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.

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).

结果：一级预防参与者（N = 3486； 34％）较年轻（63岁对64岁），女性更常见（45％对31％），糖尿病病程较长（14岁对13岁）与二级预防参与者相比（N = 6656； 66％）。二级预防组的一级终点事件发生率高于一级预防组（36.9比15.7 / 1000患者-年，P <0.001）。在整个队列中，与安慰剂相比，canagliflozin降低了主要终点（26.9比31.5 / 1000患者-年；危险比[HR]为0.86； 95％置信区间[CI]为0.75-0.97；P <0.001非劣效性，优劣P = 0.02），无统计学异质性（相互作用）在一级（HR，0.98； 95％CI，0.74-1.30）和二级预防（HR，0.82； 95％CI，0.72-0.95）之间，P值= 0.18。肾结局（HR，0.59; 95％CI，0.44–0.79 vs HR，0.63; 95％CI，0.39–1.02;交互作用P值= 0.73）和心力衰竭住院治疗（HR，0.68; 95％CI，0.51-0.90 vs.在二级预防和一级预防队列中，HR分别为0.64、95％CI为0.35-1.15，相互作用P值= 0.91）。在二级和一级预防队列中，下肢截肢率也有相似的增加（HR，2.07； 95％CI，1.43-3.00，而HR，1.52； 95％CI，0.70-3.29；交互作用P值= 0.63）。

结论：与一级预防患者相比，患有2型糖尿病和先前发生心血管事件的患者的心血管结局发生率更高。Canagliflozin降低了心血管和肾脏的预后，没有统计证据表明一级和二级预防组的治疗效果存在异质性。进一步的研究将进一步探讨卡格列净在这些患者人群中的作用。

临床试验注册： URL：https://www.clinicaltrials.gov。唯一标识符：NCT01032629和NCT01989754。