BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without prior cardiovascular disease (primary prevention). METHODS: In CREDENCE, 4401 participants with type 2 diabetes and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (N=2181; 49.6%) were younger (61 vs 65 years), more often female (37% vs 31%), and had shorter diabetes duration (15 vs 16 years) compared to secondary prevention participants (N=2220; 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80; 95% confidence interval [CI] 0.67-0.95; P=0.01), with consistent reductions in both the primary (HR, 0.68; 95% CI, 0.49-0.94) and secondary (HR, 0.85; 95% CI, 0.69-1.06) prevention groups (P-interaction 0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78; 95% CI, 0.61-1.00), nonfatal myocardial infarction (HR, 0.81; 95% CI, 0.59-1.10), and nonfatal stroke (HR, 0.80; 95% CI, 0.56-1.15). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P-interaction >0.5 for each outcome). CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events, as well as kidney failure, in patients with type 2 diabetes and chronic kidney disease, including in participants who did not have prior cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://ClinicalTrials.gov Unique identifier: NCT02065791.