Metformin has been associated with significantly reduced risks of death from COVID-19 in women

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University of Minnesota Medical School and UnitedHealth Group researchers found that metformin was associated with significantly reduced COVID-19 death risks in women in one of the world’s largest observational studies of COVID-19 patients.

Metformin is an established, generic medication for managing blood sugar levels in patients with type 2 diabetes.

It also reduces inflammation proteins like TNF-alpha that appear to make COVID-19 worse.

The study, published in The Lancet Healthy Longevity, is a retrospective cohort analysis based on de-identified patient data from UnitedHealth Group.

The team analyzed about 6,000 individuals with type 2 diabetes or obesity who were hospitalized with COVID-19 and assessed whether or not metformin use was associated with decreased mortality.

They found an association that women with diabetes or obesity, who were hospitalized for COVID-19 disease and who had filled a 90-day metformin prescription before hospitalization, had a 21% to 24% reduced likelihood of mortality compared to similar women not taking the medication. There was no significant reduction in mortality among men.

“Observational studies like this cannot be conclusive, but contribute to growing bodies of evidence. 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,” said principal investigator Carolyn Bramante, MD, MPH, who is an assistant professor in the Department of Medicine at the University of Minnesota Medical School. “A large database covering different geographic areas is rarely available. We were fortunate to have the opportunity to do this research alongside UnitedHealth Group.”

“While effective therapies to mitigate the harm of the SARS-CoV-2 virus are being developed, it is important that we also look to, and evaluate commonly used medications with good safety profiles for their potential to combat the virus,” said Deneen Vojta, MD, executive vice president, Enterprise Research and Development, UnitedHealth Group.

The results provide new directions for research against COVID-19.

In collaboration with Christopher Tignanelli, MD, assistant professor in the Department of Surgery at the University of Minnesota Medical School, Bramante submitted an investigational new drug application to the Food and Drug Administration for use of metformin for COVID-19 treatment and prevention.

The FDA approved this application. Bramante and Tignanelli received a donation from the Parsemus Foundation to conduct a multi-site prospective, randomized pilot study in collaboration with the Executive Director of Clinical Research for UnitedHealth Group R&D, Ken Cohen, MD.

This pilot trial will begin enrolling the week of Dec. 8 and will lead into a larger trial that is fully powered for important clinical outcomes if additional funding becomes available. These collaborators are still seeking this funding.


n patients with type 2 diabetes (T2D) admitted to the hospital for coronavirus disease 2019 (COVID-19), treatment with sitagliptin was associated with reduced mortality and improved clinical outcomes compared with standard-of-care treatment, according to a study published in Diabetes Care. In addition, the underlying mechanism of sitagliptin leads researchers to hypothesize the drug may be effective in patients with COVID-19 and without T2D.

The CDC lists T2D as a preexisting factor that can put individuals at an increased risk of severe illness from COVID-19. In June, it was reported that patients with diabetes account for over 20% of individuals admitted to intensive care units for COVID-19.

Sitagliptin is an oral dipeptidyl peptidase 4 (DPP-4) inhibitor and recent studies have suggested that SARS-CoV-2, the virus that causes COVID-19, may bind DPP-4 when entering cells of the respiratory tract.

“Based on the modeling of SARS-CoV-2 structure and receptors, it has been also postulated that DPP-4 may facilitate the SARS-CoV-2 entry into target cells, due to its high homology with Middle East respiratory syndrome coronavirus,” authors wrote.

Researchers conducted a multicenter, case-control, retrospective observational study to investigate the effects of sitagliptin, a blood-sugar lowering drug, in patients with T2D and concurrent COVID-19.

A total of 338 consecutive patients admitted to 7 Northern Italy hospitals between March 1 and April 30, 2020 were included in the study. Patients treated with sitagliptin were matched in a 1:1 ratio with untreated control subjects. At admission, all participants had pneumonia and oxygen saturation <95% when breathing ambient air or were receiving oxygen support.

As standard of care, patients were switched at admission “from current treatment for T2D, which included mostly metformin, but also insulin, sulfonylureas, DPP-4 inhibitors, sodium–glucose cotransporter 2 inhibitors, GLP-1 receptor agonists, glinides, and thiazolidinediones, to insulin treatment (intravenously or subcutaneously).”

Overall, 169 patients received sitagliptin as an add-on therapy to standard care and 169 controls received only standard care. Mean age of those in both groups was 69 and no major demographic differences between the 2 groups were observed.

The study’s primary endpoints included discharge from the hospital, death, and improvement of clinical outcomes, measured by an increase of at least 2 points on a 7-category modified ordinal scale.

Analyses revealed treatment with sitagliptin, compared with patients receiving standard care, was associated with:

  • Reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29–0.66]; P = .0001)
  • An improvement in clinical outcomes (60% vs. 38% of improved patients; P =.0001)
  • A greater number of hospital discharges (120 vs. 89 of discharged patients; P = .0008)
  • A decreased risk for the need of mechanical ventilation (HR 0.27 [CI 0.11–0.62]; P = .003)
  • Lower mean blood glucose levels measured during the hospitalization
  • Lower mortality (29% vs. 51%) and better outcomes in a time to clinical end point analysis in patients aged 70 years or older

At day 30, a greater number of patients who received sitagliptin were discharged from the hospital compared with the control group. No treatment-related severe adverse events were reported in the intervention group.

Based on the findings, a new randomized, placebo-controlled trial of sitagliptin is now preparing to enroll patients with T2D in Europe.

Furthermore, “given the beneficial effects observed in lowering mortality rate and improving clinical outcomes, sitagliptin may also be considered for further testing in patients with COVID- 19 and without T2D,” authors wrote.

A randomized controlled trial to test the hypothesis is moving forward toward regulatory approval, according to a press release.

Reference:

Solerte SB, D’Addio F, Trevisan R, et al. Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study. Diabetes Care. Published online September 29, 2020. doi:10.2337/dc20-1521


More information: Carolyn T Bramante et al, Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis, The Lancet Healthy Longevity (2020). DOI: 10.1016/S2666-7568(20)30033-7

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