Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus
Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus
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DOI：
10.1210/jc.2015-3167
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发表时间：
2016-01-01
影响因子：
5.8
通讯作者：
Meininger, Gary
中科院分区：
文献类型：
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作者：
Watts, Nelson B.;Bilezikian, John P.;Meininger, Gary
内容：Canagliflozin是一种钠葡萄糖协同转运蛋白2抑制剂，用于治疗2型糖尿病（T2 DM）。目的：本研究的目的是描述Canagliflozin对骨折风险的影响。设计和设置：这是一项在T2 DM患者中进行的随机III期研究。患者和干预措施：在来自9项安慰剂和活性对照研究的总体患者人群中评价了100和300 mg剂量的卡格列净（N = 10 194），以及对一项单一试验的单独分析，该试验富集了有心血管疾病既往史/风险的患者（即，卡格列净心血管评估研究[CANVAS]; N = 4327）和8项非CANVAS研究的汇总人群（N = 5867）。结果测量：评估了判定的骨折不良事件（AE）、跌倒相关AE和血容量不足相关AE的发生率。在汇总的非CANVAS研究中，卡格列净组（1.7%）和非卡格列净组（1.5%）的骨折发生率相似。在CANVAS中，卡格列净组（4.0%）与安慰剂组（2.6%）相比，骨折显著增加，上肢和下肢之间平衡。在总体人群中，卡格列净组（2.7%）的骨折发生率高于非卡格列净组（1.9%），这是由CANVAS中的骨折增加所致。CANVAS中报告的跌倒相关AE的发生率较低，但卡格列净组显著较高，可能与血容量不足相关AE相关，但在汇总的非CANVAS研究和总体人群中无显著差异。卡格列净治疗的骨折风险增加，由CANVAS患者驱动，这些患者年龄较大，有心血管疾病既往史/风险，基线估计肾小球滤过率较低，基线利尿剂使用较高。骨折增加可能由福尔斯介导;然而，卡格列净导致骨折风险增加的原因尚不清楚。
Context: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM).Objective: The purpose of this study was to describe the effects of canagliflozin on bone fracture risk.Design and Setting: This was a randomized phase 3 study in patients with T2DM.Patients and Interventions: Canagliflozin doses of 100 and 300 mg were evaluated in the overall population of patients from 9 placebo-and active-controlled studies (N = 10 194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, the CANagliflozin cardioVascular Assessment Study [CANVAS]; N = 4327) and a pooled population of 8 non-CANVAS studies (N = 5867).Outcome Measures: The incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs was assessed.Results: The incidence of fractures was similar with canagliflozin (1.7%) and noncanagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) vs placebo (2.6%) that was balanced between the upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) vs noncanagliflozin (1.9%) in the overall population, which was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population.Conclusions: Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.