Department of Medicine and Health Sciences, Division of Community Medicine, Primary Care, Faculty of Health Sciences, Department of Local Care West, County Council of Ötergötland, Linköping University, Sweden (K.R.).The George Institute for Global Health (K.R., V.P., B.N.)Faculty of Medicine (B.N.)University of New South Wales, Sydney, Australia. Royal North Shore Hospital (G.F., V.P., G.F.)Charles Perkins Centre (B.N.)University of Sydney, Australia. Harvard Medical School and Brigham and Women’s Hospital, Boston, MA (S.D.S.).Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, CA (K.W.M.).University of Groningen, University Medical Center Groningen, The Netherlands (D.d.Z.).Janssen Research & Development, LLC, Raritan, NJ (T.D.B., W.S., M.D.).Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, United Kingdom (D.R.M).Harris Manchester College, University of Oxford, United Kingdom (D.R.M.).Imperial College London, United Kingdom (B.N.).
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Background:Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure (HF) and cardiovascular death overall, in those with and without a baseline history of HF, and in other participant subgroups.Methods:The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized HF.Results:Participants with a history of HF at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and β-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized HF was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67–0.91), as was fatal or hospitalized HF (HR, 0.70; 95% CI, 0.55–0.89) and hospitalized HF alone (HR, 0.67; 95% CI, 0.52–0.87). The benefit on cardiovascular death or hospitalized HF may be greater in patients with a prior history of HF (HR, 0.61; 95% CI, 0.46–0.80) compared with those without HF at baseline (HR, 0.87; 95% CI, 0.72–1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without HF at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of HF (P=0.03).Conclusions:In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized HF across a broad range of different patient subgroups. Benefits may be greater in those with a history of HF at baseline.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.