Use of angiotensin-converting enzyme (ACE) inhibitors for hypertension control modestly heightens the risk of lung cancer compared with the use of angiotensin receptor blockers (ARBs), according to a recent study published in BMJ.

“Although these drugs have been shown to be relatively safe in the short term, concerns have been raised that their long-term use may be associated with an increased risk of cancer,” wrote authors led by Blánaid M. Hicks, PhD, Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. “These concerns have been subject to debate, with observational studies producing mixed findings, including with respect to lung cancer.”

Specifically, the use of ACE inhibitors results in the buildup of bradykinin and substance P in the lung, which may trigger lung cancer growth. However, the few preclinical and observational studies that have investigated the association of ACE inhibitors with incident lung cancer have offered limited and mixed results. Therefore, Dr. Hicks and this team conducted this large population-based study to determine whether long-term use of ACE inhibitors vs ARBs is associated with increased lung cancer risk.

Study participants included 992,061 patients who began treatment with antihypertensive medications between 1995 and 2015. The primary endpoint was adjusted hazard ratios (HRs) of incident lung cancer associated with the time-varying use of ACE inhibitors vs those of ARBs. In this cohort, the three most frequently used ACE inhibitors were ramipril (26%), lisinopril (12%), and perindopril (7%).

During the study, investigators followed the cohort for an average of 6.4 years, during which 7,952 patients were diagnosed with lung cancer (crude incidence: 1.3 per 1,000 person-years).

Large absolute numbers of lung cancer

In sum, ACE inhibitor use was correlated with a heightened risk of lung cancer vs ARBs (incidence rate: 1.6 vs 1.2 per 1,000 person years; HR: 1.14, 95% CI: 1.01-1.29), after controlling for covariates. In other words, there was a 14% higher risk of lung cancer in those patients taking ACE inhibitors. Of note, HRs slowly increased with longer periods of use, with an association salient after 5 years of use and climaxing after 10-plus years of use (ie, 31% increased risk).

The researchers conceded that the size of the risk estimates for lung cancer were small, but the effects could translate into a large absolute number of patients due to the wide prescription and prevalence of ACE inhibitor therapy.

“The results of this study also raise important questions about the new angiotensin receptor/neprilysin inhibitor sacubitril/valsartan,” the authors wrote. “Neprilysin inhibition results in increases in vasoactive and other peptides including bradykinin and substance P.”

The investigators acknowledged that their study had certain limitations. For instance, although they adjusted results for various confounders, they didn’t control for socioeconomic status, diet, exposure to radon or asbestos, family history of lung cancer, or duration and intensity of smoking.

“In this large, population-based study, the use of ACE inhibitors was associated with an elevated risk of lung cancer overall, along with evidence of a duration-response relation,” the authors concluded. “Although the magnitudes of the observed estimates are modest, these small relative effects could translate into large absolute numbers of patients at risk for lung cancer, so these findings need to be replicated in other settings.”

This story is contributed by Naveed Saleh and is a part of our Global Content Initiative, where we feature selected stories from our Global network which we believe would be most useful and informative to our doctor members.