Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)

Abstract

Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.

Methods: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).

Results: Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63).

Conclusions: Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.

Keywords: canagliflozin; clinical trial; diabetes mellitus; primary prevention; secondary prevention.

Figure 1.

Comparative effects of canagliflozin and placebo on cardiovascular, kidney, and mortality outcomes in the total population and the primary and secondary prevention cohorts in the CANVAS Program. Hazard ratios and 95% CIs were estimated using Cox regression models, with stratification by trial for all canagliflozin groups combined vs. placebo. CANVAS indicates Canagliflozin Cardiovascular Assessment Study; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; and MI, myocardial infarction. *P<0.001 for noninferiority and P=0.02 for superiority for the primary outcome of CV death, nonfatal MI, or nonfatal stroke in the overall population. †Incidence rates and HRs not calculated because of the small number of events.

Figure 2.

Effects of canagliflozin and placebo on cardiovascular and renal outcomes by primary and secondary prevention cohorts in the CANVAS Program. CANVAS indicates Canagliflozin Cardiovascular Assessment Study; CI, confidence interval; MI, myocardial infarction; and eGFR, estimated glomerular filtration rate.

Figure 3.

Summary of adverse events in the primary and secondary prevention cohorts in the CANVAS Program. CANVAS indicates Canagliflozin Cardiovascular Assessment Study; CANVAS-R, Canagliflozin Cardiovascular Assessment Study–Renal; and CI, confidence interval. *For these adverse events, the annualized event rates are reported with data from CANVAS alone through January 7, 2014, because after this time, only serious adverse events or adverse events leading to discontinuation were collected. In CANVAS-R, only serious adverse events or adverse events leading to discontinuation were collected. Owing to the differences between the 2 trials in methods of collection of the data, an integrated analysis of these adverse events is not possible.

Figure 4.

Benefits and risks per 1000 patients over 5 years with canagliflozin vs. placebo in the overall population, secondary prevention cohort, and primary prevention cohort. CI indicates confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; and MI, myocardial infarction. *Excess number is relative to the placebo group. If the number is negative, then fewer subjects in the canagliflozin group experienced the event compared with the placebo group.