Association of Dipeptidyl Peptidase-4 Inhibitor Use with COVID-19 Mortality in Diabetic Patients: A Nationwide Cohort Study in Korea

Abstract

Background/Objectives: Patients with diabetes mellitus face increased risk of severe outcomes and mortality from COVID-19. Dipeptidyl peptidase-4 (DPP-4) inhibitors, widely used antidiabetic agents, are hypothesized to affect COVID-19 outcomes via anti-inflammatory and immune-modulating mechanisms. However, real-world evidence, especially in Korean populations, remains limited. Methods: We conducted a retrospective cohort study using Korea's nationwide Health Insurance Review and Assessment (HIRA) database. Adults with diabetes hospitalized for confirmed COVID-19 between 1 March 2021, and 28 February 2022, were included and stratified by DPP-4 inhibitor use. The primary outcome was 30-day all-cause mortality. Cox proportional hazards models adjusted for age, sex, and comorbidities estimated hazard ratios (HRs). Subgroup analyses examined angiotensin receptor blocker (ARB) and insulin use. Results: Among 16,134 eligible patients, 7082 received DPP-4 inhibitors. The 30-day mortality rate was lower in DPP-4 inhibitor users than non-users (4.3% vs. 10.3%, p < 0.0001). Adjusted analyses showed DPP-4 inhibitor use was associated with reduced mortality risk (adjusted HR: 0.455; 95% CI: 0.414-0.499). Subgroup analyses yielded consistent results across ARB and insulin users. Kaplan-Meier curves demonstrated higher survival probability in the DPP-4 inhibitor group. Conclusions: In this nationwide Korean cohort, DPP-4 inhibitor use was associated with lower mortality among hospitalized diabetic patients with COVID-19. While these findings suggest a potential benefit, causality cannot be confirmed due to the observational design. Prospective studies are needed to verify these associations and explore underlying mechanisms.