Effect of Canagliflozin on Renal and Cardiovascular Outcomes across Different Levels of Albuminuria: Data from the CANVAS Program

Abstract

Background: If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more.

Methods: We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline.

Results: Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m² per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria (P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (P heterogeneity=0.004).

Conclusions: The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.

Keywords: SGLT2 inhibitor; albuminuria; canagliflozin; cardiovascular; renal.

Graphical abstract

Figure 1.

Placebo-subtracted differences in intermediate outcomes varied in participants with UACR <30, 30–300, and >300 mg/g at baseline.

Figure 2.

Canagliflozin slowed the loss of kidney function across all UACR subgroups. Effect of canagliflozin as indicated by (A) adjusted mean eGFR over time and (B) eGFR slope from week 6/13 until the end of follow-up, with the greatest effect in participants with UACR >300 mg/g at baseline. *Data are reported for week 6 in CANVAS and week 13 in CANVAS-R.

Figure 3.

There was heterogeneity in the effect of canagliflozin on the renal composite outcome in participants with UACR <30, 30–300, and >300 mg/g at baseline, while effects on cardiovascular outcomes and all-cause mortality were consistent across UACR subgroups. *A 40% reduction in eGFR, ESKD, or renal death. CV, cardiovascular; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction.

Figure 4.

Absolute benefits per 1000 participants over 5 years with canagliflozin versus placebo were consistent across UACR subgroups for cardiovascular outcomes, but absolute risk reductions for the renal composite outcome and all-cause mortality were greatest in patients with UACR >300mg/g. *Excess number is relative to the placebo group. If the number is negative, then fewer participants in the canagliflozin group experienced the event compared with the placebo group. ^†A 40% reduction in eGFR, ESKD, or renal death. HF, heart failure; MACE, major adverse cardiovascular events.

Figure 5.

The risk of most safety outcomes collected across the CANVAS Program was consistent in participants with UACR <30, 30–300, and >300 mg/g at baseline. HR, hazard ratio.