Cardiovascular Division, The George Institute for Global Health, UNSW, Sydney, Australia.
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
Diabetes Obes Metab. 2020 Oct;22(10):1753-1766. doi: 10.1111/dom.14091. Epub 2020 Jun 24.
To determine whether there was an explanation as to why the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor canagliflozin on amputation risk vary between the CANVAS program and the CREDENCE trial.
We performed a pooled analysis of patient-level data from the CANVAS program and the CREDENCE trial. Patient characteristics associated with amputation risk were assessed in univariable and multivariable regression models and compared between studies. Effects of canagliflozin on amputation risk were determined from Cox proportional hazards models and compared between studies, subgroups and for a range of amputation outcomes. Effects over time were explored by cumulative event curves.
In the CANVAS program (n = 10 142; median follow-up 2.4 years) and CREDENCE trial (n = 4401; median follow-up 2.5 years), 2.3% and 5.3% of participants, respectively, reported baseline amputation history. Key differences at baseline were the proportions with nephropathy (CREDENCE higher, 100% vs. 17.5%) and cardiovascular disease (CANVAS higher, 66% vs. 50%). There were 133 amputations in CREDENCE (3.0% annual event rate) and 187 amputations in CANVAS (1.8% annual event rate), with prior amputation being the strongest predictor of future amputation in both groups. Effects of canagliflozin on amputation risk were significantly different between trials (P .02, I = 82%), but this was not explained by participant or trial differences. There was no evidence that foot disease management protocols instituted during CREDENCE ameliorated amputation risk.
We identified no explanation for the difference in amputation risk between the CREDENCE trial and the CANVAS program. In the context of null effects of SGLT2 inhibition on amputation in CREDENCE and all other large trials, there is a possibility that the finding in CANVAS was the result of chance.
确定钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂卡格列净对截肢风险的影响在 CANVAS 项目和 CREDENCE 试验之间存在差异的原因。
我们对 CANVAS 项目和 CREDENCE 试验的患者水平数据进行了汇总分析。在单变量和多变量回归模型中评估了与截肢风险相关的患者特征，并比较了两项研究之间的差异。使用 Cox 比例风险模型确定卡格列净对截肢风险的影响，并比较了两项研究、亚组以及一系列截肢结局之间的差异。通过累积事件曲线探讨了随时间的变化。
在 CANVAS 项目（n=10142；中位随访时间 2.4 年）和 CREDENCE 试验（n=4401；中位随访时间 2.5 年）中，分别有 2.3%和 5.3%的参与者报告了基线截肢史。基线时的主要差异在于肾病（CREDENCE 更高，100% vs. 17.5%）和心血管疾病（CANVAS 更高，66% vs. 50%）的比例。CREDENCE 中有 133 例截肢（年事件发生率 3.0%），CANVAS 中有 187 例截肢（年事件发生率 1.8%），既往截肢是两组中未来截肢的最强预测因素。卡格列净对截肢风险的影响在两项试验之间有显著差异（P<.02，I=82%），但这不能用参与者或试验差异来解释。没有证据表明 CREDENCE 期间实施的足部疾病管理方案改善了截肢风险。
我们没有发现 CREDENCE 试验和 CANVAS 项目之间截肢风险差异的解释。在 CREDENCE 和所有其他大型试验中 SGLT2 抑制对截肢无影响的背景下，CANVAS 的发现有可能是偶然的。
