Metformin for COVID-19: real-time analysis of all 21 studies

Metformin Suppresses SARS-CoV-2 in Cell Culture

Parthasarathy et al., bioRxiv, doi:10.1101/2021.11.18.469078 (Preprint) (In Vitro)

In Vitro study showing metformin inhibits SARS-CoV-2 in Caco2 cells. Metformin reduced viral titers by nearly 99%, and by about 90% when cells were treated prior to infection.

Parthasarathy et al., 11/19/2021, preprint, 3 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Association Between Metformin Use and Mortality Among Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19 Infection

Ong et al., Journal of the ASEAN Federation of Endocrine Societies, doi:10.15605/jafes.036.02.20 (Peer Reviewed)

Retrospective 355 diabetic hospitalized COVID-19 patients in the Philippines, showing lower mortality with metformin use.

risk of death, 46.8% lower, RR 0.53, p = 0.02, treatment 33 of 186 (17.7%), control 57 of 169 (33.7%), NNT 6.3, adjusted, OR converted to RR, combined pre-existing and in-hospital use.

risk of death, 23.9% lower, RR 0.76, p = 0.16, treatment 28 of 109 (25.7%), control 57 of 169 (33.7%), NNT 12, OR converted to RR, pre-existing use, unadjusted.

risk of death, 85.2% lower, RR 0.15, p = 0.002, treatment 2 of 40 (5.0%), control 57 of 169 (33.7%), NNT 3.5, OR converted to RR, in-hospital use, unadjusted.

risk of death, 76.0% lower, RR 0.24, p = 0.005, treatment 3 of 37 (8.1%), control 57 of 169 (33.7%), NNT 3.9, OR converted to RR, mixed pre-existing/in-hospital use, unadjusted.

Ong et al., 10/30/2021, retrospective, Philippines, Asia, peer-reviewed, 6 authors, 1 March, 2020 - 30 September, 2020.

Preadmission usage of metformin and mortality in COVID-19 patients including the post-discharge period

Saygili et al., Irish Journal of Medical Science, doi:10.1007/s11845-021-02823-9 (Peer Reviewed)

Retrospective 586 diabetic hospitalized COVID-19 patients in Turkey, showing lower mortality with existing metformin use.

risk of death, 41.5% lower, RR 0.58, p = 0.02, treatment 120, control 120, overall mortality, Cox regression in matched group, propensity score matching.

Saygili et al., 10/29/2021, retrospective, Turkey, Europe, peer-reviewed, 5 authors.

Prior Glucose-Lowering Medication Use and 30-Day Outcomes Among 64,892 Veterans With Diabetes and COVID-19

Wander et al., Diabetes Care, doi:10.2337/dc21-1351 (Peer Reviewed)

Retrospective 64,892 veterans with diabetes in the USA, showing lower mortality with existing metformin use.

risk of death, 15.0% lower, RR 0.85, p < 0.001, treatment 29,685, control 35,207, OR converted to RR, logistic regression, within 30 days of diagnosis, control prevalance approximated with overall prevalence.

risk of ICU admission, 1.9% lower, RR 0.98, p = 0.62, treatment 29,685, control 35,207, OR converted to RR, logistic regression, within 30 days of diagnosis, control prevalance approximated with overall prevalence.

risk of hospitalization, 3.2% lower, RR 0.97, p = 0.09, treatment 29,685, control 35,207, OR converted to RR, logistic regression, within 30 days of diagnosis, control prevalance approximated with overall prevalence.

Wander et al., 10/6/2021, retrospective, database analysis, USA, North America, peer-reviewed, 8 authors.

Evaluation and management of COVID-19-related severity in people with type 2 diabetes

Wang et al., BMJ Open Diabetes Research & Care, doi:10.1136/bmjdrc-2021-002299 (Peer Reviewed)

Retrospective 16,504 COVID-19 type 2 diabetes patients, showing lower risk of ICU admission with existing metformin use.

risk of ICU admission, 12.0% lower, RR 0.88, p = 0.005, treatment 6,504, control 10,000, Cox proportional hazards.

Wang et al., 9/7/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial

Reis et al., The Lancet Regional Health - Americas, doi:10.1016/j.lana.2021.100142 (preprint 8/31/21) (Peer Reviewed)

RCT with 215 patients treated with metformin and 203 controls, showing no significant difference with treatment.

The hospitalization risk for off-protocol patients was several times higher in both arms, resulting in Simpson's paradox when combining per-protocol and off-protocol patients [1].

[1] twitter.com/Covid19Crusher/status/1470733348079288333

risk of hospitalization, 5.6% lower, RR 0.94, p = 0.88, treatment 24 of 215 (11.2%), control 24 of 203 (11.8%), NNT 152, ITT.

risk of hospitalization, 39.1% lower, RR 0.61, p = 0.28, treatment 8 of 168 (4.8%), control 14 of 179 (7.8%), NNT 33, PP.

risk of extended ER observation or hospitalization, 14.0% higher, RR 1.14, p = 0.58, treatment 34 of 215 (15.8%), control 28 of 203 (13.8%), ITT.

risk of extended ER observation or hospitalization, 12.0% lower, RR 0.88, p = 0.72, treatment 14 of 168 (8.3%), control 17 of 179 (9.5%), NNT 86, PP.

risk of ER visit, 31.0% lower, RR 0.69, p = 0.48, treatment 8 of 216 (3.7%), control 11 of 205 (5.4%), NNT 60, ITT.

risk of ER visit, 25.9% lower, RR 0.74, p = 0.62, treatment 7 of 171 (4.1%), control 10 of 181 (5.5%), NNT 70, PP.

risk of no virological cure, 1.0% lower, RR 0.99, p = 0.85, treatment 215, control 203, adjusted.

Reis et al., 8/31/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 23 authors.

Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes

Cheng et al., Cell Metabolism, doi:10.1016/j.cmet.2020.08.013 (Peer Reviewed)

Retrospective 1,213 hospitalized diabetic COVID-19 patients in China, showing no significant difference in mortality with pre-existing metformin use.

risk of death, 65.0% higher, RR 1.65, p = 0.25, treatment 678, control 535, after PSM.

Cheng et al., 8/20/2021, retrospective, propensity score matching, China, Asia, peer-reviewed, 35 authors.

Risk Factors Associated with COVID-19 Hospitalization and Mortality: A Large Claims-Based Analysis Among People with Type 2 Diabetes Mellitus in the United States

Boye et al., Diabetes Therapy, doi:10.1007/s13300-021-01110-1 (Peer Reviewed)

Retrospective 9531 COVID+ diabetes patients in the USA, showing lower risk of hospitalization with existing biguanides treatment (defined as mainly metformin in the abstract and entirely metformin in the text).

risk of hospitalization, 10.0% lower, RR 0.90, p < 0.001, treatment 2,067 of 4,250 (48.6%), control 3,196 of 5,281 (60.5%), NNT 8.4, OR converted to RR.

Boye et al., 7/18/2021, retrospective, USA, North America, peer-reviewed, 14 authors.

Retrospective Assessment of Treatments of Hospitalized Covid-19 Patients

Ravindra et al., medRxiv, doi:10.1101/2021.04.20.21255792 (Peer Reviewed)

Retrospective 1,035 hospitalized patients in India. Of 366 diabetic patients, there was lower mortality for the 53 that were on metformin.

risk of death, 29.6% lower, RR 0.70, p = 0.42, treatment 5 of 53 (9.4%), control 57 of 313 (18.2%), NNT 11, adjusted, OR converted to RR.

Excluded in after exclusion results of meta analysis: minimal details provided.

Ravindra et al., 5/5/2021, retrospective, India, South Asia, peer-reviewed, 14 authors.

Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA

Ghany et al., Diabetes & Metabolic Syndrome: Clinical Research & Reviews, doi:10.1016/j.dsx.2021.02.022 (Peer Reviewed)

Retrospective 1,139 elderly COVID+ patients in the USA, 392 with pre-existing metformin use, showing significantly lower mortality, hospitalization, and ARDS with treatment.

risk of death, 66.0% lower, RR 0.34, p < 0.001, treatment 392, control 747, multivariable, Cox proportional hazards.

risk of hospitalization, 29.0% lower, RR 0.71, p = 0.008, treatment 392, control 747, multivariable, Cox proportional hazards.

risk of ARDS, 68.0% lower, RR 0.32, p < 0.001, treatment 392, control 747, multivariable, Cox proportional hazards.

Ghany et al., 3/31/2021, retrospective, USA, North America, peer-reviewed, 8 authors.

Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: A retrospective cohort study

Jiang et al., Diabetes Research and Clinical Practice, doi:10.1016/j.diabres.2020.108619 (Peer Reviewed)

Retrospective 328 COVID-19 patients with type 2 diabetes in China, showing significantly lower risk of ARDS with existing metformin use.

risk of death, 46.0% lower, RR 0.54, p = 0.40, treatment 3 of 74 (4.1%), control 10 of 74 (13.5%), NNT 11, adjusted, mixed effect Cox, propensity score matching.

risk of ARDS, 80.2% lower, RR 0.20, p = 0.02, treatment 8 of 74 (10.8%), control 17 of 74 (23.0%), NNT 8.2, adjusted, OR converted to RR, mixed effect Cox, propensity score matching.

Jiang et al., 3/31/2021, retrospective, China, Asia, peer-reviewed, 12 authors.

Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England

Khunti et al., The Lacent Diabetes & Endocrinology, doi:10.1016/S2213-8587(21)00050-4 (Peer Reviewed)

Retrospective 2,851,465 people with type 2 diabetes in the UK, showing lower mortality with existing metformin use. Results are subject to confounding by indication because metformin is typically used early in the progression of type 2 diabetes.

risk of death, 23.0% lower, RR 0.77, p < 0.001, NNT 300, adjusted.

Khunti et al., 3/30/2021, retrospective, population-based cohort, United Kingdom, Europe, peer-reviewed, 15 authors.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

Holt et al., medRxiv, doi:10.1101/2021.03.27.21254452 (Preprint)

Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Results are subject to confounding, with only the vitamin D result fully adjusted. NCT04330599. COVIDENCE UK.

risk of case, 27.0% higher, RR 1.27, p = 0.42, treatment 12 of 429 (2.8%), control 434 of 14,798 (2.9%), NNT 737, adjusted, OR converted to RR, minimally adjusted, group sizes approximated.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Holt et al., 3/30/2021, prospective, United Kingdom, Europe, preprint, 31 authors, 1 May, 2020 - 5 February, 2021.

Metformin use and risk of COVID-19 among patients with type II diabetes mellitus: an NHIS-COVID-19 database cohort study

Oh et al., Acta Diabetologica, doi:10.1007/s00592-020-01666-7 (Peer Reviewed)

Retrospective 27,493 type II diabetes patients in the USA, 7,204 on metformin, showing significantly lower COVID-19 cases, but no significant difference in mortality.

risk of death, 26.0% higher, RR 1.26, p = 0.30, treatment 5,946, control 5,946, adjusted, multivariable, RR approximated with OR.

risk of case, 28.0% lower, RR 0.72, p < 0.001, treatment 390 of 5,946 (6.6%), control 541 of 5,946 (9.1%), NNT 39, adjusted, OR converted to RR, propensity score matching.

Oh et al., 2/13/2021, retrospective, USA, North America, peer-reviewed, 2 authors.

Metformin is Associated with Decreased 30-Day Mortality Among Nursing Home Residents Infected with SARS-CoV2

Lally et al., Journal of the American Medical Directors Association, doi:10.1016/j.jamda.2020.10.031 (Peer Reviewed)

Retrospective 775 nursing home residents in the USA, showing lower mortality with existing metformin use.

risk of death, 52.0% lower, RR 0.48, p = 0.009, treatment 16 of 127 (12.6%), control 144 of 648 (22.2%), NNT 10, adjusted, multivariable regression.

Lally et al., 1/31/2021, retrospective, USA, North America, peer-reviewed, 6 authors.

Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes

Crouse et al., Front. Endocrinol., doi:10.3389/fendo.2020.600439 (Peer Reviewed)

Retrospective 219 COVID-19+ diabetes patients in the USA, showing lower mortality with existing metformin treatment.

risk of death, 60.8% lower, RR 0.39, p = 0.02, treatment 8 of 76 (10.5%), control 34 of 144 (23.6%), NNT 7.6, adjusted, OR converted to RR, multiple logistic regression.

Crouse et al., 1/13/2021, retrospective, USA, North America, peer-reviewed, 6 authors.

Association of prescribed medications with the risk of COVID-19 infection and severity among adults in South Korea

Huh et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.12.041 (Peer Reviewed)

Retrospective database analysis with 17 existing users of HCQ and 5 severe cases, showing no significant difference for cases and higher risk for severe cases. However, HCQ users are likely systemic autoimmune disease patients and authors do not adjust for the very different baseline risk for these patients. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

[1] c19hcq.com/ferri.html

risk of progression, 1.0% higher, RR 1.01, p = 0.11, treatment 104 of 272 (38.2%), control 774 of 2,533 (30.6%), adjusted, multivariate.

risk of case, 4.0% lower, RR 0.96, p = 0.82, treatment 329 of 1,874 (17.6%), control 7,012 of 42,172 (16.6%), adjusted, multivariate.

Huh et al., 12/19/2020, retrospective, database analysis, South Korea, Asia, peer-reviewed, 8 authors.

Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis

Bramante et al., The Lancet Healthy Longevity, doi:10.1016/S2666-7568(20)30033-7 (Peer Reviewed)

Retrospective 6,256 COVID-19+ diabetes patients in the USA, showing lower mortality with existing metformin treatment, statistically significant only for women.

risk of death, 7.2% lower, RR 0.93, p = 0.15, treatment 394 of 2,333 (16.9%), control 791 of 3,923 (20.2%), NNT 31, OR converted to RR, PSM, all patients.

risk of death, 24.1% lower, RR 0.76, p = 0.02, treatment 1,129, control 2,173, PSM, women, RR approximated with OR.

risk of death, 3.5% higher, RR 1.03, p = 0.75, treatment 1,204, control 1,750, PSM, men, RR approximated with OR.

Bramante et al., 12/3/2020, retrospective, database analysis, USA, North America, peer-reviewed, 17 authors.

Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication

Chen et al., Diabetes Care, doi:10.2337/dc20-0660 (Peer Reviewed)

Retrospective 120 COVID-19 diabetes patients, showing non-statistically significantly lower mortality with existing metformin treatment.

risk of death, 33.0% lower, RR 0.67, p = 0.46, treatment 4 of 43 (9.3%), control 15 of 77 (19.5%), NNT 9.8, adjusted, OR converted to RR.

Chen et al., 7/31/2020, retrospective, China, Asia, peer-reviewed, 12 authors.

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

Wang et al., Journal of Hematology & Oncology, doi:10.1186/s13045-020-00934-x (Peer Reviewed)

Retrospective 58 multiple myeloma COVID-19 patients in the USA, showing non-statistically significant lower mortality with metformin treatment.

risk of death, 57.7% lower, RR 0.42, p = 0.43, treatment 1 of 9 (11.1%), control 13 of 49 (26.5%), NNT 6.5, OR converted to RR.

Wang et al., 7/14/2020, retrospective, USA, North America, peer-reviewed, 13 authors.

Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis

Luo et al., The American Journal of Tropical Medicine and Hygiene, doi:10.4269/ajtmh.20-0375 (Peer Reviewed)

Retrospective 283 COVID-19+ diabetes patients in China, showing lower mortality with existing metformin treatment.

risk of death, 74.7% lower, RR 0.25, p = 0.02, treatment 3 of 104 (2.9%), control 22 of 179 (12.3%), NNT 11, adjusted, OR converted to RR, multivariate.

Luo et al., 5/21/2020, retrospective, China, Asia, peer-reviewed, 9 authors.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption