Fewer Deaths in Hospitalized COVID Diabetes Patients on Sitagliptin

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Patients with type 2 diabetes hospitalized for COVID-19 who were taking just one glucose-lowering drug, the oral dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin, were 77% less likely to die compared with similar patients taking insulin, in a retrospective, observational, case-control study in Italy.

Sitagliptin (Januvia, Merck) treatment was also linked with significant and clinically meaningful drops in the rate of need for intensive care or mechanical ventilation compared with patients who received insulin, Sebastiano B. Solerte MD, PhD, and colleagues report in their study published online September 29 in Diabetes Care.

The authors acknowledge that the study's design means this finding can't be considered definitive. Despite this limitation, "We think it's reasonable to try sitagliptin if a patient is admitted to the hospital with type 2 diabetes and COVID," said Paolo Fiorina, MD, PhD, senior investigator of the study, in a statement.

The researchers are about to start a prospective, randomized trial to try to confirm the benefit seen with sitagliptin in a total of about 170 patients in the SIDIACO (The Effect of Sitagliptin Treatment in COVID-19 Positive Diabetic Patients) study.

"I'm excited by our findings, because we still have very few therapeutic options for the many diabetic patients affected by COVID," said Fiorino, a nephrologist and diabetes researcher affiliated with the Boston Children's Hospital division of nephrology and the University of Milan.

And, Fiorino told Medscape Medical News in an email, "Our data are related to sitagliptin but I believe that there will be a class effect [of DPP-4 inhibitors]."

SARS-CoV-2 Virus May Bind to DPP-4 Receptor

The Italian group notes that type 2 diabetes has been associated with worse outcomes in COVID-19 and that the presence of diabetes increases the mortality risk associated with the virus, particularly in those with more severe COVID-19.

And poorly controlled blood glucose levels are associated with markedly higher mortality in patients with type 2 diabetes and COVID-19 compared with similar patients with better metabolic control.

The researchers decided to study a DPP-4 inhibitor such as sitagliptin because of evidence that the SARS-CoV-2 virus may bind DPP-4 when entering respiratory cells.

"We decided to try sitagliptin and collect the data. COVID-19 mortality in patients with diabetes is high, and the drug is very safe, so we felt there was no reason not to use it," Fiorina explained.

During March and April 2020, they enrolled 338 consecutive adults with documented type 2 diabetes hospitalized with laboratory-confirmed SARS-CoV-2 infection at seven academic centers in Northern Italy. All patients stopped their diabetes treatment on admission, and then patients received either sitagliptin or insulin (intravenous or subcutaneous) as their sole diabetes intervention while hospitalized, in addition to all other standard-of-care medications.

Enrolled patients averaged 69 years old (> 90% were at least 70). Slightly more than two thirds were men, and average diabetes duration was about 9 years. Body mass index among the enrolled patients averaged just under 30 kg/m², and average A1c at enrollment was 7.5%.

The study's primary endpoint was the rate of death at 30 days. Overall, 31 (18%) of sitagliptin-treated patients died compared with 63 (37%) of those taking insulin, a 19% absolute difference that was significant, and that translated into a 77% relative reduction after adjustment for baseline differences in age, sex, comorbidities, and ongoing treatments.

The analysis identified two other parameters that had significant links with 30-day death. For each added year of age, mortality increased by 7%, and patients with a history of cardiovascular disease had a 2.5-fold increased mortality rate.

The data also showed that sitagliptin recipients were almost 50% less likely to be admitted to ICU, compared with insulin-treated patients (P = .03), and their need for mechanical ventilation was cut by 73% compared with those on insulin (P = .003).

The incidence of patients with a two-point or greater improvement in their clinical severity score was 52% on sitagliptin and 34% on insulin.

Researchers also ran four subgroup analyses that showed the impact of sitagliptin was consistent regardless of age (≥ 70 years vs < 70 years), sex, A1c level at entry (≤ 7.5% vs > 7.5%), or body mass index (obese or nonobese).

The authors suggested three possible key explanations for the benefits associated with sitagliptin treatment:

Binding of sitagliptin to the DPP-4 protein on cell surfaces may interfere with these proteins acting as binding sites for the SARS-CoV-2 virus.
Sitagliptin may exert anti-inflammatory and immunoregulatory effects, such as reducing excessive and prolonged cytokine responses.
Sitagliptin may improve glycometabolic control that may help moderate the clinical progression of COVID-19 infection.

As well as the planned prospective, randomized trial in those with type 2 diabetes and severe COVID-19, the researchers suggest that sitagliptin could also be tested as a potential COVID-19 treatment in patients without diabetes.

The study received no commercial funding. Solerte, Fiorina, and their coinvestigators have reported no relevant financial relationships.

Diabetes Care. Published online September 29, 2020. Abstract

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