Metformin Linked to Lower COVID-19 Mortality Rates Among Women With T2D, Obesity

Among women hospitalized with coronavirus disease 2019 (COVID-19), taking metformin—a type 2 diabetes (T2D) drug used to manage blood sugar levels—was associated with a 21.5% lower risk of death, according to a study¹ published in Lancet Health Longevity. However, similar results were not seen among men who took the medication.

Diabetes and obesity are both established risk factors for developing more severe COVID-19 complications. High levels of tumor necrosis factor α (TNFα), which contributes to insulin resistance, have been found in the lung tissues of individuals with COVID-19, whereas interleukin (IL)-6, a proinflammatory molecule, is also implicated in COVID-19 morbidity, researchers explained. In addition, individuals with T2D tend to have lower levels of IL-10, an anti-inflammatory cytokine.

Metformin “decreases TNFα and IL-6, boosts IL-10, and has been found to cause these beneficial effects significantly more in females than males in both animal and human studies,” authors wrote. The medication has also been shown to improve inflammation and cytokines associated with obesity in those with and without diabetes. Currently, over 42% of women in the United States have obesity.

Based on this information, researchers conducted a retrospective cohort analysis to understand whether home metformin use was associated with decreased mortality in people hospitalized for COVID-19, and to assess sex-specific effects.

De-identified data were amassed from UnitedHealth Group (UHG)'s Clinical Discovery Claims Database, representing patients from all 50 states with both commercial and Medicare Advantage insurance. All participants were aged 18 years or older, had T2D or obesity, and were enrolled for at least 6 months in UHG in 2019. Patients were admitted to a hospital for COVID-19 (diagnoses confirmed by polymerase chain reaction [PCR] tests) between January 1, 2020 and June 7, 2020 or reported from the hospital to UHG.

Because the data base did not include outcomes related to in-hospital complications, intensive care unit or ventilator use, analyses on these endpoints were not carried out. In-hospital mortality was defined using the hospital disposition indicator while those still in the hospital on June 7, 2020 were excluded from analyses.

A total of 6256 patients were included in the final analyses. A slim majority (52.8%; n = 3302) of participants were female. Of these, 2333 individuals (1129 females, median age 73 years) took metformin for at least 90 days within the last 12 months.

Analyses revealed:

• A total of 394 (16.9%) metformin recipients died of COVID-19 during hospital admission, compared with 791 (20.2%) of 3923 in the non-metformin group
• Metformin use was not associated with significantly decreased mortality in the overall sample of men and women by either Cox proportional hazards stratified model (hazard ratio [HR], 0.887; 95% CI, 0.782–1.008) or propensity matching (odds ratio [OR], 0.912; 95% CI, 0.777–1.071; P = .15)
• Metformin was associated with decreased mortality in women by Cox proportional hazards (HR, 0.785; 95% CI, 0.650–0.951) and propensity matching (OR, 0.759; 95% CI, 0.601–0.960; P = .021)
• There was no significant reduction in mortality among men taking metformin (HR, 0.957; 95% CI, 0.82–1.14; P = .689 by Cox proportional hazards)
• In a propensity-matched model, (matched for the same variables as the metformin analyses) TNFα inhibitors were not associated with decreased mortality (HR, 0.483; 95% CI, 0.0821–2.845; P = .421)
• In a propensity model matched on age, sex, Charlson comorbidity index, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus, TNFα inhibitors were significantly associated with decreased mortality (OR, 0.19; 95% CI, 0.038–0.983; P = .048)

Previous studies have shown male sex is a risk factor for poor COVID-19 outcomes, and metformin use did not appear to reduce mortality in the current analysis. Although TNFα inhibitor use was associated with decreased odds in mortality, findings were only significant in a limited model which may have been the result of a small sample size (n = 38).

However, “Reduced mortality in people who use TNFα inhibitors would support previous research that TNFα plays a role in the pathology of COVID-19, probably due to macrophage activation and increased cytokine release,” researchers noted.

IL-6 and TNFα are thought to contribute to COVID-19 pathology and authors hypothesized the strong sex-specific response seen in the analysis suggests TNFα reduction “might be the primary way by which metformin reduced mortality from COVID-19.” The effects of sex hormones and epigenetic changes on the Y chromosome may contribute to the sex-specific results seen with metformin.

The lack of demographic characteristics allowing for comparison within each subgroup of sex marks a limitation to the study, in addition to the study’s retrospective nature. Researchers noted their findings ought to be prospectively confirmed as the availability and safety of metformin make it a potentially appealing option to providers and patients.

“Our analysis supports the preventive use of metformin, before infection with SARS-CoV-2 [the virus which causes COVID-19], to prevent severe COVID-19 in patients with diabetes or obesity,” authors concluded.

In an accompanying editorial,² researchers caution the retrospective analysis is based on administrative records which do not provide information on effective use of the drug, duration of treatment, and dose. Whether metformin was continued upon admission to the hospital is unclear. Side effects of metformin, such as lactic acidosis, also ought to be taken into account.

Large, randomized controlled trials on the effects of metformin on COVID-19 may be difficult to carry out. “However, it is because of the low cost of metformin that randomized trials could prove a very high cost-effectiveness, particularly when dealing with highly expensive diseases, such as COVID-19,” researchers wrote.

References:

1.Bramante CT, Ingraham NE, Murray TA, et al. Metformin and risk of mortality in patients hospitalized with COVID-19: a retrospective cohort analysis. Lancet Healthy Longev. Published online December 3, 2020. doi:10.1016/S2666-7568(20)30033-7

2. Dardano A and Del Prato S. metformin: an inexpensive and effective treatment in people with diabetes and COVID-19? Lancet Healthy Longev. Published online December 3, 2020. doi: 10.1016/S2666-7568(20)30047-7