It is noteworthy that concerns with ARBs causing cancer have dated as far back to 2003 in the effects of candesartan on mortality and morbidity in patients with chronic heart failure (CHARM) trial, which reported a surprising increase in cancer deaths with candesartan versus placebo (2.3% vs. 1.6%; p = 0.038) . Additionally, a slight numerical but nonstatistically significant increase in cancers was shown with losartan in the LIFE (8% vs. 7%; p = 0.118) and telmisartan in the TRANSCEND (8% vs. 6.9%, RR 1.17, 95% CI 0.97–1.42; p = 0.094) as well as ONTARGET trials (RR 1.04 [0.77, 1.40), respectively [1, 18, 19]. Following these findings, a meta-analysis published by Sipahi and colleagues in 2010 evaluating different solid organ cancers in patients receiving ARBs compared with controls found a significantly higher incidence (7.2% vs 6%, risk ratio [RR] 1.08, 95% CI 1.01–1.15; p = 0.016) particularly with lung cancer occurrence . However, subsequent analyses have failed to confirm this association including a more recent comprehensive meta-analysis by Bangalore and colleagues that involved at least 70 randomized controlled trials [21,22,23,24,25]. Interestingly, Bangalor and colleagues did report a slight increase in cancer when ARBs were combined with ACE-Is (2.3% vs. 2%; RR 1.14, 95% CI 1.02–1.28), but fortunately, combination therapy with ACE-Is is generally not recommended due to lack of efficacy and risk for other harms . Lastly, a meta-analysis was performed by the FDA capturing 31 trials with 84,461 patients on ARBs and 71,355 patients randomized to non-ARB comparators with an average follow-up of 39 months. This ultimately ended concerns after reporting incident cancer events of 1.82 per 100 patient-years in the ARB group vs. 1.84 per 100-patient years in the non-ARB group (RR 0.99, 95% CI 0.92–1.06) . There was no association found between ARBs and cancer-related death (RR 1.04, 95% CI 0.96–1.13), breast cancer (OR 1.06, 95% CI 0.9–1.23), lung cancer (OR 1.07, 95% CI 0.89–1.29), or prostate cancer (OR 1.05, (95% CI 0.95–1.17) and eventually lead the FDA to propose guidance (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/meta-analyses-randomized-controlled-clinical-trials-evaluate-safety-human-drugs-or-biological) for conducting meta-analysis when evaluating safety of medications . Previous meta-analyses were most likely affected by significant methodological flaws and uncertainty including heterogeneity in the trial conduct/selection. It should be stated that the trials captured in the FDA’s meta-analysis were undertaken decades before the recent findings of differences in ARB manufacturing that exposed patients to carcinogens.
In vitro data have demonstrated expression of the RAS and AT1/2 receptors in various cancer cells/tissues including brain, lung, breast, prostate, and pancreatic cancers, and the use of ACE-Is and ARBs were shown to reduce the number of metastases, tumor growth, and vascularization in rodents [27,28,29]. Although there is a link between AT receptor activation and inflammation, angiogenesis, and cell proliferation, no plausible biologic mechanism has been identified to connect antagonism of AT receptors and cancer development. Moreover, if cancer risk is indeed associated with AT2 activation indirectly through AT1 antagonism, then the cancer risk should be higher with ARBs such as valsartan, olmesartan, azilsartan, and candesartan due to their much higher affinity for the AT1 receptor [27,28,29]. In summary, concerns regarding a cancer association have not been definitively established and is largely refuted in the healthcare community.