Metformin use and decreased risk of severe COVID-19 outcomes in a real-world case-control study

Rodríguez-Fernández et al., Scientific Reports, doi:10.1038/s41598-026-68017-4, EUPAS44587, Sep 2026

Metformin for COVID-19

3rd treatment shown to reduce risk in July 2020, now with p < 0.0000000001 from 114 studies.
Lower risk for mortality, ventilation, ICU, hospitalization, progression, recovery, and viral clearance.

No treatment is 100% effective.
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6,700+ studies · 220+ treatments

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Meta-analysis
Population-based case-control study of 81,348 adults in Spain, showing lower risk of hospitalization with prior metformin use. The analysis among patients with type 2 diabetes may be the most reliable. The primary analysis compares metformin users (nearly all diabetic) with a reference group that is mostly non-diabetic, where the results depends heavily on the model and the accuracy of the adjustments may be limited due to large baseline differences, the reliance on coded diagnoses rather than clinical measures such as kidney function or glycemic control, and the diabetes severity covariate being defined by the medications themselves.
Authors suggest that metformin's anti-inflammatory, immunomodulatory, and antiviral effects, including reducing cytokine storm and inhibiting SARS-CoV-2 cell entry and replication, may explain the findings.
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risk of hospitalization, 31.0% lower, OR 0.69, p = 0.03, treatment 2,496, control 2,630, adjusted per study, T2D only, prior metformin vs no antidiabetic, multivariable, RR approximated with OR.
risk of case, 7.0% lower, OR 0.93, p = 0.46, treatment 3,035, control 3,312, adjusted per study, T2D only, prior metformin vs no antidiabetic, multivariable, RR approximated with OR.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Rodríguez-Fernández et al., 11 Sep 2026, retrospective, Spain, peer-reviewed, 21 authors, study period March 2020 - December 2020, trial EUPAS44587. Contact: angel.salgado.barreira@usc.es.
$0 $500 $1,000+ Efficacy vs. cost for COVID-19 treatment protocols c19early.org October 2026 Spain Angola Colombia Kenya Mozambique Myanmar South Africa Peru Philippines Vietnam Nepal Iran Bangladesh Ethiopia Ghana Germany Mexico South Korea United Kingdom Saudi Arabia Algeria Morocco Yemen Poland Uzbekistan India China Venezuela DR Congo Madagascar Thailand Uganda Egypt Nigeria Taiwan Fiji Zambia Bosnia-Herzegovina Georgia Switzerland Dominican Republic Bolivia Côte d'Ivoire Eritrea Togo Bulgaria Greece Slovakia Iceland New Zealand Trinidad and Tobago Mongolia Czechia Belarus Israel Haiti North Macedonia Hong Kong Qatar Panama Serbia Spain favored high-profit treatments.The average efficacy of treatments was very low.High-cost protocols reduce early treatment, andforgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
$0 $500 $1,000+ Efficacy vs. cost for COVID-19treatment protocols worldwide c19early.org October 2026 Spain Angola Colombia Kenya Mozambique Myanmar South Africa Peru Philippines Vietnam Argentina Nepal Iran Bangladesh Ethiopia Ghana Germany Mexico South Korea United Kingdom Saudi Arabia Algeria Morocco Yemen Poland Uzbekistan India China Venezuela DR Congo Madagascar Thailand Uganda Egypt Taiwan Fiji Zambia Georgia Switzerland Dominican Rep. Bolivia Côte d'Ivoire Eritrea Togo Sri Lanka Bulgaria Greece Slovakia New Zealand Trinidad and Tobago Mongolia Czechia Belarus Israel North Macedonia Hong Kong Qatar Panama Serbia Spain favored high-profit treatments.The average efficacy was very low.High-cost protocols reduce early treatment,and forgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
Abstract: ## ARTICLE | Article in Press Metformin use and decreased risk of severe COVID-19 outcomes in a real-world case-control study Almudena Rodríguez-Fernández · Maruxa Zapata-Cachafeiro · Rosa M. García-Álvarez · Irene Visos-Varela · María Piñeiro-Lamas Teresa M. Herdeiro · Ángel Salgado-Barreira · Adolfo Figueiras · the COVIDrug Consortium Received: 31 July 2025 / Accepted: 19 August 2026 © The Author(s) 2026 Abstract Metformin use has been associated with a lower risk of severe COVID-19 outcomes. The aim of our study was thus to evaluate the effect of metformin use via a population-based study. We conducted a case-control study with real-world data, analysing: (i) risk of hospitalisation, with cases being subjects admitted to hospital with a PCR+ test and controls without a PCR+; (ii) risk of disease progression, including all subjects with a PCR+ test, with cases being hospitalised and controls non-hospitalised subjects; and (iii) risk of susceptibility among subjects with a PCR+ test versus those without a PCR+. Adjusted odds ratios (aOR) and their 95% confidence intervals (95%CIs) were calculated. Our study covered 81,348 subjects. Of these, 29,568 had a PCR+ test, 2753 of whom were admitted to hospital. According to our results, prior metformin use reduces the risk of hospitalisation (aOR 0.70; 95%CI 0.51-0.97) and progression of COVID-19 (aOR 0.66; 95%CI 0.45-0.98) among metformin users when compared with those not taking antidiabetic medication. There were no differences in risk of susceptibility to the SARS-CoV-2 virus (aOR 0.97; 95%CI 0.81-1.16). The results of this large-scale real-world study suggest that by reducing the risk of progression, metformin could provide an appropriate treatment option for combating the advance of COVID-19 to severe outcomes. Keywords Repurposing · Metformin · COVID-19 · Hospitalisation · Progression · Susceptibility · Realworld data Abbreviations aOR Adjusted odds ratios PHS Public health system PCR+ test Positive PCR test for COVID-19 This Article in Press is shared early to give you faster access to new research. It is citable and carries a permanent DOI. The final edited version will replace it automatically. · | RRR | Relative-risk reduction | |---------|---------------------------| | 95% CIs | 95% confidence intervals |
DOI record: { "DOI": "10.1038/s41598-026-68017-4", "ISSN": [ "2045-2322" ], "URL": "http://dx.doi.org/10.1038/s41598-026-68017-4", "alternative-id": [ "68017" ], "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "31 July 2025" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "19 August 2026" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "11 September 2026" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "label": "Competing interests", "name": "Ethics", "order": 1, "value": "The authors declare no competing interests." } ], "author": [ { "ORCID": "https://orcid.org/0000-0002-3350-1237", "affiliation": [], "authenticated-orcid": false, "family": "Rodríguez-Fernández", "given": "Almudena", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-0648-7716", "affiliation": [], "authenticated-orcid": false, "family": "Zapata-Cachafeiro", "given": "Maruxa", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-4703-0234", "affiliation": [], "authenticated-orcid": false, "family": "García-Álvarez", "given": "Rosa M.", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-6466-6213", "affiliation": [], "authenticated-orcid": false, "family": "Visos-Varela", "given": "Irene", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-3655-100X", "affiliation": [], "authenticated-orcid": false, "family": "Piñeiro-Lamas", "given": "María", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-0500-4049", "affiliation": [], "authenticated-orcid": false, "family": "Herdeiro", "given": "M. Teresa", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-4349-4947", "affiliation": [], "authenticated-orcid": false, "family": "Salgado-Barreira", "given": "Ángel", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-5766-8672", "affiliation": [], "authenticated-orcid": false, "family": "Figueiras", "given": "Adolfo", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "name": "the COVIDrug Consortium", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Bugarín-González", "given": "Rosendo", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Carracedo-Martínez", "given": "Eduardo", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "González-Barcala", "given": "Francisco J.", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Lema-Oreiro", "given": "Martina", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Mallah", "given": "Narmeen", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Pintos-Rodríguez", "given": "Samuel", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Piñeiro-Lamas", "given": "Maria", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Portela-Romero", "given": "Manuel", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Prieto-Campo", "given": "Angela", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Rodriguez-Fernández", "given": "Almudena", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Sáez", "given": "Marc", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [], "family": "Taracido-Trunk", "given": "Margarita", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" } ], "container-title": "Scientific Reports", "container-title-short": "Sci Rep", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2026, 9, 11 ] ], "date-time": "2026-09-11T14:55:31Z", "timestamp": 1789138531000 }, "deposited": { "date-parts": [ [ 2026, 9, 11 ] ], "date-time": "2026-09-11T14:55:32Z", "timestamp": 1789138532000 }, "funder": [ { "DOI": "10.13039/501100004587", "doi-asserted-by": "crossref", "id": [ { "asserted-by": "crossref", "id": "10.13039/501100004587", "id-type": "DOI" } ], "name": "Carlos III Institute of Health" } ], "indexed": { "date-parts": [ [ 2026, 9, 11 ] ], "date-time": "2026-09-11T15:15:17Z", "timestamp": 1789139717205, "version": "build-2803163510" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2026, 9, 11 ] ] }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by-nc-nd/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 9, 11 ] ], "date-time": "2026-09-11T00:00:00Z", "timestamp": 1789084800000 } }, { "URL": "https://creativecommons.org/licenses/by-nc-nd/4.0", "content-version": "am", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 9, 11 ] ], "date-time": "2026-09-11T00:00:00Z", "timestamp": 1789084800000 } } ], "link": [ { "URL": "https://www.nature.com/articles/s41598-026-68017-4", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" } ], "member": "297", "original-title": [], "prefix": "10.1038", "published": { "date-parts": [ [ 2026, 9, 11 ] ] }, "published-online": { "date-parts": [ [ 2026, 9, 11 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://www.nature.com/articles/s41598-026-68017-4" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Metformin use and decreased risk of severe COVID-19 outcomes in a real-world case-control study", "type": "journal-article", "update-policy": "https://doi.org/10.1007/springer_crossmark_policy" }
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