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Concerns about the cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors persist. This study sought to determine whether there is a differential risk of hospitalization for cardiovascular diseases (CVDs) between DPP-4 inhibitors and glimepiride.We conducted this retrospective cohort study by using the Korean National Health Insurance Service database from December 1, 2008, to December 31, 2013. The study subjects were new users of DPP-4 inhibitors or glimepiride for type 2 diabetes. Outcome was defined as hospitalization for CVDs, including angina pectoris, myocardial infarction, transient cerebral ischemic attack, heart failure, or cerebrovascular disease or any procedure involving coronary artery bypass grafting or percutaneous coronary intervention. We used a Cox proportional hazard model to estimate the adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs), to assess the risk of CVDs associated with the use of DPP-4 inhibitors compared with glimepiride.The cohort consisted of 1,045,975 patients, with 6504 in the DPP-4 inhibitors group and 13,447 in the glimepiride group. No significant increased risk of total CVDs was found (aHR, 0.87; 95% CI, 0.75–1.01) in the DPP-4 inhibitors versus glimepiride group. A decreased risk of hospitalization for CVDs was found among patients with a history of visit for CVDs (aHR, 0.73; 95% CI, 0.56–0.97) or with >2.5 years’ duration of type 2 diabetes (aHR, 0.77; 95% CI, 0.66–0.91) in the DPP-4 inhibitors versus glimepiride group.DPP-4 inhibitors did not increase cardiovascular risk compared with glimepiride regardless of CVD history and diabetes duration.