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Meta-Analysis
. 2024 Oct;12(10):735-747.
doi: 10.1016/S2213-8587(24)00219-5. Epub 2024 Sep 6.

Sodium-glucose co-transporter-2 inhibitors for hospitalised patients with COVID-19: a prospective meta-analysis of randomised trials

Claire Vale  1 , Peter J Godolphin  1 , David Fisher  1 , Peter W Horby  2 , Mikhail N Kosiborod  3 , Judith S Hochman  4 , Katie Webster  5 , Julian P T Higgins  5 , Andrew D Althouse  6 , Otavio Berwanger  7 , Remo H M Furtado  8 , Samvel B Gasparyan  9 , Richard Haynes  10 , Gary G Koch  11 , Martin Landray  12 , Eric Leifer  13 , John Marshall  14 , Srinivas Murthy  15 , Matthew D Neal  6 , Natalie Staplin  10 , Janet Diaz  16 , Jonathan A C Sterne  17 , Manu Shankar-Hari  18 ; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
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Free article
Meta-Analysis

Sodium-glucose co-transporter-2 inhibitors for hospitalised patients with COVID-19: a prospective meta-analysis of randomised trials

Claire Vale et al. Lancet Diabetes Endocrinol. 2024 Oct.
Free article

Abstract

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19.

Methods: Eligible RCTs that estimated the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality (primary outcome) were included in this prospective meta-analysis. The primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of ClinicalTrials.gov, EudraCT, and the WHO ISRCTN registry between Nov 1, 2022 and Jan 31, 2023. The search terms were "random*" AND "COVID" AND each SGLT2i, not restricted by trial status or language. Individual searches were then combined. Prespecified summary outcome data, overall and within subgroups of interest, were provided by each trial. The primary analyses were inverse variance weighted meta-analysis of odds ratios (ORs). Risk of bias was assessed using the Cochrane Risk of Bias tool. This study was registered with PROSPERO, CRD42023406442.

Findings: Three eligible trials randomly assigned 6096 participants (3025 to the SGLT2 inhibitor group and 3071 to the usual care or placebo group). 2381 (39%) patients were women and 1547 (25%) had type 2 diabetes at randomisation. By 28 days, there were 351 deaths in the SGLT2 inhibitor group and 382 deaths in the usual care or placebo group (summary OR 0·93 [95% CI 0·79-1·08]; p=0·33, I2 for inconsistency across trials 0%). The risk of bias was assessed as being low. Ketoacidosis was observed in seven participants in the SGLT2 inhibitor group and two patients in the usual care or placebo group.

Interpretation: Although administration of SGLT2 inhibitor was safe, we found no clear evidence that adding SGLT2 inhibitor therapy improved outcomes in patients hospitalised with COVID-19 compared with usual care or placebo. These data do not support the use of SGLT2 inhibitors as standard treatment in adults hospitalised for COVID-19.

Funding: None.

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Conflict of interest statement

Declaration of interests CV, PJG, DF, SBG, JM, SM, KW, JH, EL, JD, and MSH declare no competing interests. JS declares grant support for the present manuscript from UKRI Medical Research Council, National Institute for Health Research, Health Data Research UK, paid to the institution. AA declares that he became an employee of Medtronic on Oct 24, 2022, and this work on the ACTIV4a trial is entirely unrelated to his role at Medtronic. MK acknowledges consulting fees from 35Pharma, Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), NovoNordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics paid to the institution. MK also acknowledges stock options in Artera Health and Saghmos Therapeutics as personal income. GK acknowledges grants from AbbVie, Amgen, AstraZeneca UK, Bayer, Cytokinetics, Eli Lilly, Gilead Sciences, and GlaxoSmithKline, and declares a role as Principal Investigator for a collaborative biostatistical research agreement with the University of North Carolina at Chapel Hill Intra-Cellular Therapies, Kyowa Kirin, Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA), Novartis Pharmaceuticals, Otsuka Pharmaceutical Development & Commercialization, Pfizer, Sanofi US Services, Santen, UCB Biopharma SRL, and Xenon Pharmaceuticals. RH acknowledges in-kind support from Boehringer Ingelheim, Roche, Regeneron, and Combiphar in the form of Provision of IMP for trials. NS acknowledges in-kind support from Boehringer Ingelheim, Roche, Regeneron, Eli Lilly, Novo Nordisk, and Combiphar in the form of Provision of IMP for trials. RMHF acknowledges grants and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Aché, Libbs, and Pfizer. ML acknowledges in-kind support from Boehringer Ingelheim, Roche, Regeneron, GSK/Vir, and Combiphar in the form of Provision of IMP for trials. PH acknowledges in-kind support from Boehringer Ingelheim, Roche, Regeneron, GSK/Vir, and Combiphar in the form of Provision of IMP for trials and unrestricted research grants from the Medical Research Council and National Institute of Health Research (grant reference MC_PC_19056). MDN acknowledges grant support form National Institute of Health, payments to institutions from Haemonetics, Alexion, and Instrumentation Laboratories, and personal payments from Haemonetics, Takeda, Romanucci Blandin Law, and Matis Baum O'Connor.

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