Thiazide Diuretics and Risk of Colorectal Cancer

Background: Previous studies, including a recent large individual patient data meta-analysis of trials, have reported an elevated risk of colorectal cancer in users of thiazide diuretics. While this association is biologically plausible, few studies have been specifically designed to evaluate the long-term safety of this antihypertensive drug class with respect to this outcome.

Objectives: To determine whether thiazide diuretics are associated with an increased risk of colorectal cancer compared with dihydropyridine calcium channel blockers (dCCBs).

Methods: We assembled a population-based, new-user, active comparator cohort using the United Kingdom Clinical Practice Research Datalink. New users of thiazide diuretics were compared with new users of dCCBs between 1990 and 2018, with follow-up until 2019. We estimated hazard ratios (HR) with 95% confidence intervals (CIs) of incident colorectal cancer using Cox proportional hazard models, comparing thiazide diuretics with dCCBs. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. Secondary analyses investigated associations with cumulative duration and time since initiation, individual molecules, cancer type (colon, rectal), and effect modification with age, sex, history of inflammatory bowel disease, history of polyps, and aspirin use.

Results: The cohort included 377,784 initiators of thiazide diuretics and 364,300 initiators of dCCBs. After a median 4.6 years of follow-up, thiazide diuretics were not associated with an increased risk of colorectal cancer, compared with dCCBs (weighted incidence rate: 137, 95% CI 131-142 vs 142, 95% CI 137-147 per 100,000 person-years respectively; weighted HR 0.97, 95% CI 0.90-1.04). Similar results were observed in secondary analyses, although an increased risk was observed in patients with inflammatory bowel disease (weighted HR 2.46, 95% CI 1.13-5.36).

Conclusions: The results of this large population-based study suggest that thiazide diuretics are not associated with an overall increased risk of colorectal cancer when compared with dCCBs. While these findings provide some reassurance, additional research will be needed to corroborate the increased risk observed among patients with inflammatory bowel disease.