A diabetes drug with a potential side benefit: Reduced COVID-19 mortality

In 2006, the Food and Drug Administration approved the drug sitagliptin to lower blood sugar in type 2 diabetes. Now, a multicenter observational study in Italy suggests the drug also cuts mortality in diabetic patients hospitalized with COVID-19 — by as much as half.

Paolo Fiorina, MD, PhD, of Boston Children’s Hospital led the study, which involved seven Italian hospitals during the first surge of COVID-19 cases last spring. Patients who received sitagliptin in addition to insulin had a mortality rate of 18 percent, as compared with 37 percent in matched patients receiving only insulin.

Although the study was retrospective and observational, the findings — published today in Diabetes Care — have sparked a new randomized, placebo-controlled trial of sitagliptin. That study is now preparing to enroll patients in Europe.

“We think it’s reasonable to try sitagliptin if a patient is admitted to the hospital with type 2 diabetes and COVID-19,” says Fiorina, a diabetes researcher affiliated with Boston Children’s division of nephrology and the University of Milan. “I’m excited about our findings, because we still have very few therapeutic options for the many diabetic patients affected by COVID-19.”

Based on sitagliptin’s mechanism of action, Fiorina and colleagues believe it 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 in COVID-19?

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.

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.”

– Paolo Fiorina

But 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” causing 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,” says 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.”

Sitagliptin: Study design and findings

The 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 (hazard ratio, 0.27, or a 27 percent likelihood)
• less likely to need intensive care (hazard ratio, 0.51)
• more likely than controls to have at least a 2-point drop on a 7-point scale of disease severity (52 percent vs. 34 percent)
• less likely to have a worsening of clinical outcomes, as defined by any increase in the clinical severity score (26 percent vs. 46 percent)

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

For more on the new trial, visit ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT04365517.

The study was supported by SID Lombardia, the EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research, the Italian Ministry of Health, Università di Milan, The Gillian Reny Stepping Strong Center for Trauma Innovation, and Mediolanum-farma, which provided sitagliptin. Sebastiano Bruno Solerte (University of Pavia, Italy) and Francesca D’Addio (International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Italy) were co-first authors on the paper.

Read about more COVID-19 research at Boston Children’s Hospital.