A Lancet Healthy Longevity study yesterday found that metformin—a common, generic type 2 diabetes medication used to manage blood sugar levels—is associated with significantly lower COVID-19 death risk in women, but not in men.
Severe COVID-19 outcomes for people with diabetes have been widely observed, including greater risk of intensive care unit admission, intubation for mechanical ventilation, and death, possibly related to less effective glycemic, or blood sugar, control in these patients.
This retrospective cohort study of 6,256 people with type 2 diabetes or obesity hospitalized for COVID-19 from Jan 1 to Jun 7 was a collaboration between the University of Minnesota Medical School and UnitedHealth Group (UHG)—a for-profit managed healthcare company based in Minnesota.
The team analyzed de-identified data from UHG's Clinical Discovery Claims Database, which includes information from a diverse patient population in all 50 states.
The investigators identified 2,333 adults who filled 90-day metformin prescriptions within 12 months of COVID-19 diagnosis (48.4% women, mean age 73.0 years) and 3,923 non-users (55.4% women, median age 76.0 years) to assess associations between home metformin use and risk of in-hospital mortality from COVID-19.
Drug tied to 21% lower risk of death
The researchers found that metformin use was associated with a 21.5% lower risk of death in women (hazard ratio [HR], 0.785; 95% confidence interval [CI], 0.650 to 0.951; odds ratio [OR], 0.759; 95% CI, 0.601 to 0.960), but there was no significant reduction among men (HR, 0.957, 95% CI, 0.82 to 1.14; P = 0.689).
"These findings could have wide-reaching effects, because more than 42% of women in the USA have obesity," the study authors wrote. "Our analysis supports the preventive use of metformin, before infection with SARS-CoV-2, to prevent severe COVID-19 in patients with diabetes or obesity."
Anti-inflammatory action may be key
People with type 2 diabetes or obesity have higher levels of cytokines—inflammatory factors such as interleukin (IL)-6 and tumor necrosis factor α (TNFα)—that may contribute to major inflammatory reactions in severe COVID-19 patients. Metformin has documented anti-inflammatory properties that have been shown to reduce levels of IL-6 and TNFα, with greater effects in women.
"Observational studies like this cannot be conclusive, but contribute to growing bodies of evidence," said lead researcher Carolyn Bramante, MD, MPH, an assistant professor in the Department of Medicine at the University of Minnesota Medical School, in a university news release yesterday.
"Seeing a bigger association with protection in women over men may point towards inflammation reduction as a key way that metformin reduces risk from COVID-19. However, more research is needed."
Potential for broad use, caution about side effects
The wide availability, low cost, minimal need for follow-up, and extensive safety data—even during pregnancy—for metformin add to the drug's appeal to prevent severe COVID-19.
"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 suggested. "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."
The authors of a commentary in the same journal caution that the study was based on records of prescriptions filled, which do not capture effective use, duration of treatment, dose, and whether the drug was actually taken at the time of hospital admission. They also note that potential side effects would need to be considered before broad use, particularly metformin's association with lactic acidosis—a potentially life-threatening complication.
The commentary authors, Angela Dardano, MD, PhD, and Stefano Del Prato, MD, PhD, both of the University of Pisa in Italy, also noted that metformin users in the study were younger than non-users and had a lower prevalence of comorbidities commonly associated with poorer outcomes in diabetic people with COVID-19.
In addition, the study gathered data from multiple hospitals that may have used different protocols. These factors warrant caution in drawing broad conclusions about drug-related mortality reductions and point to the need for large, randomized controlled trials, Dardano and Del Prato wrote.
The study's authors are seeking funding for a multisite prospective, randomized trial of metformin, with the pilot trial set to begin enrollment on Dec 8.