Bristol-Myers Squibb, Princeton, NJ, USA.
University of Nebraska Medical Center, Omaha, NE, USA.
Diabetes Ther. 2015 Sep;6(3):357-75. doi: 10.1007/s13300-015-0128-9. Epub 2015 Sep 1.
Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, decreases plasma glucose levels by suppressing renal glucose reabsorption and increasing urinary glucose excretion. Previously published pre-clinical data suggest that dapagliflozin lacks carcinogenic potential. This article reviews data on bladder cancer with dapagliflozin to illustrate the challenges in assessing bladder cancer in drug development programs in patients with type 2 diabetes mellitus (T2DM).
Clinical cases of bladder cancer were analyzed in a pooled population of >9000 patients in 21 phase 2b/3 dapagliflozin clinical trials of up to 208 weeks' duration.
In the 21-study pool, demographic and baseline characteristics were generally consistent between dapagliflozin and comparator groups. The overall incidence of malignancies was also balanced between the treatment groups, with an incidence rate ratio (IRR) of 1.035 [95% confidence interval (CI): 0.724, 1.481]. Nine of 5936 dapagliflozin-treated patients and 1 of 3403 comparator-treated patients reported bladder cancer, with an IRR of 5.168 (95% CI: 0.677, 233.55). All of these patients had clinical attributes typical of bladder cancer in the general population (≥60-year-old males; 8 of the 10 patients were current/former smokers). All cases of bladder cancer were reported within 2 years of starting study treatment. There was an absence of detailed workup of hematuria prior to randomization, and no hematuria workup data were collected proactively in the dapagliflozin trials, which is typical of clinical practice. Failure to exclude bladder cancer prior to randomization increases the chance of recruiting patients with pre-existing bladder cancer in clinical trials and may delay the final diagnosis. Of the nine dapagliflozin-treated patients with bladder cancer, eight had microscopic hematuria prior to start of treatment or within 6 months of initiating study treatment.
The assessment of bladder cancer data illustrates the challenges of characterizing cancer risk in T2DM drug development programs. The totality of evidence to date does not suggest a causal relationship between dapagliflozin and bladder cancer.
AstraZeneca.
达格列净是一种钠-葡萄糖共转运蛋白 2 抑制剂，通过抑制肾脏对葡萄糖的重吸收和增加尿葡萄糖排泄来降低血糖水平。先前发表的临床前数据表明，达格列净缺乏致癌潜力。本文回顾了达格列净治疗膀胱癌的数据，以说明在 2 型糖尿病 (T2DM) 患者药物开发项目中评估膀胱癌所面临的挑战。
在 21 项达格列净 2b/3 期临床试验的汇总人群中，对>9000 例患者的膀胱癌临床病例进行了分析，这些试验的持续时间长达 208 周。
在 21 项研究汇总中，达格列净和对照组之间的人口统计学和基线特征通常是一致的。治疗组之间恶性肿瘤的总体发生率也保持平衡，发生率比 (IRR) 为 1.035[95%置信区间 (CI)：0.724，1.481]。在 5936 例达格列净治疗患者中有 9 例和 3403 例对照治疗患者报告膀胱癌，IRR 为 5.168(95%CI：0.677，233.55)。所有这些患者均具有普通人群膀胱癌的典型临床特征(≥60 岁男性;10 例患者中有 8 例为现/曾经吸烟者)。所有膀胱癌病例均在开始研究治疗后 2 年内报告。在随机分组前未对血尿进行详细检查，并且在达格列净试验中也未主动收集血尿检查数据，这在临床实践中是很常见的。在随机分组前未能排除膀胱癌会增加在临床试验中招募患有先前存在的膀胱癌患者的机会，并可能延迟最终诊断。在 9 例达格列净治疗的膀胱癌患者中，有 8 例在治疗开始前或开始研究治疗后 6 个月内有镜下血尿。
膀胱癌数据的评估说明了在 T2DM 药物开发项目中描述癌症风险的挑战。迄今为止的所有证据都不表明达格列净与膀胱癌之间存在因果关系。
阿斯利康。
