Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program

Abstract

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.

Keywords: SGLT2 inhibitor; canagliflozin; heart failure; randomized trial; type 2 diabetes mellitus.

Figure 1.

Effects of canagliflozin on heart failure outcomes. A through D, Effects of canagliflozin on cardiovascular death or hospitalized heart failure (A), fatal or hospitalized heart failure (B), fatal heart failure (C), and hospitalized heart failure (D). CI indicates confidence interval; and HF, heart failure.

Figure 2.

Proportional and absolute effects of canagliflozin compared with placebo on cardiovascular and renal outcomes in patients with and without a history of heart failure at baseline. *HR (canagliflozin compared to placebo) and its 95% CI are estimated using a Cox proportional hazard model including treatment as the explanatory variable. The model for CV death is stratified by prior CV disease subgroup and study. The models of renal endpoints are stratified for stage of baseline chronic kidney disease, measured by estimated glomerular filtration rate (<60, ≥60 mL/min/1.73 m²) and by study. †Serious decline in kidney function was defined as a 40% reduction in the estimated glomerular filtration rate, the need for renal replacement therapy, or death from renal causes. ARD indicates absolute risk difference over 5 years; CI, confidence interval; HF, heart failure; and HR, hazard ratio.

Figure 3.

Effects on cardiovascular death or hospitalized heart failure in subgroups defined by demographic and disease characteristics. History of CV disease–yes indicates patients were included on the basis of atherosclerotic cardiovascular disease history, whereas history of CV disease–no indicates patients were included on the basis of risk factors alone. BMI indicates body mass index; CANVAS, Canagliflozin Cardiovascular Assessment Study; CANVAS-R, Canagliflozin Cardiovascular Assessment Study–Renal; CI, confidence interval; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; HR, hazard ratio; and RAAS, renin angiotensin aldosterone system.

Figure 4.

Proportional and absolute effects of canagliflozin compared with placebo on key safety outcome in patients with and without a history of heart failure at baseline. *Based on ITT dataset, whereas all other analyses based on on-treatment dataset. †For these adverse events, the annualized incidence rates are reported based on the CANVAS study alone through January 7, 2014, because, after this time, only serious adverse events or adverse events leading to discontinuation were collected. In the CANVAS-R study, only serious adverse events or adverse events leading to discontinuation were collected for these events. ARD indicates absolute risk difference over 5 years; CANVAS, Canagliflozin Cardiovascular Assessment Study; ITT, intent-totreat; CANVAS-R, Canagliflozin Cardiovascular Assessment Study–Renal; CI, confidence interval; HF, heart failure; and HR, hazard ratio.