• Bruce Neal, Vlado Perkovic, Kenneth W Mahaffey, Dick de Zeeuw, Greg Fulcher, Ngozi Erondu, Wayne Shaw, Gordon Law, Mehul Desai, David R Matthews, and CANVAS Program Collaborative Group.
• From the George Institute for Global Health, Faculty of Medicine, UNSW Sydney (B.N., V.P.), the Charles Perkins Centre (B.N.), and the Royal North Shore Hospital (V.P., G.F.), University of Sydney, and the Faculty of Medicine, University of New South Wales (B.N.) - all in Sydney; Imperial College London, London (B.N.), and the Oxford Centre for Diabetes, Endocrinology, and Metabolism and Harris Manchester College, University of Oxford, Oxford (D.R.M.) - both in the United Kingdom; the Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA (K.W.M.); the University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (D.Z.); and Janssen Research and Development, Raritan, NJ (N.E., W.S., G.L., M.D.).
• N. Engl. J. Med. 2017 Aug 17; 377 (7): 644657644-657.

AbstractBackground Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).

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