Elsevier

The Lancet

Volume 352, Issue 9123, 18 July 1998, Pages 179-184
The Lancet

Articles
Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?

https://doi.org/10.1016/S0140-6736(98)03228-0Get rights and content

Summary

Background

Previous studies have reported an increased risk of cancer with calcium-channel blockers in man. Other work in animals suggests that inhibitors of angiotensin-l-converting enzyme (ACE) protect against cancer. We aimed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs.

Methods

Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. The patients' records are linked with the Registrar General Scotland and the West of Scotland Cancer Registry.

Findings

Compared with the West of Scotland controls, the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0·72 (95% Cl 0·55–0·92) and 0·65 (0·44–0·93). Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors (calcium-channel blockers 1416, diuretics 2099, β-blockers 2681), the corresponding relative risks were 1·10 (0·97–1·22) and 1·03 (0·87–1·20). The relative risk of cancer was lowest in women on ACE inhibitors: 0·63 (0·41–0·93) for incident cancer; 0·48 (0·23–0·88) for fatal cancer; and 0·37 (0·12–0·87) for female-specific cancers. The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years. Calcium-channel blockers, diuretics, and β-blockers had no apparent effect on risk of cancer.

Interpretation

Long-term use of ACE inhibitors may protect against cancer. The status of this finding is more that of hypothesis generation than of hypothesis testing; randomised controlled trials are needed.

Introduction

Some studies suggest that calcium-channel blockers increase the risk of cancer,1, 2, 3 but most findings,4, 5, 6, 7 including our own,8 do not support this idea. In our previous study8 the risk of cancer was low in some of our controls, so we explored the possibility that a drug taken by controls might protect against cancer. Inhibitors of angiotensin-I-converting enzyme (ACE) were the most likely candidate.

ACE inhibitors decrease production of angiotensin II,9 but also have other actions that might affect the development of cancer.10 Angiotensin II stimulates neovascularisation,11, 12 which is a requirement for tumour growth.10, 11, 12, 13 Some cancers contain renin, the enzyme that produces angiotensin, and in some cells the renin lies within cancer blood vessels.14, 15 Since tumours also have receptors for angiotensin II,16, 17 there is potential here for a paracrine effect.15 A second action of angiotensin II is as a growth factor: in tissue culture and in the absence of blood vessels, it stimulates cell replication18, 19 and increases expression of genes that control cell growth.20, 21, 22 In vitro, ACE inhibitors retard growth of cultured cancer cells23, 24 and in vivo they inhibit angiogenesis and growth of induced cancer in rats.10, 25 Two studies suggest that the inhibitory effect of captopril involves a mechanism other than a decrease in angiotensin-II production.10, 24 Tests of endostatin, an antiangiogenic agent, show clear inhibitory effects on tumour growth in mice.26

Two studies in human beings included in their control group patients on ACE inhibitors; compared with other controls receiving β-blockers, the relative risks of cancer in controls on ACE inhibitors were 0·731 and 0·79.4 In neither study was the reduction in risk of cancer significant, and in Pahor and colleagues' study,1 the number of participants was small. We aimed to investigate the risk of cancer in patients receiving ACE inhibitors in a retrospective cohort study.

Section snippets

Methods

Our analysis was based on 5207 hypertensive patients who received drug treatment in the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. 4930 (95%) patients were taking one or more of four antihypertensive drugs: ACE inhibitors (1559 patients), calcium-channel blockers (2295), diuretics (3297), and β-blockers (3679). The remaining 277 received other antihypertensive drugs, or other types of drugs. We excluded from the analysis 584 patients who did not receive drug treatment.

Results

Compared with the West of Scotland controls, the relative risks of incident and fatal cancer in the 5207 hypertensive patients taken together were 1·00 (95% CI 0·89–1·11) and 0·94 (0·79–1·08), respectively (table 2). The relative risks of incident and fatal cancer were significantly lower than expected in patients on ACE inhibitors: 0·72 (0·55–0·92) and 0·65 (0·44–0·93). In patients on other antihypertensive drugs, these risks were not lower: 1·10 (0·97–1·22) and 1·03 (0·87–1·20). In patients

Discussion

Our main finding is that fewer than expected incident and fatal cancers occurred in patients taking ACE inhibitors. This finding was seen in comparison with West of Scotland controls (table 2) and in the different Kaplan-Meier analyses as improved survival and increased freedom from incident cancer compared with patients on other antihypertensive drugs (figure 3). The risk of cancer was not lower than expected in patients taking other classes of antihypertensive drug (figure 1); nor did

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