Dipeptidyl Peptidase-4 Inhibitor Use and Risk of Major Adverse Cardiovascular Events in Patients with COPD and Diabetes: A Nationwide Retrospective Cohort Study

Background: Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder frequently followed by cardiovascular disease and diabetes mellitus (DM) that may increase the risk of major adverse cardiovascular events (MACE). Dipeptidyl peptidase-4 inhibitors (DPP-4i) are widely used antidiabetic agents with potential anti-inflammatory and cardiovascular protective effects beyond glycemic control. This study investigated the association between DPP-4i use and the risk of MACE in patients with COPD and comorbid DM. Methods: This nationwide retrospective cohort study used data from Taiwan’s National Health Insurance Research Database between 2016 and 2021. Patients aged ≥ 40 years with at least one hospitalization for COPD and a diagnosis of DM were included. DPP-4i users were identified by prescription records (ATC code A10BH*), and non-users were defined as patients receiving other antidiabetic agents without DPP-4i. The primary outcome was MACE, defined as a composite of cardiovascular death, myocardial infarction, and stroke. Cox proportional hazards analysis was used to estimate hazard ratios (HRs) of MACE with 95% confidence intervals (CIs), adjusting for demographic characteristics, comorbidities, and overall disease burden. Results: A total of 24,215 patients with COPD and DM were included, of whom 5737 (23.7%) were DPP-4i users and 18,478 (76.3%) were non-users. During follow-up, DPP-4i users had a significantly lower incidence of MACE compared with non-users (17.88% vs 26.34%, p < 0.0001). Non-DPP-4i use was associated with a higher risk of MACE (adjusted HR: 1.56; 95% CI: 1.46– 1.67; p < 0.0001) compared with DPP-4i use. The association of DPP-4i was consistent across sex, age groups, and patients with prior myocardial infarction, stroke, or hypertension. Conclusion: In this nationwide retrospective cohort study, DPP-4i use was associated with a lower risk of MACE among patients with COPD and comorbid DM. These findings suggest that DPP-4i may provide cardiovascular benefits beyond glycemic control in this high-risk population. However, given the observational design, causal relationships cannot be established, and the findings should be interpreted with caution due to potential residual confounding and selection bias. Further randomized controlled trials are warranted to confirm findings.