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Type 2 diabetes mellitus is associated with a substantial risk of cardiovascular and renal disease.1,2 The use of inhibitors of sodium–glucose cotransporter 2 (SGLT2) results in favorable effects on biomarkers, including glycemia, blood pressure, weight,3 intrarenal hemodynamics, and albuminuria,4 and may also reduce the risk of serious cardiovascular complications, kidney disease, and death.5–7 The CANVAS Program, comprising two sister trials, was designed to assess the cardiovascular safety and efficacy of canagliflozin and to evaluate the balance between any potential benefits of the drug and the risks associated with it, such as genitourinary infection, diabetic ketoacidosis, and fracture. The Canagliflozin Cardiovascular Assessment Study (CANVAS)8 was initiated in December 2009, before the approval of canagliflozin by the Food and Drug Administration (FDA), with the initial goal of showing cardiovascular safety. The first approval of the compound by the FDA occurred in March 2013, with interim data from CANVAS. Owing to the inclusion of unmasked interim cardiovascular outcome data in the regulatory filing documents, a planned expansion of the sample size to enable a test of cardiovascular protection was not undertaken. Instead, CANVAS–Renal (CANVAS-R)9 was designed as a second CANVAS-like, double-blind, randomized, placebo-controlled trial to be analyzed jointly with CANVAS, to meet a post-approval cardiovascular safety commitment to regulatory agencies. CANVAS-R, which commenced in 2014, was also designed to assess effects on albuminuria. The integrated analysis of CANVAS and CANVAS-R as the CANVAS Program10 was undertaken to maximize statistical power to detect plausible effects of canagliflozin on cardiovascular, kidney, and safety outcomes as suggested from evolving evidence about SGLT2 inhibitors.6,7
Methods
Program Design and Oversight
A total of 667 centers in 30 countries were involved in the two trials. The trials were scheduled for joint close-out and analysis when at least 688 cardiovascular events had been observed and the last participant who had undergone randomization had approximately 78 weeks of follow-up; this occurred in February 2017. The protocols for the two trials8,9 were approved by the ethics committee at each site and are available with the full text of this article at NEJM.org. All the participants provided written informed consent. The trials were sponsored by Janssen Research and Development and...