Abstract
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.
Highlights
Angiotensin-receptor blockers (ARBs) are a widely used class of drugs approved for the treatment of several highly prevalent conditions, including hypertension, heart failure and diabetic nephropathy, as well as for primary prevention of cardiovascular events [1–4]
The Food and Drug administration (FDA) announced that they have started testing all the other drugs in the ARB class for nitrosamines, since the synthesis of other ARBs can have similarities to the synthesis of valsartan and nitrosamines can be a common impurity developing during synthesis of all ARBs [8]
Given its size, inclusion of data directly provided by the pharmaceutical companies not available elsewhere and detailed public disclosure enabling examination of cumulative exposure-cancer risk relationship, trial-level data from the published report of the ARB Trialists Collaboration was used for the current analysis [25]
Summary
Angiotensin-receptor blockers (ARBs) are a widely used class of drugs approved for the treatment of several highly prevalent conditions, including hypertension, heart failure and diabetic nephropathy, as well as for primary prevention of cardiovascular events [1–4]. In 2018, regulatory agencies identified N-nitrosodimethylamine (NDMA), a possible human carcinogen nitrosamine compound in several formulations of a commonly used ARB (valsartan), resulting in a major progressive recall [6, 7]. N-nitrosodiethylamine (NDEA), another possibly carcinogenic nitrosamine, was identified in at least 3 different ARB containing drug products, namely valsartan, losartan and irbesartan, resulting in further recalls in 2018 and 2019 [9–11]. This was followed by the discovery of a third nitrosamine in several ARB drug products, again resulting in recalls [12]. Throughout 2021, multiple lots of three different ARBs were progressively recalled again, this time due to another potentially carcinogenic impurity, namely azido compounds [13]
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