Two large-scale trials, DELIVER and EMPEROR-Preserved, in heart failure with mildly reduced or preserved ejection fraction have been done, providing power to examine therapeutic effects on cardiovascular mortality and in patient subgroups when combined with the earlier trials in reduced ejection fraction. Methods: We did a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF). Using trial-level data with harmonised endpoint definitions, we did a fixed-effects meta-analysis to estimate the effect of SGLT2 inhibitors on various clinical endpoints in heart failure The primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure. We assessed heterogeneity in treatment effects for the primary endpoint across subgroups of interest. This study is registered with PROSPERO, CRD42022327527. Findings: Among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0·80 [95% CI 0·73–0·87]) with consistent reductions in both components: cardiovascular death (0·88 [0·77–1·00]) and first hospitalisation for heart failure (0·74 [0·67–0·83]). In the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0·77 [0·72–0·82]), cardiovascular death (0·87 [0·79–0·95]), first hospitalisation for heart failure (0·72 [0·67–0·78]), and all-cause mortality (0·92 [0·86–0·99]). These treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials. Treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction. Interpretation: SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting. Funding: None.

Original languageEnglish
Pages (from-to)757-767
Number of pages11
JournalThe Lancet
Volume400
Issue number10354
DOIs
Publication statusPublished - 3 Sept 2022
Externally publishedYes

Bibliographical note

Funding Information:
The DELIVER and DAPA-HF were funded by AstraZeneca, the EMPEROR trials were funded by Boehringer Ingelheim and Eli Lilly, and SOLOIST-WHF was funded by Sanofi and Lexicon Pharmaceuticals.

Funding Information:
MV has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi; received speaker fees from AstraZeneca, Novartis, and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. KFD's employer has been remunerated by AstraZeneca for clinical trial work. KFD also reports speakers’ fees from AstraZeneca and research funding from Boehringer Ingelheim. KFD, PSJ, and JJVM are funded by a British Heart Foundation Centre of Research Excellence Grant. BLC has received consulting fees from Boehringer Ingelheim. PSJ's employer has been remunerated by AstraZeneca, Bayer, and Novo Nordisk for clinical trial work. PSJ also reports consulting and speakers’ fees from Novartis, AstraZeneca, and Boehringer Ingelheim; and research funding Boehringer Ingelheim. RadB has received research grant support from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. AFH reports research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic, and Verily; and consulting Fees from Amgen, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Cytokinetics, Merck, Novartis and NovoNordisk. SEI has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. MNK reports research grant support from AstraZeneca and Boehringer Ingelheim; and consulting fees from Alnylam, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Esperion, Eli Lilly, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Pharmacosmos, Novo Nordisk, Sanofi, and Vifor. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board, steering committee, or executive committee for Abbott, Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and non-executive director of Us2.ai. FM has received personal fees from AstraZeneca. SJS reports research grants from the US National Institutes of Health, Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. ASD reports institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis; and consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Merck, Novartis, Parel, Regeneron, Roche, and Verily. JJVM has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart Lung and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta.

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© 2022 Published by Elsevier Ltd. All rights reserved

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