Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program

Abstract

Background: Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes.

Methods: To assess whether eGFR declines <57% could detect canagliflozin's effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect.

Results: Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect.

Conclusions: Declines in eGFR <57% may provide robust estimates of canagliflozin's effects on renal outcomes if the analysis controls for the drug's acute hemodynamic effect.

Clinical trial registry name and registration number: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754.

Keywords: SGLT2 inhibitors; Type 2 diabetes; canagliflozin; eGFR decline.

Copyright © 2020 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Canagliflozin decreased the risk of the composite renal outcome on the basis of (A) 57%, (B) 50%, (C) 40%, and (D) 30% eGFR reductions compared with placebo. eGFR decline was on the basis of reductions sustained for two consecutive measurements ≥30 days apart unless identified on the last available measurement. Log-rank test was used to assess the treatment effect of canagliflozin versus placebo.

Figure 2.

Compared with a 57% eGFR reduction, the effect sizes for canagliflozin versus placebo were attenuated when using 50%, 40%, or 30% eGFR reductions in the composite renal outcome. The prespecified study outcome was on the basis of reductions that were sustained for two consecutive measurements ≥30 days apart or those identified on the last available measurement. Sustained reductions only were defined as reductions that were sustained for two consecutive measurements ≥30 days apart. All reductions were defined as sustained or unsustained reductions.

Figure 3.

The attenuation of effect associated with using lesser eGFR reductions in the composite renal outcome was mostly removed by controlling for the acute hemodynamic effects of canagliflozin. Sustained and unsustained reductions are defined as in Figure 2. Acute hemodynamic effects were controlled for by using first postbaseline eGFR measurements for those assigned to canagliflozin.

Figure 4.

Required sample sizes were mostly not affected by use of lesser eGFR reductions (A panel) but were much decreased by controlling for the acute hemodynamic effects of canagliflozin (B panel). Effects of using prespecified definitions of eGFR decline (diamond-shaped data points), only sustained reductions in eGFR (circular data points), or all reductions sustained or unsustained (triangular data points).

Figure 5.

Proposed design of a randomized clinical trial assessing the effects of a therapy with an acute effect on eGFR. The acute effect of a therapy might be controlled by having a short active run-in period prior to randomization, which generates both on-treatment and off-treatment baseline eGFR measures for each participant; people randomized to the intervention arm would have subsequent eGFR levels compared with those at the end of the active run-in period, whereas those randomized to the control arm could be compared with the eGFR measurement prior to the run-in period.