Effects of canagliflozin compared with placebo on major adverse cardiovascular and kidney events in patient groups with different baseline levels of HbA1c, disease duration and treatment intensity: results from the CANVAS Program

Abstract

Aims/hypothesis: Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control.

Methods: We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (<10, 10 to 16, >16 years) and HbA1c (≤53.0 mmol/mol [<7.0%], >53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance <0.05).

Results: At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA1c > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0-18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37.

Conclusions/interpretation: In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c.

Trial registration: ClinicalTrials.gov NCT01032629 NCT01989754.

Keywords: Baseline HbA1c; Complications; Disease duration; Treatment intensity; Type 2 diabetes complexity.

© 2021. The Author(s).

Figures

Fig. 1

HRs for (a) cardiovascular and (b) kidney outcomes according to baseline treatment intensity. HRs cannot be directly calculated from event numbers because the trials had different randomisation ratios and different follow-up durations. The follow-up for CANVAS was 295.9 weeks and for CANVAS-R was 108.0 weeks. Cana, canagliflozin; CV, cardiovascular; HF, heart failure; MI, myocardial infarction

Fig. 2

HRs for (a) cardiovascular and (b) kidney outcomes according to baseline disease duration. HRs cannot be directly calculated from event numbers because the trials had different randomisation ratios and different follow-up durations. The follow-up for CANVAS was 295.9 weeks and for CANVAS-R was 108.0 weeks. CV, cardiovascular; HF, heart failure; MI, myocardial infarction

Fig. 3

Cubic spline model for HR for MACE with canagliflozin vs placebo according to baseline disease duration. The y-axis is plotted on a log scale

Fig. 4

Cubic spline model for HR for MACE with canagliflozin vs placebo according to baseline HbA1c. The y-axis is plotted on a log scale

Fig. 5

HRs for (a) cardiovascular and (b) kidney outcomes according to baseline HbA1c. HRs cannot be directly calculated from event numbers because the trials had different randomisation ratios and different follow-up durations. The follow-up for CANVAS was 295.9 weeks and for CANVAS-R was 108.0 weeks. CV, cardiovascular; HF, heart failure; MI, myocardial infarction