Department of Cardiology, Acibadem University Medical School, Istanbul, Turkey.
PLoS One. 2022 Mar 2;17(3):e0263461. doi: 10.1371/journal.pone.0263461. eCollection 2022.
Angiotensin-receptor blockers (ARBs) are a class of drugs approved for the treatment of several common conditions, such as hypertension and heart failure. Recently, regulatory agencies have started to identify possibly carcinogenic nitrosamines and azido compounds in a multitude of formulations of several ARBs, resulting in progressive recalls. Furthermore, data from several randomized controlled trials suggested that there is also a clinically increased risk of cancer and specifically lung cancer with ARBs; whereas other trials suggested no increased risk. The purpose of this analysis was to provide additional insight into the ARB-cancer link by examining whether there is a relationship between degree of cumulative exposure to ARBs and risk of cancer in randomized trials. Trial-level data from ARB Trialists Collaboration including 15 randomized controlled trials was extracted and entered into meta-regression analyses. The two co-primary outcomes were the relationship between cumulative exposure to ARBs and risk of all cancers combined and the relationship between cumulative exposure and risk of lung cancer. A total of 74,021 patients were randomized to an ARB resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent). 61,197 patients were randomized to control. There was a highly significant correlation between the degree of cumulative exposure to ARBs and risk of all cancers combined (slope = 0.07 [95% CI 0.03 to 0.11], p<0.001), and also lung cancer (slope = 0.16 [95% CI 0.05 to 0.27], p = 0.003). Accordingly, in trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk of all cancers combined (I2 = 31.4%, RR 1.11 [95% CI 1.03 to 1.19], p = 0.006). There was a statistically significant increase in risk of lung cancers in trials where the cumulative exposure was greater than 2.5 years (I2 = 0%, RR 1.21 [95% CI 1.02 to 1.44], p = 0.03). In trials with lower cumulative exposure to ARBs, there was no increased risk of all cancers combined or lung cancer. Cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme inhibitor treatment or the type of control (i.e. placebo or non-placebo control). Since this is a trial-level analysis. the effects of patient characteristics such as age and smoking status could not be examined due to lack of patient-level data. In conclusion, this analysis, for the first time, reveals that risk of cancer with ARBs (and specifically lung cancer) increases with increasing cumulative exposure to these drugs. The excess risk of cancer with long-term ARB use has public health implications.
血管紧张素受体阻滞剂（ARBs）是一类已获批准用于治疗多种常见疾病的药物，例如高血压和心力衰竭。最近，监管机构开始在多种 ARB 制剂中发现可能致癌的亚硝胺和叠氮化合物，这导致了逐步召回。此外，几项随机对照试验的数据表明，ARBs 也会导致癌症风险，特别是肺癌风险增加；而其他试验则表明没有增加的风险。本分析旨在通过检查 ARB 累积暴露程度与随机试验中癌症风险之间是否存在关系，为 ARB-癌症联系提供更多的见解。ARB 试验者协作组的试验水平数据包括 15 项随机对照试验，提取并输入到荟萃回归分析中。两个主要次要结局是 ARB 累积暴露与所有癌症合并风险之间的关系，以及 ARB 累积暴露与肺癌风险之间的关系。共有 74021 名患者被随机分配到 ARB 中，导致每天高剂量（或等效剂量）的累积暴露总共有 172389 人年。61197 名患者被随机分配到对照组。ARB 累积暴露程度与所有癌症合并风险之间存在高度显著的相关性（斜率=0.07 [95%CI 0.03 至 0.11]，p<0.001），也与肺癌相关（斜率=0.16 [95%CI 0.05 至 0.27]，p=0.003）。因此，在累积暴露超过 3 年的每日高剂量暴露的试验中，所有癌症合并的风险增加具有统计学意义（I2=31.4%，RR 1.11 [95%CI 1.03 至 1.19]，p=0.006）。在累积暴露超过 2.5 年的试验中，肺癌风险增加具有统计学意义（I2=0%，RR 1.21 [95%CI 1.02 至 1.44]，p=0.03）。在 ARB 累积暴露较低的试验中，没有增加所有癌症合并或肺癌的风险。ARB 累积暴露风险关系独立于背景血管紧张素转换酶抑制剂治疗或对照类型（即安慰剂或非安慰剂对照）。由于这是一项试验水平的分析，由于缺乏患者水平的数据，因此无法检查患者特征（如年龄和吸烟状况）的影响。总之，本分析首次揭示，ARB （特别是肺癌）的癌症风险随着这些药物的累积暴露量的增加而增加。长期使用 ARB 会增加癌症风险，这对公共健康有影响。
