Clues from Diabetes

Blood sugar drug may reduce mortality in patients hospitalized with COVID-19, type 2 diabetes

Colorized micrograph has dozens of yellow specks stuck to a textured red cell surface
A colorized micrograph shows SARS-CoV-2 particles, yellow, infecting a cell, red. Image: NIAID

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

A multicenter observational study in Italy suggests that sitagliptin, a drug approved by the U.S. Food and Drug Administration to lower blood sugar in type 2 diabetes, cuts mortality in diabetic patients hospitalized with COVID-19.

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Results from the study, which involved seven hospitals during the first surge of COVID-19 cases in spring 2020 and was led by Paolo Fiorina, lecturer on pediatrics, part-time, at Harvard Medical School and a research associate in the Division of Nephrology at Boston Children’s Hospital, were reported Sept. 29 in the journal Diabetes Care.

The authors report that patients who received sitagliptin in addition to insulin had a mortality rate of 18 percent. Matched patients receiving only insulin had a mortality rate of 37 percent.

Sitagliptin appears to block SARS-CoV-2 from entering cells and reduces inflammation, the authors said.

The results of retrospective and observational studies such as this one are generally considered a level below the gold standard of a randomized, placebo-controlled clinical trial. The team's findings are promising enough, however, that they have sparked just such a trial of sitagliptin, which is now preparing to enroll patients in Europe.

“I’m excited about our findings, because we still have very few therapeutic options for the many diabetic patients affected by COVID-19,” said Fiorina, a diabetes researcher who is also affiliated with the University of Milan.

“We must now confirm our findings in a placebo-controlled, prospective study,” he said. 

Based on sitagliptin’s mechanism of action, Fiorina and colleagues believe the drug could also help fight COVID-19 even in nondiabetic patients. A separate randomized, controlled trial to test that idea is moving toward regulatory approval.

Why sitagliptin?

Sitagliptin belongs to a class of drugs known as DPP-4 inhibitors, which are prescribed to an estimated 15 to 20 percent of patients with type 2 diabetes. The drug lowers blood sugar by blocking the receptor for the enzyme DPP-4, also called CD26, which increases production of insulin.

Recent studies suggest that DPP-4 has two side actions that are relevant to COVID-19. It may help the SARS-CoV-2 coronavirus get into respiratory cells. It also curbs inflammation, reducing production of the cytokine IL-6 that contributes to the cytokine storm that causes organ complications in COVID-19.

Sitagliptin’s main action—lowering blood sugar—may also help boost survival. Previous studies have shown that diabetic patients with worse glycemic control have worse COVID-19 outcomes.

“We decided to try sitagliptin and collect the data,” said Fiorina. “We see high COVID-19 mortality in diabetic patients, and the drug is very safe, so we felt there was no reason not to use it.”

Study design and findings

The current study enrolled 338 consecutive patients with type 2 diabetes and COVID-19 pneumonia who were admitted to seven academic hospitals in northern Italy in March and April.

Of these, 169 received only IV insulin for their type 2 diabetes—the standard of care—and served as controls. The other 169 also received sitagliptin. The researchers matched the two groups for age and sex and reviewed their outcomes retrospectively.

Illness severity, other clinical characteristics and use of other treatments for COVID-19 were similar in the two groups.

In addition to increased survival, patients treated with sitagliptin were:

  • Less likely than controls to need mechanical ventilation .
  • Less likely to need intensive care .
  • More likely than controls to have at least a two-point drop on a seven-point scale of disease severity .
  • Less likely to have a worsening of clinical outcomes, as defined by any increase in the clinical severity score .

“We think it’s reasonable to try sitagliptin if a patient is admitted to the hospital with type 2 diabetes and COVID-19,” said Fiorina.

The study was supported by SID Lombardia, the EFSD/JDRF/Lilly Programme in Type 1 Diabetes Research, the Italian Ministry of Health, the University of Milan, a Stepping Strong Innovator Award, and Mediolanum Farmaceutici, a pharmaceutical company that provided sitagliptin.

Sebastiano Bruno Solerte and Francesca D’Addio were co-first authors on the paper.

Adapted from a post on Discoveries, the Boston Children's clinical and research innovation portal.