Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study

OBJECTIVE To evaluate the cardiovascular safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, in direct comparisons with DPP-4 inhibitors (DPP-4i), GLP-1 receptor agonists (GLP-1RA), or sulfonylureas, as used in routine practice. DESIGN Population based retrospective cohort study. SETTING Nationwide sample of patients with type 2 diabetes from a large de-identified US commercial healthcare database (Optum Clinformatics Datamart). PARTICIPANTS Three pairwise 1: 1 propensity score matched cohorts of patients with type 2 diabetes 18 years and older who initiated canagliflozin or a comparator non-gliflozin antidiabetic agent (ie, a DPP-4i, a GLP-1RA, or a sulfonylurea) between April 2013 and September 2015. MAIN OUTCOME MEASURES The primary outcomes were heart failure admission to hospital and a composite cardiovascular endpoint (comprised of being admitted to hospital for acute myocardial infarction, ischemic stroke, or hemorrhagic stroke). Hazard ratios and 95% confidence intervals were estimated in each propensity score matched cohort controlling for more than 100 baseline characteristics. RESULTS During a 30 month period, the hazard ratio for heart failure admission to hospital associated with canagliflozin was 0.70 (95% confidence interval 0.54 to 0.92) versus a DPP-4i (n=17 667 pairs), 0.61 (0.47 to 0.78) versus a GLP-1RA (20 539), and 0.51 (0.38 to 0.67) versus a sulfonylurea (17 354). The hazard ratio for the composite cardiovascular endpoint associated with canagliflozin was 0.89 (0.68 to 1.17) versus a DPP-4i, 1.03 (0.79 to 1.35) versus a GLP-1RA, and 0.86 (0.65 to 1.13) versus a sulfonylurea. Results were similar in sensitivity analyses further adjusting for baseline hemoglobin A1c levels and in subgroups of patients with and without prior cardiovascular disease or heart failure. CONCLUSIONS In this large cohort study, canagliflozin was associated with a lower risk of heart failure admission to hospital and with a similar risk of myocardial infarction or stroke in direct comparisons with three different classes of non-gliflozin diabetes treatment alternatives as used in routine care.