Abstract 8947: A Meta-Analysis of Cardiovascular Outcomes in Clinical Trials of Dapagliflozin
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular (CV) disease. Dapagliflozin (DAPA), a selective SGLT2 inhibitor, is currently under evaluation for the treatment of T2DM. DAPA reduces hyperglycemia by promoting renal glucose excretion, independent of insulin secretion or action, also reducing weight and blood pressure. In response to FDA recommendations for new T2DM therapies, a pre-specified meta-analysis was conducted of data from 14 phase 2/3 studies (n=6228) to assess the CV safety of all DAPA doses (2.5 to >10mg/d) pooled (n=4287), relative to all comparators (active or placebo) pooled (n=1941). CV events were systematically identified from investigator reports of adverse events and adjudicated by an independent committee. Adjudication was blinded to treatment allocation and conducted prospectively for the majority of trials. The primary end point was a composite of time to first event of CV death, myocardial infarction (MI), stroke, or hospitalization for unstable angina. The secondary end point included the primary end point, unplanned coronary revascularization, and hospitalization for heart failure. Baseline characteristics were balanced between groups: mean age=56 years, body mass index=31.5 kg/m2, and T2DM duration=6 years. Characteristics mirrored CV risk in the general T2DM population and included hypertension (62%), dyslipidemia (49%), smoking history (40%), and CV disease history (19%). A total of 78 primary end point events were confirmed with a stratified event rate (subjects with events/1000 subject years) of 11.3 for DAPA vs 16.6 for comparators. The estimated hazard ratio (HR) using a Cox proportional hazards method was 0.674 (98% CI: 0.385, 1.178; 95% CI: 0.421, 1.078). Analyses of the secondary end point (HR: 0.632; 95% CI: 0.416, 0.959) and of a composite CV death, MI, and stroke end point (HR: 0.596; 95% CI: 0.357, 0.996) were consistent with primary results. Analyses by dose (DAPA 2.5, 5 and 10 mg) were comparable to overall results. Review of data from the 4-month safety update confirmed the conclusions from the initial pre-specified analysis. The results suggest that DAPA is not associated with an increase in CV risk, and are consistent with a potential reduction in CV risk.
- © 2011 by American Heart Association, Inc.