Chronic high-dose angiotensin receptor blocker use associated with cancer risk
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Cumulative exposure to high-dose angiotensin receptor blockers was associated with excess risk for cancer, according to a meta-regression analysis published in PLOS One.
“About 200 million people are treated with an angiotensin receptor blocker (ARB) globally. This analysis shows that when 200 million people are exposed to daily high doses of an ARB for 4.7 years, 1.7 million excess cancers could be caused by this class of drugs,” Ilke Sipahi, MD, FACC, FESC, associate professor of cardiology at Acibadem Maslak Hospital in Istanbul, told Healio. “If ARBs had been superior to other drugs for prevention of cardiovascular events, such benefits could potentially offset the excess cancer risk. However, there is evidence that ARBs may be inferior to many other antihypertensives. For example, while ACE inhibitors reduce mortality and myocardial infarctions in hypertensives, ARBs do not reduce the risk of either of these. Therefore, other antihypertensives with good safety and efficacy data should become the preferred first-line agents in hypertension.
“It already changed my practice,” Sipahi told Healio. “I rarely prescribe an ARB for hypertension now. However, I continue to prescribe the sacubitril/valsartan combination (Entresto, Novartis) in heart failure because of the mortality benefit there.”
To better understand the relationship between angiotensin receptor blocker (ARB) use and cancer risk, Sipahi utilized data from 15 randomized controlled trials from the ARB Trialists Collaboration including to perform a meta-regression analysis. The co-primary outcomes were incidence of any cancers and incidence of lung cancer.
This analysis included 74,021 patients across the 15 trials who were randomly assigned to an ARB, accounting for 172,389 person-years of daily high-dose ARB exposure. A total of 61,197 patients comprised the control arm of participants assigned to placebo or non-placebo control.
The most common ARBs in this meta-regression analysis were telmisartan (Micardis, Boehringer Ingelheim; 38.9%) and valsartan (33%). Trials of candesartan, irbesartan and losartan were also included.
As Healio previously reported, ARBs were associated with modest risk for new cancer diagnoses in a prior meta-analysis; however, the data only examined telmisartan, losartan and candesartan, and the trials included in the meta-analysis were not designed to explore cancer endpoints.
ARBs and any cancer diagnosis
In the present analysis, Sipahi observed that cumulative ARB exposure was associated with greater risk for any new cancers compared with controls (slope = 0.07; 95% CI, 0.03-0.11; P < .001). This relationship remained significant, regardless of background ACE inhibitor use (P for all = .006).
There was an excess in any new cancers observed in trials where average cumulative ARB exposure was more than 3 years compared with controls (7.3% vs. 6.2%; I2 = 31.4%; RR = 1.11; 95% CI, 1.03-1.19; P = .006). No increase in cancer risk was observed in trials with 3 or fewer years of cumulative ARB exposure compared with controls (5.5% vs. 6.4%; I2 = 13.7%; RR = 0.94; 95% CI, 0.89-0.99; P = .02).
Sipahi estimated that 120 patients aged 65 to 69 years needed to be treated with an ARB for 4.7 years for one excess diagnosis of any cancer to occur.
Impact on lung cancer
Sipahi observed that cumulative ARB exposure was associated with greater risk for lung cancer compared with controls (slope = 0.16; 95% CI, 0.05-0.27; P = .003). This relationship remained significant, regardless of background ACE inhibitor use (P for all = .006).
There was an excess in lung cancer diagnoses observed in trials where average cumulative ARB exposure was more than 2.5 years compared with placebo (1.2% vs. 0.9%; I2 = 0%; RR = 1.21; 95% CI, 1.02-1.44; P = .03). No increase in lung cancer risk was observed in trials with cumulative ARB exposure of less than 2.5 years compared with controls (0.6% vs. 0.8%; I2 = 40.9%; RR = 0.86; 95% CI, 0.73-1.01; P = .06).
Sipahi estimated that 464 patients aged 65 to 69 years needed to be treated with an ARB for 4.6 years for one excess diagnosis of lung cancer to occur and observed no association between cumulative exposure to ARBs and risk for prostate cancer (P = .27) or breast cancer (P = .71).
“While this research is a trial-level analysis, Thomas Marciniak, MD, from the FDA already performed a patient-level analysis and confirmed the excess lung cancer risk with these drugs in 2015,” Sipahi told Healio. “Nevertheless, the FDA did not officially disclose these findings or place a cancer warning on these drugs. It is time for the FDA to do a proper official analysis about the cancer risk with these drugs and especially look at the exposure-risk relationship.”
Perspective
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Why would anybody take an antihypertensive drug that “does not reduce outcome” of total mortality, “never been shown to reduce MIs”, “inferior to an active control”, “did not prolong survival” and now “increases the risk of cancer and specifically lung cancer with increasing cumulative exposure?”
The author does not offer any thoughts as to the mechanism by which ARBs could exert a carcinogenic effect. There is one possible hypothesis in this regard which is holds true for most efficacious CV drugs: as proposed by Diamond and Kaul in the kinetic model, the normative state can transition either to a cancer state resulting in death from cancer or a CVD state resulting in death from CV causes. Therapies that reduce the CVD state increase life expectancy and may thereby increase the cancer state and hence death from cancer. The less likely a patient is to die of atherosclerotic CVD, the more likely they will die of other extra CV causes, of which cancer is the most common. Conversely, treatments reducing cancer mortality are prone to increase the risk of dying from CVD.
One can therefore arrive at the provocative inference, unless a CV drug ‘causes’ cancer it should not be considered an efficacious CV drug. If (and this remains a big if in our mind) the data of Dr. Sipahi will stand further scrutiny, they simply could reflect the powerful benefits of ARBs in reducing CV outcome (and thereby extending life expectancy). The fact that Dr. Sipahi seemed to have observed a cumulative effect — the higher the dose and the longer the exposure, the higher the cancer risk — attests to this hypothesis.
Why then are we not seeing a significant risk of cancer in numerous randomized CV trials? It is exceedingly unlikely that in a follow-up period of a mere 3 to 4 years, a minute increase in life expectancy of a few days to weeks will allow us to document an increased cancer risk. However, CV drugs are usually prescribed for years, even decades and the increase in life expectancy and thereby the risk of cancer becomes progressively more significant with time.
As to Dr. Sipahi’s assertion of ARBs being “inferior to many other classes of antihypertensives for prevention of mortality and cardiac morbidity,” we point to our analysis of almost 1 million patients published 3 weeks ago (Messerli FH, et al. Circulation. 2022;doi:10.1161/CIRCULATIONAHA.121.057835); in a head-to-head comparison with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke and end-stage kidney disease.
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