Metformin Treatment Again Linked to Fewer Deaths From COVID-19

Nancy A. Melville

January 20, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

People with type 2 diabetes who develop COVID-19 show a substantially reduced risk of dying if they are taking metformin, shows a new study that adds to prior research indicating the drug might somehow play a role in reducing the severity of infection.

"Unlike several previous analyses, this was a study in a racially diverse population with a high proportion of Blacks/African Americans and...[it] revealed that metformin treatment of diabetes prior to diagnosis with COVID-19 was associated with a dramatic threefold reduced mortality in subjects with type 2 diabetes, even after correcting for multiple covariates," first author Anath Shalev, MD, of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, told Medscape Medical News.

But Anne Peters, MD, a professor of clinical medicine at the Keck School of Medicine, University of Southern California, in Los Angeles, said caution is needed when interpreting these findings.

"It's hard to tease out the true effects because, for instance, those treated with insulin may be a sicker subset of patients with diabetes than those on metformin, or those with comorbidities such as renal insufficiency may not be treated with metformin" she told Medscape Medical News.

"In general, though, treatment obviously matters and people who are better treated tend to do better, so while I think this study raises the question of what role metformin plays in the risk of mortality and COVID-19, I don't think it necessarily proves the association," Peters asserted.

Diverse Population

The new study, published this month in Frontiers of Endocrinology, included 25,326 individuals who were tested for COVID-19 at the University of Alabama at Birmingham Hospital between February and June 2020.

Overall, 2.4% tested positive for COVID-19 (n = 604), which the authors note is likely a low figure because screening included asymptomatic hospital staff and patients having elective procedures.

Black/African American patients had a significantly higher risk of COVID-19 positivity compared with White patients (odds ratio [OR], 2.6; P < .0001). Rates were also higher among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93) compared to those without each condition (all P < .0001).

The overall mortality rate in COVID-19-positive patients was 11%. Diabetes was associated with a dramatically increased risk of death (OR, 3.62; P < .0001), and remained an independent risk factor even after adjusting for age, race, sex, obesity, and hypertension.

Notably, the reduction in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was significant: 11% of those patients died compared with 23% of those with diabetes not taking metformin (OR, 0.33; P = .021).

Similar Findings Reported Across Varied Populations

The study adds to mounting research suggesting metformin could have a protective effect on COVID-19 mortality, including an early report from Wuhan, China, findings from the French CORONADO study, and a US study linking treatment with decreased mortality among women with COVID-19.

Of note, the effects of metformin on mortality in the current study were observed in men and women alike, as well as in high-risk subgroups including African Americans.

"The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with type 2 diabetes and COVID-19, might be generalizable," the authors write.

"Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment," they add.

Speculation of Mechanisms Includes Anti-Inflammatory Effects

While the mechanisms behind metformin's potential role in reducing mortality risk in COVID-19 are unknown, the authors note that the most obvious assumption — that improved glycemic control may be a key factor — is disputed by the study's finding that blood glucose levels and A1c were not significantly different among COVID-19 survivors taking versus not taking metformin.

They point instead to metformin's known anti-inflammatory and anti-thrombotic properties.

"We therefore hypothesize that by exerting some of these effects, metformin might improve outcomes and we are now in the process of investigating this possibility further," Shalev said.

Peters noted that anti-inflammatory properties, themselves, are not necessarily unique to metformin in the treatment of diabetes.

"Many other agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce inflammation, so I don't know if that would explain it, but it certainly could help," she said. "[Reducing inflammation] is a hypothesis you see commonly with diabetes drugs, but I think there are also a lot of metabolic benefits from metformin."

"It was fascinating that they had the A1c data and that survival with metformin didn't appear to be as related to A1c levels as one might think," she added.

Notably, a key advantage, should the effects and mechanisms be validated, is metformin's high accessibility, Peters added.

"This doesn't necessarily tell us what we can do to reduce the health care disparities surrounding COVID-19, but the fact that metformin is low cost and easily available is very important, so maybe it will help as we try to grapple with other risk factors."

The authors have reported no relevant financial relationships.

Front Endocrinol. Published January 13, 2021. Full text

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