Association between long-term exposure to antihypertensive drugs and risk of cancer: a large population-based retrospective cohort study

Objective: Several meta-analyses have examined whether antihypertensive drugs alter the risk of cancer. However, in most studies follow-up was relatively short and adherence to antihypertensive drugs was not accounted for. We analysed the relationship between long-term exposure to antihypertensive drugs and risk of cancer. Design and method: Retrospective population-based cohort study based on healthcare utilization databases of Lombardy Region (Italy). We selected all individuals aged 40 - 85 years newly dispensed with at least one antihypertensive drug from between 2009 and 2011, and with no previous history of cancer. Exposure to angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), beta-blockers (BB), thiazides/thiazide-likes, loop diuretics and mineralocorticoid receptor antagonists (MRA) was evaluated by using an “as-treated” approach, according to which each cohort member was classified based on the duration of exposure to each class of drugs. Patients were followed-up from the date of the first dispensation of antihypertensive drug and ended at the earliest date between onset of cancer, migration, death or December 31, 2020. The association between the duration of exposure to each class of drug (considered as a time-dependent covariate) and cancer risk was evaluated by Cox regression models, adjusted for sex, age and the Multisource Comorbidity Score, and mutually adjusted for the exposure to each class of drugs. Results: The study cohort included 339,842 new users of antihypertensive drugs (median age 59 years, 49.5% males). During a median follow-up of 10.2 years, 36,778 cancers occurred. There was no evidence of consistent significant associations of the risk of cancer with ACEI, ARB and thiazides. An increasing but weak risk was associated to a medium-long term exposure to CCB and with a long-term exposure to BB. With the limit that the number of users was much smaller, exposure to MRA was associated to a significant increase in the risk of cancer at all exposure levels. Conclusions: In our study, treatment adherence allowed a more accurate evaluation of true exposure to a potentially carcinogenic drug influence. The results showed an increased risk with the exposure to some antihypertensive agents, in particular with the MRA.