Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Harris Manchester College, University of Oxford, Mansfield Road, Oxford, OX1 3TD, UK.
Diabetologia. 2019 Jun;62(6):926-938. doi: 10.1007/s00125-019-4839-8. Epub 2019 Mar 12.
AIMS/HYPOTHESIS: The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.
The effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.
There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100 mg and 300 mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.
CONCLUSIONS/INTERPRETATION: The CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.
目的/假设：卡格列净心血管评估研究（CANVAS）计划的主要分析表明，卡格列净对心血管风险较高的 2 型糖尿病患者的心血管和肾脏结局有有益影响，但也意外增加了主要或次要下肢截肢的风险。这些次要分析更详细地探讨了这一发现。
计算了 CANVAS 计划中卡格列净对不同类型和近似病因以及不同剂量卡格列净的截肢风险的影响。确定了截肢风险与基线特征的单变量和多变量关联，并比较了卡格列净在各亚组中的比例和绝对效果。
187 名（1.8%）参与者发生非创伤性下肢截肢（小截肢 71%，大截肢 29%）；与之前发表的研究结果一致，卡格列净组和安慰剂组的发生率分别为每 1000 名参与者年 6.30 例和 3.37 例（HR 1.97[95%CI 1.41, 2.75]）。缺血性和感染性病因以及 100mg 和 300mg 剂量的风险相似。总体截肢风险与基线既往截肢（主要或次要）史（HR 21.31[95%CI 15.40, 29.49]）和其他已确立的危险因素密切相关。随机治疗与参与者特征之间没有相互作用可以解释卡格列净对截肢风险的影响。对于研究的每个临床亚组，预计的截肢事件数量都少于避免的主要不良心血管事件数量。
结论/解释：CANVAS 计划表明，卡格列净增加了该研究人群的截肢（主要是小截肢）风险。确定了截肢的预期危险因素，如既往截肢史、外周血管疾病和周围神经病变，但未确定卡格列净的特定病因机制或易患亚组。
