Table 1.
Overview of papers in 2020 with findings related to metformin and Covid-19.
| Author | Population | Methods | Finding | Mechanism or other findings | ||
|---|---|---|---|---|---|---|
| Outcomes in Covid-19 | ||||||
| Luo et al. (8) Am J Trop Med Hyg | 283 adults with T2DM hospitalized with Covid-19 in Wuhan. | Retrospective cohort, 104 adults on metformin with 179 not on metformin. Metformin use appears to be home metformin use. | - Hospital mortality, metformin vs no metformin: 2.9% vs 12.3% (p=0.01)- No difference in length of stay- No associations with other T2DM meds- OR for survival: 4.36 (1.22-15.59, p=0.02) | Lower glucose levels in the metformin group, 9.19 vs 7.36 (p<0.01), no difference in neutrophils or lymphocytes. | ||
| Cariou et al (9), “Coronado study” Diabetalgia | 1,317 adults with T2DM in France, with or without home metformin use | Multi-center observational study. Main outcome: mortality or intubation; Secondary outcome was mortality | - HbA1C not associated with main outcome (p=0.28) or death (p=0.91) - Preadmission metformin use associated with lower mortality OR 0.59 (0.42, 0.84),- No association with other T2DM meds - OR mortality with insulin 1.71 (1.20, 2.43) | CRP 1.99, (1.69, 2.43), lymphocyte count (OR 0.69, 0.60-0.80), fibrinogen OR 1.32 (1.09, 1.58) and AST (OR 2.23, 1.70-2.93) predicted mortality. | ||
| Crouse et al. (10), Frontiers in Endocrinology | 25,326 subjects tested for Covid-19 between 2/25/20 and 6/22/20 in Alabama. | Retrospective electronic health records study assessing mortality in Covid-19 | - Association between prior metformin use and a reduction in mortality (OR 0.33, 95% CI 0.13-0.84; p=0.02) compared to those with T2DM not on metformin. | Glucose levels similar between both groups, Metformin mechanism may reside outside of its glycemia. | ||
| Bramante et al (11), Lancet Health and Longevity | 6,256 adults with T2DM or obesity hospitalized for Covid-19 in the US | Retrospective review of USA UnitedHealth Group claims data; 2,333 in metformin group, 3,923 in no-metformin group | - Metformin associated with reduced mortality in females: OR 0.759 (0.601, 0.960) by propensity matching; OR 0.780 (0.631, 0.965) by mixed effects; OR 0.785 (0.650, 0.951) by Cox proportionalhazards. | In same sample, TNFα inhibitors were associated with decreased mortality (only 38 patients), suggesting TNFα a possible pathway. | ||
| Lalau et al (12), Diabetes & Metabolism | 2449 adults with T2DM with or without previous metformin use | Multi-center observational study. Main outcome: mortality or intubation within 7 days and 28 days of admission | - Mortality rate in metformin users vs non: day 7 (8.2 vs 16.1%, P < 0.0001); day 28 (16.0 vs 28.6%, P < 0.0001)- Mortality by propensity score weighting, metformin users vs non: day 7 OR 0.67 (0.47−1.01); day 28 0.71 (0.54−0.94). | Metformin users presented greater case severity on admission regarding clinical, radiological, and biological features, compared with non-users. | ||
| Lukito et al (13), Diabetes & Metab Synd: Clin Res& Rev | Meta-analysis of 10,233 adults across 9 studies | The mean NOS of the included studies was 8.55 ± 0.52, indicating high-quality studies. | - Metformin use associated with lower mortality in pooled non-adjusted model, OR 0.45 (0.25, 0.81), p=0.008; and adjusted (OR 0.64 (0.43, 0.97), p = 0.035. | SARS-CoV-2 damages β-cells. Optimal control of T2DM, for chronic and transient cases, may help in treating COVID-19 | ||
| Mechanistic, diabetes, and safety findings in Covid-19 | ||||||
| Chen et al. (14) Diabetes Care | 904 patients with Covid-19, 136 of whom had T2DM | Characteristics and outcomes of patients with T2DM and Covid-19. No results reporte for use of GLP-1 receptor agonists. | - Metformin users vs non-users: No significant difference in likelihood of ‘poor prognosis’: 30% vs. 50%, p=0.688- In PCR-confirmed cases, no difference in in-hospital death (18.2% vs 26.1%, p=0.77). No associations with DDP-4i’s | Metformin users had lower IL-6 (4.07 vs 11.1, p=0.02). In PCR-confirmed cases, IL-6 was also lower in metformin users than non-metformin users (4.77 vs 11.1, p=0.024). | ||
| Zhu et al. (15) Cell metabolism | 952 adults with T2DM Covid-19 and in Hubei, China | Retrospective review. Metformin was given in hospital to 278 patients. | - Metformin was more likely to be given to those with poor glucose control.- No metformin specific results reported. | Worse glucose control associated with mortality and end-organ complications. | ||
| Montastruc et al. (16) | 10,771 ICSRs involving hydroxychloroquine | Retrospective review, outcomes of mortality | - Hydroxychloroquine + metformin associated with a ROR of 57.7 (23.9-139.3) compared to hydroxychloroquine- Hydroxychloroquine + metformin was associated with a ROR value of 6.0 (2.6-13.8) compared to metformin alone | More autophagosomes in heart, liver, kidneys of mice treated with both. Synergism of inhibition of mitochondrial complex I, and autophagy from hydroxychloroquine (17). | ||
| Huh et al (18), medrxiv.org | 65,149 adults,claims data in S Korea. | Case control study, metformin (n=219) vs control (n=3604) | - Risk of Infection, crude OR 0.69 (0.60-0.80), aOR: 0.95 (0.81-1.11). | Covariates: sex, age, region, comorbidities, meds, utilization | ||
| Nafakhi et al, Diabetes & Metab Synd: Clin Research & Reviews | 192 patients with COVID-19 pneumonia, of whom 67 patients had T2DM | Retrospective cohort of patients with newly diagnosed COVID-19 pneumonia; August 20, to October 5, 2020 in Iraq | - Metformin use associated with lower ICU days, OR 0.30 (0.20-0.40, p=0.03); hospital days, OR 0.40 (0.20-0.30,p=0.02); and in-hospital mortality OR 0.10 (0.1–0.6), p = .025. | Insulin use was associated with extensive lung injury and post-acute COVID-19 pneumonia partial recovery | ||
| Cheng et al. (19) | 1,213 patients with Covid-19 and T2DM | Retrospective cohort of individuals hospitalized | HR Acidosis 2.73 (1.04-7.13,p=0.04); lactic acidosis 4.46 (1.11,18.00,p=0.04) | Appears to be for use of 2-3g/day during hospitalization. | ||
| Evidence that metformin does reduce TNF-alpha in both males and females. | ||||||
| Author | Population | Finding | ||||
| Krysiak et al. (20) | Humans, 36% female, did not compare men vs women. | After 12 weeks of treatment, metformin “reduced plasma C-reactive protein levels and monocyte release of TNFα and IL-6, as well as tended to reduce monocyte release of IL-1β and monocyte chemoattractant protein-1, which was accompanied by an improvement in insulin sensitivity. | ||||
| Andrews et al. (21) | Humans, men only with obesity and diabetes, ave age 55 years. | Those “treated with metformin had lower levels of hsCRP expression of TNFα and TLR 2/4, than their counterparts not receiving the drug.” | ||||
| Hyun et al. (22) | Mice, male only | Metformin suppresses scavenger receptors in macrophages, down-regulates TNFα | ||||
| Metformin and sex-specific findings. | ||||||
| Author | Population | Finding | ||||
| Park, J, et al. (23) | Patients with colorectal cancer | Interaction test between metformin and sex after adjustment for relevant factors revealed that female CRC patients taking metformin exhibited a significantly lower CRC-specific mortality rate than male CRC patients taking metformin (HR = 0.369, 95%CI: 0.155-0.881, P = 0.025). Subgroup analysis revealed significant differences in CRC-specific mortality between the metformin and non-metformin groups in female patients (HR = 0.501, 95%CI: 0.286-0.879, P = 0.013) but not male patients (HR = 0.848, 95%CI: 0.594-1.211, P = 0.365). | ||||
| DPP (24 ) | Adults with overweight & preDM | Metformin reduced CRP by 7% in men and 14% in women | ||||
| Quan, H, et al. (25) | 105 human patients | Combined exenatide and metformin showed better effects on female than male patients for improving insulin sensitivity and serum lipid profile, reducing insulin resistance, increasing adiponectin levels, and decreasing the levels of HbA1c, BMI, resistin, TNF-alpha, CRP (p<0.05). | ||||
| Naffaa et al (26), | 113, 749 patients who started metformin from 1998-2014. | Adherence assessed by the mean proportion of follow-up days covered (PDC) with metformin. Adherence with was associated with a reduced risk of developing RA in women, not men. | ||||
| Jiang et al. (27) | 328 patients with T2D and Covid, 100 of which were on metformin while hospitalized | In the mixed-effected model, metformin use was associated with the lower incidence of ARDS. | ||||
| Metformin may have potential benefits in reducing the incidence of ARDS in patients with COVID-19 and type 2 diabetes. However, this benefit differs significantly by gender as confirmed by subgroup analysis, metformin use was associated with the lower incidence of ARDS in females. | ||||||
T2DM, Type 2 diabetes mellitus; PCR, Polymerase chain reaction; GLP-1, glucadon-like-peptide 1; DDP-4, Dipeptidyl peptidase-4; WBC, White blood cells, HbA1C, Hemoglobin A1c; CRP, C-reactive protein, AST, Aspartate aminotransferase; OR, odds ratio; ROR, Risk Odd Ratio; AMPK, adenosine monophosphate protein kinase; mTOR, mammalian target of rapamycin; NFK, nuclear factor kappa light enhancer of activated B cells (NFKB); TLR, Toll Like Receptor. DPP, Diabetes Prevention Research Group; CRC, Colorectal cancer; BMI, Body mass index; RA, Rheumatoid arthritis.