Does Metformin Reduce Risk for Death in COVID-19?

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Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.

The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.

The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.

Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a "mini review" by André J. Scheen, MD, PhD, published August 1 in Diabetes and Metabolism.

Scheen, of the Division of Diabetes, Nutrition, and Metabolic Disorders and the Division of Clinical Pharmacology at Liège University, Liège, Belgium, discusses possible mechanisms behind this observation.

"Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19," he says.

"However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials," Scheen writes.

Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News: "Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use."

She added, "I don't think we have enough data to suggest metformin use for COVID-19 mitigation at this point."

Alabama Authors Say Confounding Effects "Unlikely"

In the retrospective analysis of electronic health records from their institution, Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between February 25 and June 22, 2020. Of those individuals, 40% had diabetes.

Death occurred in 11% (n = 67); the odds ratio for death among those with, vs without, diabetes was 3.62 (P < .0001).

Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50 – 70 vs <50, male sex, and diabetes emerged as independent predictors of death.

Of the 42 patients with diabetes who died, 34 (81%) had used metformin, and eight (19%) had not, a significant difference (odds ratio 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).

"In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin," the authors say.

The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (odds ratio, 0.17; P = .0231).

"This makes any potential confounding effects from skewing metformin users towards healthier subjects without these additional comorbidities very unlikely," Crouse and colleagues contend.

After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.

For metformin, the odds ratio was 0.33 (P = .0210).

But Lipska pointed out, "Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies.... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers."

If Metformin Does Reduce COVID-19 Deaths, Multiple Mechanisms Likely

In his article, Scheen notes that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasizes.

He notes that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.

In Totality, Four Studies Suggest 25% Death Reduction With Metformin

Taken together, the four observational studies that Scheen reviews showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).

The largest of these, from the United States, included 6256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).

The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn't designed to address that issue.

In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).

Two smaller observational studies produced similar trends toward survival benefit with metformin.

Nonetheless, Scheen cautions: "Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19."

He adds: "Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes."

Lipska agrees: "RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile."

Scheen concludes, however, "There are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure."

Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Scheen has disclosed no relevant financial relationships.

medRxiv. Published online July 31, 2020. Full text

Diabetes Metab. Published online August 1, 2020. Full text

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