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Metformin was significantly associated with decreased mortality in women with obesity or type 2 diabetes who were admitted to hospital for coronavirus disease 2019 (COVID-19), although no significant link was found in men, according to findings published in The Lancet Healthy Longevity.
“Our analysis supports the preventive use of metformin, before infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to prevent severe COVID-19 in patients with diabetes or obesity,” said the authors led by Carolyn T Bramante, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Researchers conducted a retrospective cohort analysis using claims data from the UnitedHealth Group (UHG)’s Clinical Discovery Claims Database, which includes de-identified data for individuals with COVID-19 admissions in all 50 US states, covering a diverse range of ages, ethnicities and regions.
They found that 6,256 of the 15,380 individuals with pharmacy claims data were eligible for inclusion in the study. Patients had to be over 18, have at least 6 months of continuous enrolment in UHG last year, and be admitted to hospital with COVID-19 between January 1 and June 7, 2020. Among this cohort of 6256 individuals, the median age was 73 years, and 52.8% were women. Type 1 diabetics were excluded from the analysis.
The primary outcome was in-hospital mortality from COVID-19, with the independent variable being home metformin use, defined as more than 90 days of prescription claims during the year before admission to hospital for COVID-19. The exploratory independent variable of interest was home use of TNFα inhibitors. The UHG database did not include outcomes related to in-hospital complications, intensive care unit, or ventilator use, so an analysis on these endpoints was not possible.
Of the 2,333 people in the metformin group, 394 (16.9%) died of COVID-19 during admission to hospital for the disease, 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 both 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 =0.15).
However, among women, the drug was associated with lower death rates 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 =0.021). There was no significant reduction in mortality among men (HR 0.957, 95% CI 0.82–1.14; P =0.689 by Cox proportional hazards).
Of the 15,362 people included in the exploratory analyses, 38 (0.25%) had claims for a TNFα inhibitor. Results showed these drugs were non-significantly associated with decreased mortality (HR 0.350, 95% CI 0.087–1.415) in the Cox proportional hazards model. In a propensity-matched model, matched for the same variables as the metformin analyses, TNFα inhibitors were not associated with decreased mortality (0.483, 0.0821–2.845; P =0.421).
The authors noted that metformin reduces TNFα and other inflammatory adipokines that are high in people with obesity and type 2 diabetes and contribute to COVID-19 severity, while it boosts levels of the anti-inflammatory cytokine IL-10. They also highlighted previous research showing that metformin causes these beneficial effects significantly more in females than males in both animal and human studies.
The current study “highlights the need to differentiate whether starting metformin at the time of diagnosis of SARS-CoV-2 infection will convey the same benefits as use of metformin before SARS-CoV-2 infection,” the authors said. “Metformin is one of the few COVID-19 therapies that could be given to all adults, regardless of current or potential pregnancy status, as long as they do not have severe kidney disease,” they noted, whilst also pointing to the drug’s low cost. “If our findings are replicated in other analyses and prospective trials, metformin should be widely distributed for prevention of severe COVID-19 in people with diabetes or a BMI of at least 30 kg/m2,” the authors said.
Limitations included the retrospective nature of the analysis, and the inability to assess outcomes other than mortality, such as length of stay or need for mechanical ventilation. Moreover, while claims data show metformin was prescribed as a home medication for at least 90 days within the last 12 months, they do not give information about adherence. The authors also pointed to potential selection bias that could come from using claims data, noting that metformin is sometimes purchased without insurance claims and therefore some individuals in the control group might have been exposed to the treatment, which would reduce the observed effect size.
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