This study explored heterogeneous treatment effects (HTEs) of the real-world use of dipeptidyl peptidase-4 inhibitors (DPP-4is) vs. sulfonylureas (SUs) on cardiovascular diseases (CVDs) and mortality in patients with type 2 diabetes. Utilizing Taiwan’s National Health Insurance Research Database, 19,853 propensity score-matched pairs of DPP-4i and SU stable users were identified. Classification and regression tree analyses and Cox models were applied to explore HTEs, according to various patient characteristics, on the composite CVDs, three-point major adverse cardiovascular event (MACE), and all-cause mortality. The absolute risk difference (ARD), hazard ratio (HR), and 95% confidence interval (CI) were estimated for comparing treatment effects. CVD history, ischemic stroke, or transient ischemic attack (IS/TIA) history, and age at treatment initiation were significant treatment effect modifiers. Patients with prior IS/TIA but without any other prior CVDs benefited most in reduced risks of composite CVDs from using DPP-4i vs. SU (ARD −4.31%, 95% CI −7.48% to −1.14%, HR 0.81, 95% CI 0.69 ~ 0.95), followed by those without prior IS/TIA and CVDs and initiated with DPP-4i at age < 69.3 years (ARD −0.90%, 95% CI −1.47% to −0.32%, HR 0.86, 95% CI 0.77 ~ 0.97). Patients with prior IS/TIA benefited most in reduced risks of three-point MACE from using DPP-4i vs. SU (ARD −4.22%, 95% CV −6.66% to −1.78%, HR 0.80, 95% CI 0.69 ~ 0.93), followed by those without prior IS/TIA and initiated with DPP-4i at age < 69.3 years (ARD −0.68%, 95% CI −1.08% to −0.29%, HR 0.81, 95% CI 0.70 ~ 0.93). Consideration of CVD and IS/TIA histories and age could facilitate individualized diabetes management of using DPP-4i vs. SU. Future studies are warranted given the hypothesis-generating nature in this exploratory research.
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