Studies find link between metformin and reduced COVID-19 mortality, mixed results for DPP-4 inhibitors

Prior metformin use was associated with a threefold decrease in mortality from COVID-19 in one study of patients with type 2 diabetes, while three other studies found mixed results on whether dipeptidyl peptidase-4 (DPP-4) inhibitors affect COVID-19 outcomes.


Metformin use prior to COVID-19 diagnosis was associated with about a threefold decrease in mortality from COVID-19 in a recent study. Researchers conducted a retrospective analysis of 25,326 patients (30.8% African American) tested for COVID-19 between Feb. 25 and June 22, 2020, at a hospital in Alabama. The primary outcome was mortality in COVID-19-positive patients. Results were published on Jan. 13 by Frontiers in Endocrinology.

Diabetes was associated with increased risk for COVID-19 infection and mortality and emerged as an independent risk factor after researchers controlled for age, race, sex, obesity, and hypertension. Treatment with metformin prior to COVID-19 diagnosis was independently associated with a significant reduction in mortality in those with diabetes and COVID-19 (odds ratio, 0.33; 95% CI 0.13 to 0.84; P=0.0210). Among other limitations, the study size did not allow for separate analyses of additional subgroups, including those with type 1 diabetes or on other antidiabetic drugs besides metformin, the authors noted. “At this point, the mechanisms by which metformin might improve prognosis in the context of COVID-19 are not known,” they wrote. “Our findings suggest that they go beyond any expected improvement in glycemic control or obesity as blood glucose, HbA1C, or [body mass index] were not lower in COVID-19 survivors on metformin.”

Another study found that glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors were not associated with improved COVID-19 outcomes compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Researchers used nationwide registries in Denmark to identify all individuals with confirmed SARS-CoV-2 infection as of Nov. 1, 2020. The primary outcome was death within 30 days after a positive SARS-CoV-2 test, and secondary outcomes included hospital admission. Results were published on Jan. 27 by Diabetes, Obesity and Metabolism.

Overall, 370 individuals used GLP-1 receptor agonists, 284 used DPP-4 inhibitors, and 342 used SGLT-2 inhibitors in the 90 days before testing positive. Compared to current users of SGLT-2 inhibitors, patients who used GLP-1 receptor agonists had an adjusted 30-day mortality relative risk (RR) of 0.89 (95% CI, 0.34 to 2.33), whereas users of DPP-4 inhibitors had an adjusted RR of 2.42 (95% CI, 0.99 to 5.89). In addition, use of GLP-1 receptor agonists or DPP-4 inhibitors compared to SGLT-2 inhibitors was not associated with decreased risk of hospital admission. These results should be interpreted cautiously due to the limited sample size, the authors noted.

In contrast, another study supported the safety of DPP-4 inhibitors for diabetes management during the COVID-19 pandemic. Researchers conducted a secondary propensity score analysis of the CORONADO (CORONAvirus and Diabetes Outcomes) study of 2,449 patients with type 2 diabetes hospitalized for COVID-19 at 68 centers in France to assess the association between use of DPP-4 inhibitors and the severity of COVID-19 infection. The composite primary end point combined mechanical ventilation and death. Results were published online on Feb. 2 by Diabetes, Obesity and Metabolism.

Overall, 596 (24.3%) participants used DPP-4 inhibitors before hospital admission. The primary outcome occurred at similar rates in users and nonusers of DPP-4 inhibitors (27.7% vs. 28.6%, P=0.68). There was no significant association between use of DPP-4 inhibitors and the primary outcome by day 7 or day 28. The study did not evaluate medication adherence and was limited by the observational design of the CORONADO study, among other limitations, the authors noted. “These data support safe use of this class of drugs for treating diabetes during the COVID-19 pandemic and they should not be discontinued,” they concluded.

Another study also supported the safety of DPP-4 inhibitors in COVID-19. Adult patients in South Korea who had type 2 diabetes and a positive test result for COVID-19 as of May 15, 2020, were classified into two groups: users of DPP-4 inhibitors (alone or with other antidiabetic drugs) and users of other noninsulin second- or third-line antidiabetic drugs, such as SGLT-2 inhibitors, GLP-1 receptor agonists, and/or sulfonylureas (reference group). The primary outcome was all-cause mortality, and the secondary outcome was severe manifestations of COVID-19 (a composite of ICU admission and use of noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation). Results were published as an e-letter on Feb. 5 by Diabetes Care.

A total of 586 patients were included in the study cohort. There were 47 deaths among 453 users of DPP-4 inhibitors (incidence rate, 1.73 per 1,000 person-days) and 22 deaths among 133 people in the reference group (incidence rate, 3.18 per 1,000 person-days). While the unadjusted survival curves demonstrated a significantly lower probability of all-cause mortality and severe manifestations of COVID-19 among those who used DPP-4 inhibitors, the adjusted model showed that DPP-4 inhibitor use was not significantly associated with all-cause mortality (hazard ratio, 0.74; 95% CI, 0.43 to 1.26) or severe manifestations of COVID-19 (hazard ratio, 0.83; 95% CI, 0.45 to 1.53). “However, our findings hint at clinical relevance as potential benefits associated with DPP-4 inhibitors were observed in this patient population, although our estimates had wide 95% CIs due to limited power; recent studies reported similar beneficial effects,” the authors wrote. “While awaiting the results of ongoing randomized controlled trials investigating this issue, our findings provide further clinical insight for health care professionals in managing the ongoing pandemic.”