卡格列净与 2 型糖尿病患者骨折风险：CANVAS 计划研究结果。
Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program.
机构信息
The George Institute for Global Health, UNSW Sydney, Level 5, 1 King St, Newtown, Sydney, NSW, 2042, Australia.
Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Diabetologia. 2019 Oct;62(10):1854-1867. doi: 10.1007/s00125-019-4955-5. Epub 2019 Aug 10.
AIMS/HYPOTHESIS: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R.
METHODS
This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time.
RESULTS
A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls.
CONCLUSIONS/INTERPRETATION: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01032629, NCT01989754.
目的/假设：卡格列净的 CANagliflozin 心血管评估研究 (CANVAS) 计划报告了骨折风险增加，与该计划包含的两项试验之间存在发现的异质性，CANVAS 和 CANVAS-R。本分析的目的是确定为什么在 CANVAS 和 CANVAS-R 之间观察到的骨折影响可能不同。
方法
本研究是对两项高度相似的试验（CANVAS 和 CANVAS-R）的分析，共纳入 10142 名 2 型糖尿病患者和心血管疾病病史或高危患者，接受卡格列净（每日一次联合 100/300mg）或安慰剂治疗。本分析评估的结局包括总体和骨折类型、部位、与跌倒的关系、剂量和随访时间的骨折影响。
结果
共有 496 名患者在随访期间记录了≥1 次骨折事件（卡格列净组为每 1000 患者年 15.40 例，安慰剂组为 11.93 例；HR 1.26 [95% CI 1.04，1.52]）。CANVAS（n=4330：HR 1.55 [95% CI 1.21，1.97]）和 CANVAS-R（n=5812：HR 0.86 [95% CI 0.62，1.19]）之间的骨折效应存在显著异质性（p=0.005）。骨折风险的研究间异质性不能通过基线特征、随机治疗与患者特征的相互作用、剂量效应、随访时间、代谢效应、与跌倒相关的不良事件或可能导致跌倒的不良事件的差异来清楚解释。
结论/解释：没有证据能清楚地解释 CANVAS 计划中观察到的骨折风险或两项研究之间的骨折风险异质性。最近的 Canagliflozin 和糖尿病肾病的肾脏事件（CREDENCE）试验报告的骨折结果为阴性，这表明在 CANVAS 中观察到的相关性可能是偶然发现，尽管仍有可能存在未识别的与跌倒相关的机制。
试验注册
ClinicalTrials.gov NCT01032629，NCT01989754。
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