GLP-1RA, DPP-4i do not prevent COVID-19 but reduce hospitalization risk in infected patients

New research suggests that in older adults with type 2 diabetes (T2D) who are taking metformin, using dipeptidyl peptidase-4 inhibitors (DPP4is) and glucagon-like peptide-1 receptor agonists (GLP1RAs) has a null effect on the risk of COVID-19 infection. However, among those who do contract the virus, the use of these drugs appears to lower the risk of hospitalization.

In a population-based cohort of people with T2D at least 66 years of age, the primary outcome of  COVID-19 infection risk was similar between DPP4i/GLP1RA users and users of sodium-glucose cotransporter-2 inhibitors (SGLT2is) or sulfonylureas (SUs), at 10.3 percent vs 10.4 percent, respectively (weighted risk difference [RD], −0.06, 95 percent confidence interval [CI], −0.79 to 0.66; relative risk [RR], 0.99, 95 percent CI, 0.93–1.07). [BMJ Open Diabetes Res Care 2025;13:e004677]

On the other hand, DPP4i/GLP1RA users had a lower risk of 30-day all-cause hospitalization compared with SGLT2i/SU users (25.5 percent vs 27.8 percent; weighted RD, −6.72 percent, 95 percent CI, −10.4 to −3.02; weighted RR, 0.79, 95 percent CI, 0.70–0.89). Furthermore, a trend towards a lower associated risk of cardiovascular (CV) events was observed among DPP4i/GLP1RA users (5.3 percent vs 5.9 percent; weighted RD, −1.91 percent, 95 percent CI, −4.00 to 0.18; RR, 0.73, 95 percent CI, 0.54–1.00).

“There is a lack of clinical evidence on the effect of DPP4i/GLP1RA on the risk of COVID-19 infection. While there has been a suggestion that DPP4i or GLP1RA might prevent COVID-19 infection based primarily on animal studies, the clinical relevance has been debated… Our findings do not support the hypothesis that DPP4i or GLP1RA reduce risk of [contracting] COVID-19 infection,” the authors said. [Endocr Rev 2020;41:bnaa011]

The authors noted that the DPP4i/GLP1RA group consisted mostly of DPP4i users, and the finding on the association between DPP4i/GLP1RA use and potentially reduced CV events may be explained by the hypothesized inhibitory effect of DPP4i on myocardial inflammation caused by SARS-CoV-2. [Endocr Rev 2020;41:bnaa011; J Cell Mol Med 2020; 24:10274-10278]

“Thus, if there is any benefit of DPP4i in lowering risk of CV events, it may be confined to a short-term period around COVID-19 infection rather than a long-term reduction in risk (which would not be expected based on landmark DPP4i trials),” they added. [N Engl J Med 2013;369:1327-1335; N Engl J Med 2013;369:1317-1326; N Engl J Med 2015;373:232-242]

The study included 81,332 older adults with T2D being treated with metformin and who had undergone at least one COVID-10 PCR test. Of these, 26,485 were users of DPP4i/GLP1RA (mean age 76 years, 47 percent female, 91 percent DPP4i users), 14,487 were users of SGLT2i/SU (mean age 75 years, 39 percent female), and 40,360 who used neither DPP4i/GLP1RA nor SGLT2i/SU (mean age 77 years, 49 percent female). Twenty-five percent of participants in the DPP4i/GLP1RA group and 20 percent of those in the SGLT2i/SU group used insulin, and 80 percent and 83 percent in the respective groups used statins. 

Stratified analyses showed that among participants without a history of coronary artery disease (CAD), heart failure (HF), stroke, or chronic kidney disease (CKD), and a cohort without any of those comorbidities. CAD, HF, CKD, or stroke, DPP4i/GLP1RA use was associated with a lower risk of mechanical ventilation (weighted RD, −1.77 percent, 95 percent CI, −3.69 to 0.15; weighted RR, 0.63, 95 percent CI, 0.40–0.99) and all-cause hospitalization (weighted RD, −5.65, 95 percent CI, −9.74 to 1.56; weighted RR, 0.80, 95 percent CI, 0.69–0.93) compared with SGLT2i/SU use.

Among those who did have a history of CAD, HF, CKD, or stroke, DPP4i/GLP1RA users had a lower risk of all-cause hospitalization (weighted RD, −9.78 percent, 95 percent CI, −18.1 to −1.48; weighted RR, 0.76, 95 percent CI, 0.61–0.94) but higher risk of mechanical ventilation (weighted RD, 2.05 percent, 95 percent CI, 0.51–3.59; weighted RR, 2.44, 95 percent CI, 1.11–5.38).

The authors acknowledged several study limitations, including the observational nature and the lack of data on BMI, smoking behaviour, cardiac function, and specialist care. These findings remain hypothesis-generating.

“Future research should examine the timing of T2D medication use with respect to [the risk of contracting] COVID-19 infection and adverse outcomes, specifically when an agent could optimally be started,” they said.

“Until more answers to these questions are available from randomized controlled trials, any possible impact of T2D medications on COVID-19 infection or related outcomes should not be used to inform clinical decisions,” they added.