Nearly a decade ago, a front-page story in the Wall Street Journal blew the lid off a highly controversial internal squabble at the FDA involving a popular category of blood pressure medicines. ARBs (angiotensin receptor blockers) are among the most frequently prescribed drugs in the world. Millions of people take such medications daily. But back in May 2013, the WSJ let the controversial cancer cat out of the bag. Although the official report from the FDA declared ARBs safe, a new analysis published in PLoS One, March 2, 2022 puts ARBs under a cancer cloud once again.
ARBs ON THE U.S. MARKET
- Atacand (candesartan)
- Avapro (irbesartan)
- Benicar (olmesartan)
- Cozaar (losartan)
- Diovan (valsartan)
- Edarbi (azilsartan)
- Micardis (telmisartan)
- Teveten (eprosartan)
ARBs and a Cancer Cloud:
We first became aware of a possible linkage between ARBs and cancer after reading an article in Lancet Oncology (online, June 14, 2010). The researchers reviewed data from randomized controlled trials (RCTs) and information on cancer deaths.
The authors concluded:
“In conclusion, this meta-analysis shows that ARBs are associated with a modestly increased risk of new cancer occurrence. Among the solid organ cancers examined, only the risk of lung cancer was significantly increased. Given limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular ARB. Our findings warrant further investigation.”
A year later, on June 2, 2011, the FDA issued its own analysis that contradicted this concern:
“The U.S. Food and Drug Administration (FDA) has completed a review of the potential risk of cancer associated with the class of medications known as angiotensin receptor blockers (ARBs). FDA has concluded that treatment with an ARB medication does not increase a patient’s risk of developing cancer.”
The FDA left little doubt that it had reviewed the matter carefully and declared all clear. No cancer cloud and nothing to worry about. Case closed!
The Cancer Cloud That Wouldn’t Disappear:
We contacted the author of the original research to try and get a handle on what was going on. In addition, we dug into the data a bit further ourselves. To our surprise, we found that the FDA included research that lasted little more than one year. The average follow up was 39 months for the 31 trials included in the FDA analysis. That might not have been long enough to detect a true cancer signal.
After talking to experts at the National Toxicology Program about how long it would take to detect a cancer signal from a known carcinogen, it became clear that 3.5 years was woefully inadequate. These scientists doubted you could prove cigarette smoking caused cancer after such a short period of time. But the FDA was satisfied that its analysis slammed the door on this controversy.
We contacted the FDA and posed the following concern:
“If the FDA relies primarily on RCTs [randomized controlled trials] to assess cancer risk and most such studies last no longer than a few years, the agency will be handicapped in its power to evaluate a risk to patients.”
The FDA did not respond to our concern.
The Cancer Cloud Reappears:
Barely three weeks later (June 20, 2011), however, a study from Taiwan published in the Journal of Clinical Oncology revealed that patients with diabetes taking ARBs such as candesartan (Atacand) and telmisartan (Micardis) experienced an increased risk of cancer.
In September of 2011 another study pointed to problems. This time it came from Germany. Researchers detected lung cancer at a significantly higher rate in kidney transplant patients who had smoked and had been given ACE inhibitors or ARBs. In a sense, these people were like canaries in the coal mine. Because of their susceptibility, they were a highly vulnerable population.
Despite such mounting evidence, the FDA has stood by its official conclusion that there is no cancer risk associated with ARBs.
The Rift Within the FDA:
The Wall Street Journal uncovered a substantial rift within the agency itself. Dr. Thomas Marciniak was an FDA reviewer. He was concerned that the data the agency had reviewed might have been incomplete.
According to the Wall Street Journal report:
“Dr. Marciniak said in an internal analysis viewed by the Journal that the FDA meta-analysis didn’t count cases of ‘lung carcinomas’ as lung cancers, which they are.”
Dr. Marciniak analyzed the raw data supplied by the drug companies and discovered that there was roughly a 24% increased risk of lung cancer among patients who took ARBs. He encouraged his colleagues at the FDA to inform doctors and patients about this risk.
His FDA bosses, however, discounted his research and were in no mood to issue any warning. If anything, they circled the wagons. Dr. Marciniak’s boss, Ellis Unger, apparently told the Wall Street Journal that the cancer cloud was a “diversion.”
“We have no reason to tell the public anything new.”
The New Cancer Cloud Hanging Over ARBs:
The new study in PloS One (March 2, 2022) contradicts the FDA’s all clear announcement. The author analyzed data from 15 randomized controlled trials including nearly 140,000 patients. He reports that an excess risk of cancer starts to appear after approximately three years of exposure to a high-dose ARB and increases with time. For lung cancer, the risk was statistically significant after 2.5 years.
We always like to quote an author when there are useful insights. We found these comments especially enlightening:
“The current study shows that risk of cancer with ARBs increases with increasing exposure at a trial-level. This relationship at least partially explains the heterogeneity in the results of the investigations examining the ARB-cancer issue in randomized trials. Accordingly, if the analysis mainly includes long-term, high exposure trials, there is a significant increase in overall cancers and lung cancer. On the other hand, if an analysis includes a high number of patients with low exposure to ARBs, the excess risk of cancer coming from high exposure trials is diluted.”
Let me offer you my interpretation. If you were to examine the relationship between cigarette smoking and cancer you could “dilute” the results of your investigation if you included people who only smoked a few cigarettes daily or who only smoked for a couple of years. If, on the other hand, you analyzed data from heavy smokers who had been smoking for 5 to 10 years or longer, the results would be obvious. The literal and figurative cancer cloud would be revealed.
The Cancer Cloud Hypothesis:
Why might ARBs increase the risk for cancer? If you have been reading our newspaper column or our newsletters, you know that many popular ARBs such as irbesartan, losartan and valsartan have been recalled because of nitrosamine contamination. Nitrosamines are frequently described as “probable” carcinogens. We would go further and say that nitrosamines are bad actors. A cancer cloud has been hanging over these chemicals for decades. You can read about ARB recalls at this link.
How long have nitrosamines been lurking in ARBs? Who knows? The FDA was slow to pick up on this contamination. Could contaminants such as NDMA or NDEA be responsible for the cancer link to ARBs? That is a question that may never be answered since long-term research would have to be funded by the FDA or some other government agency. Generic drug companies are not likely to conduct such studies.
There is another possible mechanism. The author of the new research posits:
“Alternatively, previous studies using mouse models and cancer cell lines have directly implicated the renin-angiotensin system in the regulation of cell proliferation, angiogenesis, tumor expansion, as well as metastasis. For example, evidence indicates that angiotensin II receptor type-1 (AT1R) blockade with an ARB, which results in unopposed angiotensin II receptor type-2 (AT2R) stimulation is capable of causing tumor angiogenesis in vivo. Therefore, the exact mechanism of the increased cancer risk with ARBs is currently not clear.”
Sorry, we know that is an inside baseball explanation. It has to do with how these medications work in the body and is not related to contamination.
THE PEOPLE’S PHARMACY BOTTOM LINE:
What are we to make of all this? First, we have asked the FDA repeatedly about how it determines if a drug causes cancer. You would be surprised to learn that there are a great many medications on the market that raise the risk of tumors in animals. The FDA lists this in the official prescribing information, but rarely requires drug companies to do long-term follow-up studies to determine if there is a problem in humans. That leaves physicians, pharmacists and patients in the lurch. Short term clinical trials that only last a year or two are not likely to detect a cancer signal.
Even when there is a signal that a drug is linked to cancer, the FDA seems puzzled about what to do about the problem. Just such a concern was raised about the diabetes drug Actos (pioglitazone). A study published in the Journal of the National Cancer Institute (Aug. 9, 2012) suggested that people with type 2 diabetes who took Actos were two to three times more likely to be diagnosed with bladder cancer compared to those taking other antidiabetes drugs.
France and Germany banned Actos in 2011 because of these cancer concerns.
The FDA requires this information in the official Medication Guide that comes with the drug:
“There may be an increased chance of having bladder cancer when you take ACTOS. You should not take ACTOS if you are receiving treatment for bladder cancer. Tell your doctor right away if you have any of the following symptoms of bladder cancer:
- blood or a red color in your urine
- an increased need to urinate
- pain while you urinate”
Needless to say, such a warning puts patients in a terrible double bind.
In the meantime, we strongly believe that no one should stop taking ARBs or Actos without discussing the controversies with the prescribing doctor. That said, we hope patients will discuss the cancer cloud with their health professionals. Doctors, pharmacists and nurses need to be aware of these cancer concerns so they won’t be taken by surprise if the FDA ever takes action. The article in PLoS One (March 2, 2022) is available in full text for free at this link.
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