Metformin for COVID-19: real-time analysis of all 43 studies

Metformin for COVID-19: real-time meta analysis of 41 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, ventilation, and hospitalization. 24 studies from 23 independent teams in 8 different countries show statistically significant improvements in isolation (21 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 29% [22‑35%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids recovery but is not antiviral.

• Results are robust — in exclusion sensitivity analysis 28 of 41 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.

• Most studies analyze existing use with diabetic patients. Many results are subject to confounding by indication — metformin is typically used early in the progression of type 2 diabetes. Prophylaxis results typically include continuing use after infection and hospitalization, and greater benefit is seen for more serious outcomes. The beneficial effect of metformin may be more related to later stages of COVID-19. The TOGETHER RCT shows 27% lower mortality. While not statistically significant, p = 0.53, this is consistent with the mortality results from all studies, 36% [28‑43%].

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. None of the metformin studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments are more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix. Other meta analyses for metformin can be found in [Hariyanto, Kow, Lukito, Yang], showing significant improvements for mortality and progression.

Covid Analysis et al., 8/12/2022, preprint, 1 author.

Results From the COVID-OUT Trial, a Phase-3 trial of Outpatient Treatment for Covid-19 Using Metformin, Ivermectin, and Fluvoxamine

Bramante et al. (Preprint)

Results for COVID-OUT were reported in a presentation, however they are not currently available due to a news embargo. There were no statistically significant results for metformin, ivermectin, or fluvoxamine, except for a post-hoc metformin composite. Null results are expected based on the trial design and size (with metformin having higher power and a greater chance of showing a result despite the design).

We note that embargo and delay of clinical trial results during a pandemic is not consistent with a goal of minimizing mortality and morbidity, but is consistent with a goal of maximizing press for a trial designed to produce a null result.

Trial outcomes were changed on January 20, 2022 [clinicaltrials.gov], and again on March 2, 2022 [clinicaltrials.gov (B)]. COVIDOUT.

Medication delivery varied significantly over the trial. In this presentation [vimeo.com], author indicates that delivery was initially local, later via FedEx, was much slower in August, there were delays due to team bandwidth issues, and they only realized they could use FedEx same day delivery in September.

1. clinicaltrials.gov, https://clinicaltrials.gov/ct2/his..94?A=15&B=16&C=merged#StudyPageTop.

2. clinicaltrials.gov (B), https://clinicaltrials.gov/ct2/his..94?A=16&B=17&C=merged#StudyPageTop.

3. vimeo.com, https://vimeo.com/622665410.

Bramante et al., 7/8/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, preprint, 3 authors, trial NCT04510194 (history) (COVID-OUT).

Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans

Hunt et al., Journal of General Internal Medicine, doi:10.1007/s11606-022-07701-3

Retrospective 26,508 consecutive COVID+ veterans in the USA, showing lower mortality with multiple treatments including metformin. Treatment was defined as drugs administered ≥50% of the time within 2 weeks post-COVID+, and may be a continuation of prophylactic treatment in some cases, and may be early or late treatment in other cases. Further reduction in mortality was seen with combinations of treatments.

risk of death, 67.0% lower, RR 0.33, p < 0.001, treatment 73 of 3,956 (1.8%), control 1,539 of 22,552 (6.8%), NNT 20, adjusted, day 30.

Hunt et al., 6/29/2022, retrospective, USA, peer-reviewed, 8 authors, study period 1 March, 2020 - 10 September, 2020.

Screening Large Population Health Databases for Potential COVID-19 Therapeutics: A Pharmacopeia-Wide Association Study (PWAS) of Commonly Prescribed Medications

MacFadden et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofac156

Retrospective 26,121 cases and 2,369,020 controls ≥65yo in Canada, showing no significant differences in cases with chronic use of metformin.

risk of case, 1.0% lower, OR 0.99, p = 0.45, RR approximated with OR.

MacFadden et al., 3/29/2022, retrospective, Canada, peer-reviewed, 9 authors, study period 15 January, 2020 - 31 December, 2020.

Metformin Use in Relation to Clinical Outcomes and Hyperinflammatory Syndrome Among COVID-19 Patients With Type 2 Diabetes: A Propensity Score Analysis of a Territory-Wide Cohort

Wong et al., Frontiers in Endocrinology, doi:10.3389/fendo.2022.810914

Retrospective 1,214 COVID+ type 2 diabetes patients in Hong Kong, showing lower mortality and improved recovery with metformin use.

risk of death, 59.0% lower, OR 0.41, p = 0.01, treatment 786, control 428, adjusted, propensity score weighting, multivariable, RR approximated with OR.

risk of no recovery, 60.6% lower, OR 0.39, p = 0.005, treatment 786, control 428, adjusted, propensity score weighting, multivariable, RR approximated with OR.

clinical improvement, 63.5% better, OR 0.36, p = 0.009, treatment 786, control 428, adjusted, propensity score weighting, multivariable, RR approximated with OR.

risk of no hospital discharge, 55.8% lower, OR 0.44, p = 0.009, treatment 786, control 428, adjusted, propensity score weighting, multivariable, RR approximated with OR.

Wong et al., 3/7/2022, retrospective, China, peer-reviewed, 11 authors, study period 21 January, 2020 - 31 January, 2021.

Glycemic Control and Clinical Outcomes in U.S. Patients With COVID-19: Data From the National COVID Cohort Collaborative (N3C) Database

Wong et al., Diabetes Care, doi:10.2337/dc21-2186

N3C retrospective 39,616 COVID-19 patients with diabetes in the USA, showing lower mortality, ventilation, and hospitalization with metformin use.

risk of death, 51.0% lower, HR 0.49, p < 0.001, treatment 10,408, control 29,208, Cox proportional hazards.

risk of mechanical ventilation, 41.0% lower, OR 0.59, p < 0.001, treatment 10,408, control 29,208, adjusted, multivariable, RR approximated with OR.

risk of hospitalization, 40.0% lower, OR 0.60, p < 0.001, treatment 10,408, control 29,208, adjusted, multivariable, RR approximated with OR.

Wong et al., 2/24/2022, retrospective, USA, peer-reviewed, 15 authors.

Metformin use in patients hospitalized with COVID-19: lower inflammation, oxidative stress, and thrombotic risk markers and better clinical outcomes

Usman et al., Journal of Thrombosis and Thrombolysis, doi:10.1007/s11239-022-02631-7

Retrospective 75 diabetes patients, 34 on metformin, showing improved clinical outcomes with treatment, without statistical significance.

risk of death, 59.8% lower, RR 0.40, p = 0.21, treatment 3 of 34 (8.8%), control 9 of 41 (22.0%), NNT 7.6.

risk of mechanical ventilation, 75.9% lower, RR 0.24, p = 0.05, treatment 2 of 34 (5.9%), control 10 of 41 (24.4%), NNT 5.4.

hospitalization time, 33.7% lower, relative time 0.66, p = 0.13, treatment 34, control 41.

Usman et al., 1/18/2022, retrospective, USA, peer-reviewed, 10 authors.

Metformin use is associated with a decrease in risk of hospitalization and mortality in COVID-19 diabetic patients: a population-based study in Lombardy

Ojeda-Fernández et al., Diabetes, Obesity and Metabolism, doi:10.1111/dom.14648

Retrospective 31,966 COVID+ patients using anti-hyperglycemic drugs in Italy, showing lower mortality and ICU admission with metformin use.

risk of death, 16.2% lower, RR 0.84, p < 0.001, treatment 1,476 of 6,556 (22.5%), control 1,787 of 6,556 (27.3%), NNT 21, OR converted to RR, propensity score matching.

risk of death, 22.1% lower, RR 0.78, p < 0.001, treatment 968 of 6,556 (14.8%), control 1,261 of 6,556 (19.2%), NNT 22, OR converted to RR, in-hospital mortality, propensity score matching.

risk of ICU admission, 22.4% lower, RR 0.78, p = 0.01, treatment 166 of 6,556 (2.5%), control 212 of 6,556 (3.2%), NNT 143, OR converted to RR, propensity score matching.

risk of hospitalization, 2.7% lower, RR 0.97, p = 0.11, treatment 3,551 of 6,556 (54.2%), control 3,670 of 6,556 (56.0%), NNT 55, OR converted to RR, propensity score matching.

risk of death, 8.3% lower, RR 0.92, p = 0.06, treatment 793 of 3,297 (24.1%), control 876 of 3,297 (26.6%), NNT 40, OR converted to RR, excluding patients previously treated with insulin, propensity score matching.

risk of death, 16.0% lower, RR 0.84, p = 0.003, treatment 512 of 3,297 (15.5%), control 618 of 3,297 (18.7%), NNT 31, OR converted to RR, excluding patients previously treated with insulin, in-hospital mortality, propensity score matching.

risk of ICU admission, 39.2% lower, RR 0.61, p = 0.002, treatment 64 of 3,297 (1.9%), control 102 of 3,297 (3.1%), NNT 87, OR converted to RR, excluding patients previously treated with insulin, propensity score matching.

risk of hospitalization, 2.2% higher, RR 1.02, p = 0.36, treatment 1,822 of 3,297 (55.3%), control 1,792 of 3,297 (54.4%), OR converted to RR, excluding patients previously treated with insulin, propensity score matching.

Ojeda-Fernández et al., 1/10/2022, retrospective, Italy, peer-reviewed, 11 authors.

Association of the patterns of use of medications with mortality of COVID-19 infection: a hospital-based observational study

Wallace et al., BMJ Open, doi:10.1136/bmjopen-2021-050051

Retrospective 9,532 hospitalized COVID+ veterans in the USA, showing lower mortality with metformin use. The study provides results for use before, after, and before+after. Before+after should more accurately represent prophylaxis up to COVID-19 infection (and continued use). Before included use up to 2 years before, and after included use up to 60 days later.

risk of death, 72.0% lower, HR 0.28, p < 0.001, treatment 103 of 1,203 (8.6%), control 1,536 of 6,970 (22.0%), NNT 7.4, adjusted, before+after, propensity score weighting, Cox proportional hazards.

Wallace et al., 12/31/2021, retrospective, database analysis, USA, peer-reviewed, 6 authors.

The association between metformin treatment and COVID-19 outcomes according to metformin continuation during hospitalisation

Al-Salameh et al., Diabetes & Metabolism, doi:10.1016/j.diabet.2021.101297

Retrospective 140 diabetic patients in France, showing lower mortality for patients where metformin use was continued after hospitalization.

risk of death/ICU, 55.5% lower, RR 0.45, p = 0.04, treatment 9 of 47 (19.1%), control 22 of 50 (44.0%), NNT 4.0, adjusted, OR converted to RR, metformin continued, multivariable.

risk of death/ICU, 68.4% higher, RR 1.68, p = 0.02, treatment 34 of 43 (79.1%), control 22 of 50 (44.0%), adjusted, OR converted to RR, metformin discontinued, multivariable.

Al-Salameh et al., 11/30/2021, retrospective, France, peer-reviewed, 4 authors.

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.

Metformin Use in Patients Hospitalized With COVID-19: Lower Inflammation, Oxidative Stress, and Thrombotic Risk Markers and Better Clinical Outcomes

Bliden et al., Circulation, 144:A12228 (Preprint)

Retrospective 75 diabetes patients, 34 on metformin, showing lower mortality with treatment in unadjusted results with minimal group details.

risk of death, 59.8% lower, RR 0.40, p = 0.21, treatment 3 of 34 (8.8%), control 9 of 41 (22.0%), NNT 7.6.

risk of mechanical ventilation, 75.9% lower, RR 0.24, p = 0.05, treatment 2 of 34 (5.9%), control 10 of 41 (24.4%), NNT 5.4.

Excluded in after exclusion results of meta analysis: unadjusted results with minimal group details.

Bliden et al., 11/8/2021, retrospective, USA, preprint, 9 authors.

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

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, peer-reviewed, 6 authors, study period 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

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, 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

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, peer-reviewed, 8 authors.

Impact of overlapping risks of type 2 diabetes and obesity on coronavirus disease severity in the United States

Ando et al., Scientific Reports, doi:10.1038/s41598-021-96720-x

Retrospective 28,093 COVID+ patients in the USA, showing lower risk of hospitalization with metformin use.

risk of hospitalization, 39.0% lower, HR 0.61, p = 0.04, treatment 19 of 663 (2.9%), control 1,056 of 27,430 (3.8%), adjusted, multivariable, Cox proportional hazards.

Ando et al., 9/9/2021, retrospective, USA, peer-reviewed, 6 authors, study period 1 January, 2020 - 30 November, 2020.

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

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, peer-reviewed, 4 authors.

The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus

Yang et al., Diabetes Research and Clinical Practice, doi:10.1016/j.diabres.2021.108977 (meta analysis)

Meta analysis of 17 studies including 20,719 COVID-19 patients with diabetes, showing lower risk of mortality and severity with metformin.

risk of death, 36.0% lower, OR 0.64, p < 0.001, RR approximated with OR.

Yang et al., 8/31/2021, 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)

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

For multiple major issues with this trial see [doyourownresearch.substack.com].

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 [twitter.com].

750mg twice daily for 10 days. NCT04727424.

1. doyourownresearch.substack.com, https://doyourownresearch.substack..ether-trial-false-interim-analyses.

2. twitter.com, https://twitter.com/Covid19Crusher/status/1470733348079288333.

risk of death, 26.6% lower, RR 0.73, p = 0.53, treatment 7 of 215 (3.3%), control 9 of 203 (4.4%), NNT 85, day 28.

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, primary outcome.

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 viral clearance, 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, peer-reviewed, 23 authors, trial NCT04727424 (history) (TOGETHER).

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

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, HR 1.65, p = 0.25, treatment 678, control 535, after PSM.

Cheng et al., 8/20/2021, retrospective, propensity score matching, China, 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

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, peer-reviewed, 14 authors.

Therapeutic prevention of COVID-19 in elderly: a case–control study

Blanc et al., GeroScience, doi:10.1007/s11357-021-00397-z

Retrospective 179 patients in France exposed to COVID-19 showing, without statistical significance, a higher risk of cases, and a lower risk of mortality among cases with existing metformin treatment.

risk of death, 78.6% lower, RR 0.21, p = 0.06, treatment 1 of 14 (7.1%), control 25 of 75 (33.3%), NNT 3.8, COVID+.

risk of case, 43.7% higher, RR 1.44, p = 0.12, treatment 11 of 16 (68.8%), control 78 of 163 (47.9%).

Blanc et al., 7/17/2021, retrospective, France, peer-reviewed, 22 authors.

Outcome and death risk of diabetes patients with Covid-19 receiving pre-hospital and in-hospital metformin therapies

Tamura et al., Diabetology & Metabolic Syndrome, doi:10.1186/s13098-021-00695-8

Retrospective 188 hospitalized patients in Brazil, showing lower risk of mortality with metformin use. Authors note that, although pre-hospital metformin use improved clinical parameters at admission, continuous use during hospitalization is essential. Patients that used pre-hospital metformin therapy but interrupted the treatment during hospitalization showed higher mortality than those that continued metformin therapy.

risk of death, 96.6% lower, OR 0.03, p = 0.02, treatment 115, control 73, adjusted, in-hospital use, multivariable, RR approximated with OR.

Tamura et al., 7/13/2021, retrospective, Brazil, peer-reviewed, 4 authors, study period 10 March, 2020 - 13 November, 2020.

Retrospective Assessment of Treatments of Hospitalized Covid-19 Patients

Ravindra et al., medRxiv, doi:10.1101/2021.04.20.21255792

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%), adjusted, OR converted to RR.

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

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

Drug repositioning candidates identified using in-silico quasi-quantum molecular simulation demonstrate reduced COVID-19 mortality in 1.5M patient records

Alamgir et al., medRxiv, doi:10.1101/2021.03.22.21254110 (Preprint)

In Silico study followed by PSM analysis of the National COVID Cohort Collaborative data in the USA, showing 27% lower mortality with metformin use.

ABSTRACTBackgroundDrug repositioning is a key component of COVID-19 pandemic response, through identification of existing drugs that can effectively disrupt COVID-19 disease processes, contributing valuable insights into disease pathways. Traditional non in silico drug repositioning approaches take substantial time and cost to discover effect and, crucially, to validate repositioned effects.MethodsUsing a novel in-silico quasi-quantum molecular simulation platform that analyzes energies and electron densities of both target proteins and candidate interruption compounds on High Performance Computing (HPC), we identified a list of FDA-approved compounds with potential to interrupt specific SARS-CoV-2 proteins. Subsequently we used 1.5M patient records from the National COVID Cohort Collaborative to create matched cohorts to refine our in-silico hits to those candidates that show statistically significant clinical effect.ResultsWe identified four drugs, Metformin, Triamcinolone, Amoxicillin and Hydrochlorothiazide, that were associated with reduced mortality by 27%, 26%, 26%, and 23%, respectively, in COVID-19 patients.ConclusionsTogether, these findings provide support to our hypothesis that in-silico simulation of active compounds against SARS-CoV-2 proteins followed by statistical analysis of electronic health data results in effective therapeutics identification.

risk of death, 27.0% lower, OR 0.73, p < 0.001, treatment 11,062, control 11,062, all patients, RR approximated with OR.

risk of death, 34.0% lower, OR 0.66, p = 0.007, treatment 5,369, control 5,369, diabetic patients with CCI≤3, RR approximated with OR.

risk of death, 30.0% lower, OR 0.70, p = 0.02, treatment 2,525, control 2,525, non-diabetic patients with CCI≤3, RR approximated with OR.

Alamgir et al., 4/6/2021, retrospective, database analysis, USA, preprint, 11 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

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, HR 0.34, p < 0.001, treatment 392, control 747, adjusted, multivariable, Cox proportional hazards.

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

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

Ghany et al., 3/31/2021, retrospective, USA, 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

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, HR 0.54, p = 0.40, treatment 3 of 74 (4.1%), control 10 of 74 (13.5%), 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, 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

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, HR 0.77, p < 0.001, adjusted.

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

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

Holt et al., Thorax, doi:10.1136/thoraxjnl-2021-217487

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. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. 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%), 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, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021, trial NCT04330599 (history) (COVIDENCE UK).

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study

Wargny et al., Diabetologia, doi:10.1007/s00125-020-05351-w

Retrospective 2,796 hospitalized diabetes patients with COVID-19 in France, showing lower mortality with metformin use.

risk of death, 28.3% lower, RR 0.72, p = 0.03, treatment 247 of 1,553 (15.9%), control 330 of 1,241 (26.6%), NNT 9.4, adjusted, OR converted to RR, multivariable, day 28.

risk of no hospital discharge, 14.8% lower, RR 0.85, p = 0.02, treatment 690 of 1,553 (44.4%), control 702 of 1,241 (56.6%), NNT 8.2, adjusted, OR converted to RR, multivariable, day 28.

Wargny et al., 2/17/2021, retrospective, France, peer-reviewed, 43 authors, study period 10 March, 2020 - 10 April, 2020, trial NCT04324736 (history) (CORONADO).

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

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, OR 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, 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

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

risk of death, 52.0% lower, HR 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, 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

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, 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

Retrospective database analysis showing no significant differences with pre-existing metformin use.

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, multivariable.

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, multivariable.

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

Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19

Lalau et al., Diabetes & Metabolism, doi:10.1016/j.diabet.2020.101216

Retrospective 2,449 hospitalized COVID-19 diabetes patients in France, 1,496 with existing metformin use, showing lower mortality with treatment. Statistical significance was reached in model 1 but not in models 2-4 which also adjust for HbA1c, eGFR, and diabetes duration, but have a lower number of patients. CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes).

risk of death, 22.2% lower, OR 0.78, p = 0.16, treatment 671, control 419, day 28, model 2, propensity score matching, RR approximated with OR.

risk of death/intubation, 17.8% lower, OR 0.82, p = 0.21, treatment 671, control 419, day 28, model 2, propensity score matching, primary outcome, RR approximated with OR.

risk of mechanical ventilation, 6.8% lower, OR 0.93, p = 0.72, treatment 671, control 419, day 28, model 2, propensity score matching, RR approximated with OR.

Lalau et al., 12/10/2020, retrospective, France, peer-reviewed, 33 authors, study period 10 March, 2020 - 10 April, 2020.

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

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, OR 0.76, p = 0.02, treatment 1,129, control 2,173, PSM, women, RR approximated with OR.

risk of death, 3.5% higher, OR 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, peer-reviewed, 17 authors.

Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study

Pérez-Belmonte et al., BMC Medicine, doi:10.1186/s12916-020-01832-2

Retrospective 2,666 type 2 diabetes COVID-19 patients in Spain, showing higher mortality with existing metformin use (not statistically significant).

risk of death, 10.4% higher, RR 1.10, p = 0.48, treatment 79 of 249 (31.7%), control 79 of 249 (31.7%), OR converted to RR, mixed effect logistic regression, propensity score matching.

Pérez-Belmonte et al., 11/16/2020, retrospective, propensity score matching, Spain, peer-reviewed, 26 authors.

The Effect of Metformin Consumption on Mortality in Hospitalized COVID-19 patients: a systematic review and meta-analysis

Lukito et al., Diabetes & Metabolic Syndrome: Clinical Research & Reviews, doi:10.1016/j.dsx.2020.11.006 (meta analysis)

Meta analysis of 9 studies showing lower mortality with metformin use.

Lukito et al., 11/11/2020, peer-reviewed, 6 authors.

Risk of Metformin in Patients With Type 2 Diabetes With COVID‐19: A Preliminary Retrospective Report

Gao et al., Clinical and Translational Science, doi:10.1111/cts.12897

Retrospective 110 hospitalized COVID-19 patients with diabetes in China, showing increased risk of severity with metformin.

risk of progression, 225.0% higher, RR 3.25, p = 0.045, treatment 16 of 56 (28.6%), control 4 of 54 (7.4%), OR converted to RR, progression to life threatening complications.

Gao et al., 10/19/2020, retrospective, China, peer-reviewed, 7 authors, study period 31 January, 2020 - 20 March, 2020.

Risk factors for severe disease in patients admitted with COVID-19 to a hospital in London, England: a retrospective cohort study

Goodall et al., Epidemiology and Infection, doi:10.1017/S0950268820002472

Retrospective 981 hospitalized patients in the UK, showing no significant difference with metformin use.

risk of death, 3.0% lower, HR 0.97, p = 0.81, treatment 74 of 210 (35.2%), control 280 of 771 (36.3%), NNT 93.

Goodall et al., 10/13/2020, retrospective, United Kingdom, peer-reviewed, 7 authors, study period 12 March, 2020 - 15 April, 2020.

Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19

Li et al., Endocrine Practice, doi:10.4158/EP-2020-0466

Retrospective 131 type II diabetes patients with COVID pneumonia, showing lower mortality with existing metformin use. Acarbose (commonly used in China as an initial therapy for diabetes) did not have a similar association with mortality, suggesting that the result may not be explained by metformin being used early in type II diabetes.

risk of death, 77.7% lower, HR 0.22, p = 0.02, treatment 2 of 37 (5.4%), control 21 of 94 (22.3%), NNT 5.9, adjusted, multivariable.

risk of mechanical ventilation, 27.0% higher, RR 1.27, p = 1.00, treatment 1 of 37 (2.7%), control 2 of 94 (2.1%).

Li et al., 10/1/2020, retrospective, China, peer-reviewed, 16 authors, study period 23 January, 2020 - 19 March, 2020.

Mortality risk with preadmission metformin use in patients with COVID‐19 and diabetes: A meta‐analysis

Kow et al., Journal of Medical Virology, doi:10.1002/jmv.26498 (meta analysis)

Meta analysis of 5 studies showing lower mortality with metformin use.

Kow et al., 9/30/2020, peer-reviewed, 2 authors.

Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection

Hariyanto et al., Obesity Medicine, doi:10.1016/j.obmed.2020.100290 (meta analysis)

Meta analysis of 5 studies showing lower mortality with metformin use.

Hariyanto et al., 8/18/2020, peer-reviewed, 2 authors.

The Clinical Characteristics and Outcomes of Patients with Moderate-to-Severe Coronavirus Disease 2019 Infection and Diabetes in Daegu, South Korea

Kim et al., Diabetes & Metabolism Journal, doi:10.4093/dmj.2020.0146

Retrospective 235 hospitalized diabetes patients in South Korea, showing lower mortality and lower progression to severe disease with metformin.

risk of death, 64.0% lower, OR 0.36, p = 0.10, treatment 113, control 122, adjusted, multivariable, RR approximated with OR.

risk of progression, 52.0% lower, OR 0.48, p = 0.13, treatment 113, control 122, adjusted, multivariable, RR approximated with OR.

Kim et al., 8/12/2020, retrospective, South Korea, peer-reviewed, 32 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

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, 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

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, peer-reviewed, 13 authors.

Clinical Characteristics and Disease Progression in Early-Stage COVID-19 Patients in South Korea

Choi et al., Journal of Clinical Medicine, doi:10.3390/jcm9061959

Retrospective 293 patients in South Korea, showing higher risk of progression with metformin use, without statistical significance.

risk of progression, 100% higher, RR 2.00, p = 0.26, treatment 6 of 36 (16.7%), control 3 of 36 (8.3%), propensity score matching.

Choi et al., 6/23/2020, retrospective, South Korea, peer-reviewed, median age 29.0, 8 authors, study period 5 March, 2020 - 18 March, 2020.

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

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, peer-reviewed, 9 authors.

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption