Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program
（图2）基于57%、50%、40%和30%eGFR降低的主要结局事件率，Canagliflozin低于安慰剂组；这些事件分别发生在每1000患者年1.9对3.7、3.6对5.8、8.2对12.3和20.3对26.5名参与者中。Canagliflozin对57%eGFR降低、ESKD和肾死亡复合物的影响大小与ESKD和肾脏死亡复合物相似。当eGFR减少57%被eGFR减少50%、40%或30%所取代时，效果会逐渐减弱。
在排除最后一次可用测量中eGFR降低后，观察到类似的效应大小，尽管事件发生率降低了约一半，但没有持续下降的证据。当包括所有减少时，比例效应估计值进一步降低，Canagliflozin与安慰剂的效应估计值不再显著。Canagliflozin对主要结局的治疗效果模式在基线参与者类别中基本一致。
（图4）（A圆形数据点）补充表2显示了证明复合肾脏结果的一系列效应大小所需的样本量。对于基于使用所有基线和随访测量的主要分析方法，将eGFR下降阈值从57%降低到30%对所需的样本量几乎没有影响。需要持续减少（A菱形数据点）需要在所有eGFR下降阈值上使用较小的样本量，与估计值相比，估计值还包括在最后一次访问时检测到的eGFR减少，这些减少无法确认持续效应或持续和不持续的减少（B三角形数据点）。
当使用所有基线和随访测量值时，与eGFR为60 ml/min/1.73 m2的参与者相比，基线eGFR为每1.73 m2 60 ml/min的参与者需要更小的样本量，以减少eGFR
（图4B）使用Canagliflozin的治疗基线数据，消除了Canagliflozin对eGFR的急性血液动力学影响的混杂效应，大大减少了所需的样本量，而不管eGFR的降低是否持续；当在复合肾脏结局中使用持续和不持续的较小eGFR降低时，需要较小的样本量。
当使用Canagliflozin组的治疗基线值时，eGFR为60美元和每1.73平方米60毫升/分钟的参与者所需的样本量减少到相似的程度。
使用较小的eGFR下降阈值可能为鉴定SGLT2抑制剂和其他旨在保护肾功能的药物的肾脏保护作用提供了一种有效且高成本效益的方法。有必要在前瞻性试验中进行进一步调查。
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.
