Study rekindles cancer-ARB question, this time in diabetics

June 23, 2011

Taipei, Taiwan - A new analysis of patients treated with antihypertensive therapy has rekindled the question as to whether or not angiotensin receptor blockers (ARBs) cause cancer[1]. In this latest study of diabetic patients treated with ARBs, candesartan (Atacand, AstraZeneca) was associated with a significant risk of cancer, while there was a trend toward an increased risk with telmisartan (Micardis, Boehringer Ingelheim).

The drug class was not associated with a risk of overall cancer incidence, while losartan appeared to decrease the risk of developing cancer.

"One explanation for this finding of null association is that cancer risk associated with ARBs might not be a class effect, and examining different ARBs as a group will dilute the risk estimates for individual drugs," write Dr Chia-Hsuin Chang (Taiwan University, Taipei) and colleagues in the report, published online June 20, 2011 in the Journal of Clinical Oncology. The researchers add that there are few long-term trials that have enrolled a sufficient number of patients to evaluate the risk of cancer with individual ARBs.

Recently, a Food and Drug Administration (FDA) review concluded that ARBs do not pose a cancer risk to patients. That review was sparked by a controversial meta-analysis published in 2010 by Dr Ilke Sipahi (University Hospitals Case Medical Center, Cleveland, OH) and colleagues, one that showed there was a significant 8% increased risk of cancer in patients who used the antihypertensive medications. The European Medicines Agency (EMA) was the first agency to react to the meta-analysis but it is still reviewing the data. Results of the EMA review are expected shortly.

The Sipahi et al meta-analysis

As reported by heartwire , Sipahi and colleagues performed a meta-analysis of more than 60 000 patients included in the ONTARGET , PROFESS , LIFE, TRANSCEND , and CHARM-Overall trials and reported that patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with those in the control groups (7.2% vs 6.0%; risk ratio [RR] 1.08; p=0.016). Specifically, the group found that new lung-cancer occurrence was 25% higher in those randomly assigned to ARBs than in control subjects.

Other analyses that followed, however, including an observational cohort study and another meta-analysis, as well as a meta-analysis of almost 325 000 individuals from 70 clinical trials that found no excess risk of cancer or cancer death with any single antihypertensive drug, concluded that treatment with ARBs did not increase the risk of cancer compared with non-ARB therapy.

Study of diabetic patients treated with ARBs

In this epidemiological case-control study by Chang and colleagues, the researchers studied 21 750 new diabetic patients who began antihypertensive treatment over a six-month period in 2000 and were treated with ARB therapy for a mean cumulative duration of 603 days. During the study period, valsartan (Diovan, Novartis), losartan, and irbesartan (Avapro, Sanofi-Aventis/Bristol-Myers Squibb) were the most commonly used ARBs.

There were 1281 incident cancer cases identified, including liver (22%), colorectal (15%), lung (11%), and urologic cancer (6%). Overall, there was no significant association between ARB use and cancer, and even a trend toward a negative association of overall cancer incidence with a higher mean daily dose and longer cumulative treatment duration. Among the ARBs, candesartan was associated with a 79% increased risk of cancer (odds ratio 1.79; 95% CI 1.05-3.06) and telmisartan was associated with a trend toward increased risk (odds ratio 1.54; 95% CI 0.97-2.43).

Speaking with heart wire , Sipahi said the candesartan finding is particularly relevant given that the first signal of excess cancer deaths emerged in the CHARM trial, a study of candesartan used in the treatment of heart failure. The ONTARGET trial also showed an increased risk of cancer in patients treated with telmisartan, as did the TRANSCEND trial, he said.

"This new epidemiologic study not only shows an increased risk of cancer with candesartan, it also shows a very strong statistical trend toward increased risk with telmisartan," said Sipahi. "Now we have additional epidemiologic studies showing an increased risk of cancer with two different ARBs."

Patient-level vs trial-level data

Sipahi reiterated his displeasure with the FDA review of cancer risk with ARBs, saying that these new data should require the agency to review the data on a patient-level basis, a position he first stated when the agency published its conclusions in June 2011.

"The FDA did a very weak analysis," he said. "They just compiled trial-level data from the drug companies and didn't look at patient-level data. I was extremely surprised by it, because the FDA made a statement regarding our findings and stated that 'the Sipahi analysis is not based on patient-level data.' " The agency went on to say that knowledge of the specific timing and nature of events in specific events would help in interpreting the findings, he added.

Sipahi agreed with the agency's interpretation of his analysis but expected the FDA to perform a more rigorous review of the data. When the agency published its conclusions, Dr Mary Ross Southworth, deputy director for safety in the Division of Cardiovascular and Renal Drugs in the FDA's Center for Drug Evaluation and Research, told heart wire that the agency "decided against a patient-level meta-analysis because we were not convinced that such an analysis would provide any better information about the relationship between ARBs and cancer than a more comprehensive trial-level meta-analysis."

Sipahi said that cumulative exposure to the drug is an important variable that the FDA should revisit. The risk of cancer is weaker in short-duration ARB studies or trials where patient compliance with the medication is low. "Among the trials the FDA examined, there are studies with high exposure that show an excess in cancer, including the ONTARGET and TRANSCEND trials, and those with low exposure to ARBs," Sipahi told heart wire . "The FDA lumped all these trials into one pile and diluted the risk coming from these high-exposure trials."

The FDA recently issued an update to its ongoing safety review of pioglitazone (Actos, Takeda), informing physicians that use of the drug for more than 12 months is linked to an increased risk of bladder cancer. In contrast to its ARB review, the FDA's pioglitazone review considered patient-level data and cumulative exposure to the drug, Sipahi pointed out.

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