Effect of antidiabetic medication adherence on risk of all-cause mortality and cardiovascular diseases in type 2 diabetes patients: Impact of antidiabetic adherence on cardiovascular disease

This retrospective cohort study aims to examine the association between adherence to thiazolidinedione (TZD) therapy and the risk of all-cause mortality and cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus, compared with utilization of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulfonylureas (SUs), using real-world national data from the Korean National Health Insurance Service (2009-2018). Two matched cohorts were established: TZDs versus DPP-4 inhibitors (n = 7875) and TZDs versus SUs (n = 5837). Adherence was measured using the proportion of days covered during the first year, with high adherence defined as proportion of days covered ≥0.8. Outcomes included myocardial infarction, stroke, CV death, hospitalization for heart failure, major adverse CV events, and all-cause mortality. Cox proportional hazards models were applied using intention-to-treat and adherence-stratified analyses. At 12 months, DPP-4 inhibitor users demonstrated higher adherence and persistence compared to the TZD users, whereas adherence was comparable between TZD and SU users. In cohort 1, TZD therapy was associated with increased risks of stroke (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.01-1.23) and all-cause mortality (HR 1.10, 95% CI: 1.01-1.20) compared with DPP-4 inhibitors. In cohort 2, TZDs were associated with lower risks of myocardial infarction (HR 0.80, 95% CI: 0.65-0.99), major adverse CV events (HR 0.85, 95% CI: 0.76-0.95), hospitalization for heart failure (HR 0.86, 95% CI: 0.75-1.00), and all-cause mortality (HR 0.83, 95% CI: 0.74-0.93) compared with SUs. High adherence to TZDs was consistently associated with more favorable CV and survival outcomes, in comparison to SUs. In this nationwide cohort, TZD therapy, especially with high adherence, reduced CV risk and mortality compared with SUs and DPP-4 inhibitors, highlighting the importance of sustained TZD adherence for optimal long-term outcomes in routine clinical practice.