By William B. Ershler, MD, Editor
SYNOPSIS: In a nested, case-control analysis using a large computerized clinical dataset, a 16% reduction in colorectal cancer incidence was observed after 3 or more years of angiotensin inhibitor and/or angiotensin receptor blocker treatment of hypertension. This modest reduction in risk could be of great significance considering the widespread use of drugs in this class. However, additional confirmatory research is required.
SOURCE: Makar GA, Holmes JH, Yang Yu-Xiao. Angiotensin-converting enzyme inhibitor therapy and colorectal cancer risk. JNCI. 2014;106.
There has been considerable interest, even enthusiasm, about the potential role of angiotensin 1-converting enzyme inhibitors (ACEI) in protecting against cancer since the original report 15 years ago demonstrating a 28% reduced cancer incidence among ACEI-treated patients compared with controls.1 Subsequent studies have failed to demonstrate protection from colorectal cancer (CRC) or cancer in general.2-4 In a meta-analysis of 70 randomized, controlled trials, no evidence of benefit was observed on cancer incidence or mortality,5 although this secondary analysis included several small trials of short duration of treatment and was dominated by results from one very large study.6,7 Thus the question remains open whether drugs in this class protect against incident cancer or malignant proliferation. There have been a number of preclinical studies demonstrating the potential importance of both angiotensin II and renin in promoting both tumor cell proliferation and neovascularization.8,9
Currently, ACEIs and/or angiotensin receptor blockers (ARBs) are widely prescribed for the management of hypertension, and whether their use reduces the risk of CRC remains unclear. Taking advantage of a large computerized medical record database, Makar and colleagues sought to determine whether exposure to these agents would have a secondary benefit on CRC incidence. They conducted a nested case-control study using EPIC’s General Practice Research Database (1987–2002). The study cohort consisted of hypertensive patients. Case patients were those diagnosed with CRC after the diagnosis of hypertension. Each incident CRC case was compared to 10 control (non-CRC, hypertensive) subjects matched by age, sex, and both calendar year and duration of follow-up. The association between CRC and ACE-I/ARB exposure was assessed with conditional logistic regression.
There were 2,847 incident CRC cases matched with 28,239 control subjects. The adjusted odds ratios (ORs) of CRC were 0.84 (95% confidence interval [CI] = 0.72 to 0.98; p = .03) for 3 or more years of ACE-I/ ARB therapy and 0.75 (95% CI = 0.58 to 0.97; p = .03) for 5 or more years of exposure. The strength of this association was stronger for those receiving higher doses (OR = 0.53; 95% CI = 0.35 to 0.79; p = .003 for ≥ 3 years of high-dose exposure). Among patients receiving antihypertensive medications, the association with long-term therapy was no longer statistically significant beyond five years, but the benefit of high-dose therapy remained (OR = 0.59; 95% CI = 0.39 to 0.89; p = .01 for ≥ 3 years of high-dose exposure).
COMMENTARY
This study capitalized on a large primary care database in the United Kingdom and found a 16% reduction in CRC incidence after 3 or more years of ACEI/ ARB therapy among patients with a diagnosis of hypertension. The magnitude of this reduction increased with longer exposure and higher dose of therapy. The strengths of this analysis are the large sample size and the careful methodology undertaken. But, as with any retrospective analysis, even those with large datasets and careful design, there are bound to be limitations, and some of which are emphasized in the accompanying editorial.10 In short, confounding factors, are difficult to control for in a large clinical dataset (e.g., obesity, tobacco use, treatment compliance), and several of these factors might relate both to antihypertensive drug choice and cancer risk. Among hypertensive patients, the selection of ACEI or ARB treatment might be based upon factors such as renal function or BMI that, in themselves, might associate with risk for CRC. Yet, although the risk reduction was modest (16%), there was a dose and duration effect that would support an interaction of ACEI/ARB treatment and cancer protection. If indeed this interaction is confirmed, additional future research will be required to define the mechanism, as this might provide potential targets for future cancer prevention trials. However, although the findings to date are intriguing and potentially very important, it is too early to recommend the use of ACEIs and/or ARBs tor the purpose of CRC prevention.
REFERENCES
-
Lever AF, Hole DJ, Gillis CR, et al. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 1998;352(9123):179-184.
-
Azoulay L, Assimes TL, Yin H, Bartels DB, et al. Long-term use of angiotensin receptor blockers and the risk of cancer. PLoS One 2012;7(12):e50893.
-
Boudreau DM, Koehler E, Rulyak SJ, Haneuse S, et al. Cardiovascular medication use and risk for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(11):3076-3080.
-
Friis S, Sorensen HT, Mellemkjaer L, et al. Angiotensin-converting enzyme inhibitors and the risk of cancer: a population-based cohort study in Denmark. Cancer 2001;92(9):2462-2470.
-
Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol. 2011;12(1):65-82.
-
Barrios V, Escobar C. Angiotensin-receptor blockade, cancer, and concerns. Lancet Oncol. 2010;11(9):819-820; author reply 821-822.
-
Meredith PA, McInnes GT. Angiotensin-receptor blockade, cancer, and concerns. Lancet Oncol. 2010;11(9):819; author reply 821-822.
-
Chiu T, Santiskulvong C, Rozengurt E. ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2003;285(1):G1-11.
-
Yasumaru M, Tsuji S, Tsujii M, et al. Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway. Cancer Res. 2003;63(20):6726-6734.
-
Song M, Giovannucci EL. Antihypertension and colorectal cancer prevention: getting two birds with one stone? J Natl Cancer Inst. 2014;106(2):djt438.
