Long-Term/High-Dose Use of ACE Inhibitors Associated With Reduced Colorectal Cancer Risk in Hypertensive Subjects
Preclinical data suggest a role of angiotensin II in colorectal cancer. In a study reported in the Journal of the National Cancer Institute, Makar et al assessed whether use of angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) treatment for hypertension was associated with reduced risk for colorectal cancer. They found that long-term and long-term/high-dose treatment with these agents appears to reduce colorectal cancer risk.
Study Details
The study, a nested case-control study using a UK General Practice Research Database for 1987 to 2002, included patients diagnosed with colorectal cancer after the diagnosis of hypertension. Each case patient was matched with up to 10 control subjects with hypertension for age, sex, calendar year, and duration of follow-up.
A total of 2,847 case patients were matched with 28,239 control subjects. Women constituted 50.0% of the case group and 50.2% of the control group, mean ages at start of follow-up were 69.8 and 69.5 years, and mean duration of follow-up before index date was 4.4 years in both groups.
More case patients had unknown smoking status (16.9% vs 14.6%, P < .01), diabetes (10.4% vs 9.0%, P = .01), and had been taking folates for < 3 years (1.2% vs 0.7%, P < .01). Case subjects had more doctor visits per year during follow-up (6.3 vs 5.1, P < .01). More control subjects had taken aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) for ≥ 3 years (8.9 vs 10.1, P = .01), thiazides for ≥ 3 years (11.9% vs 13.3%, P = .04), and beta-blockers for ≥ 3 years (14.8% vs 16.9%, P = .01). Proportions of patients with < 3 years of ACE inhibitor/ARB exposure were 18.1% and 18.4%, and proportions with ≥ 3 years of exposure were 7.3% and 7.7%.
Reduced Risk
In an adjusted model including matching factors and average number of doctor visits per year, ≥ 3 years of ACE inhibitor/ARB exposure was associated with a 16% reduction in risk of colorectal cancer (odds ratio [OR] = 0.84, P = .03) and ≥ 5 years of exposure was associated with a 25% reduction (OR = 0.75, P = .03). There was no significant reduction in colorectal cancer risk for ≥ 3 to > 5 or ≥ 5 years of exposure to calcium channel blockers, beta-blockers, or thiazides.
In a model adjusting for matching factors and body mass index, smoking history, history of cholecystectomy, diabetes mellitus, exposure to other medications (hormone replacement therapy, statins, aspirin and NSAIDs, insulin, oral hypoglycemic agents, calcium, and folate), and frequency of physician contact during follow-up, the adjusted odds ratio was 0.85 (P = .04) for ≥ 3 years of exposure to ACE inhibitors/ARBs. ARB therapy accounted for only 2% of all ACE inhibitor/ARB prescriptions; analysis limited to ACE inhibitors alone showed a similar outcome.
Long-term (≥ 3 years of continuous use)/high-dose (≥ 2 defined daily dose) exposure to ACE inhibitors/ARBs was associated with a 47% reduction in colorectal cancer risk (adjusted OR = 0.53, P = .003). A similar analysis for calcium channel blocker use showed no significant effect on risk.
Comparison Among Antihypertensive Users
An unmatched analysis restricted to subjects exposed to antihypertensive medications and adjusted for matching factors and average number of doctor visits showed significant risk reductions only for ACE inhibitor/ARB use < 3 years (OR = 0.89, P = .03) and calcium channel blocker use < 3 years (OR = 0.90, P = .04), with no significant effect for longer duration of use of these agents or for any duration of use for beta-blockers or thiazides. However, exposure to high-dose ACE inhibitors/ARBs (≥ 2 defined daily dose) for ≥ 3 years was associated with a 41% reduction in colorectal cancer risk (OR = 0.59, P = .01), whereas long-term/high dose calcium channel blocker use was not associated with risk.
Low-dose (< 2 defined daily dose) use for < 3 years of both ACE inhibitors/ARBs (OR = 0.89, P = .03) and calcium channel blockers (OR = 0.90, P = .04) was associated with a significant reduction in risk. Unmatched analysis comparing exposure to ACE inhibitors/ARBs alone with exposure to all other antihypertensive agents showed that patients with ≥ 3 years of ACE inhibitor/ARB exposure had significantly reduced colorectal cancer risk (OR = 0.67, P = .03, with no significant difference observed with shorter exposures.
The investigators concluded: “[ACE inhibitors] appear to possibly be associated with a decreased risk of [colorectal cancer], although the preponderance of evidence from this analysis indicates that the potential benefit may be somewhat modest and may be more evident in those receiving higher doses of medication for a long period of time. These results suggest that the angiotensin pathway is a potential target for development of new chemopreventive agents for [colorectal cancer].”
Yu-Xiao Yang, MD, MSCE, FACP, of the Perelman School of Medicine at the University of Pennsylvania, is the corresponding author for the Journal of the National Cancer Institute article.
The study was supported by a grant from the National Institutes of Health. The study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
