AimsGlimepiride has good cardiovascular safety. However, whether glimepiride benefits clinical cardiovascular outcomes is unclear.Methods and resultsA total of 21 451 inpatients with type 2 diabetes (T2D) and chronic heart failure (CHF) were analysed, including 638 who received glimepiride treatment and 20 813 who did not. Propensity score matching yielded 509 pairs (glimepiride and non-glimepiride groups), and both groups were followed up. Kaplan-Meier and Cox regression analyses were used to compare all-cause mortality, cardiovascular mortality, hospitalizations and emergency visits for heart failure, and hospitalizations for acute myocardial infarction or stroke. During follow-up, the all-cause mortality [adjusted hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35-0.63; P < 0.001], cardiovascular mortality (adjusted HR, 0.34; 95% CI, 0.24-0.48; P < 0.001), and number of hospitalizations and emergency visits for heart failure (adjusted HR, 0.42; 95% CI, 0.36-0.50; P < 0.001) and hospitalizations for acute myocardial infarction or stroke (adjusted HR, 0.53; 95% CI, 0.38-0.73; P < 0.001) were significantly lower in the glimepiride group; the conclusion remained similar in all subgroups. Furthermore, high-dose glimepiride use (2-4 mg/day) was associated with lower cardiovascular mortality than low-dose (1 mg/day) (adjusted HR, 0.55; 95% CI, 0.31-0.99; P = 0.047). Glimepiride exhibited good molecular docking with soluble epoxide hydrolase (sEH) and increased the level epoxyeicosatrienoic acid (EET).ConclusionLong-term continuous glimepiride use is associated with better survival, fewer hospitalizations and emergency visits for heart failure, and fewer hospitalizations for acute myocardial infarction or stroke in patients with T2D and CHF. High-dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride. The cardiovascular protective effect of glimepiride may be related to the EET level increase through sEH inhibition.Lay SummaryLong-term continuous glimepiride use is associated with better survival, fewer hospitalizations, and emergency visits for heart failure. High-dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride. [GRAPHICS] .