Wednesday, July 6, 2011
Actos causes bladder cancer. Maybe we should have kept Avandia?
Both Germany and France have now suspended the marketing of Actos (pioglitazone) due to concerns of a link between Actos and bladder cancer. Though we have known about bladder cancer concerns for some time, these recent concerns about the bladder cancer link stem from a recent report analyzing the FDA's Adverse Event Reporting System (AERS), which found that 93 cases of cancer were recorded between 2004 and 2009 in patients treated with antidiabetic drugs, of which 31 patients were treated with pioglitazone, representing a statistically significant increased risk of bladder cancer (ROR 4.30, 95% confidence interval, 2.82-6.52; P less than 0.0001). Interestingly, the FDA announced that it was going to look into the link between Actos and bladder cancer only a few days before it made its final decision on what to do with Avandia (as if they didn't know about the Actos cancer risk before the July 2010 advisory board).
Despite the many things you have heard about Avandia, back in July 2010, the FDA decided to severely restrict the use of Avandia for three reasons:
1. Despite limited and conflicting data, there seemed to be a signal of myocardial infarction for patients taking Avandia.
2. The one study proving Avandia's safety, RECORD (see here for more details) was discredited by FDA scientists due to potential reporting errors.
3. The advisers on the panel felt strongly that despite limited and conflicting evidence, the signal was enough to be concerned and because Actos (similar drug in same class) did not seem to show this signal, why would doctors ever want to prescribe Avandia?
I have blogged extensively about Steven Nissen, MD, and his meta-analysis that triggered the whole Avandia scare. Meta-analyses have major limitations. Another group of researchers using the same data as Nissen's with different statistical techniques concluded that Avandia did not cause heart attacks. Large, randomized trials are the only way to determine certainty, and all available large trials (DREAM, ADOPT, ACCORD, etc.) with rosiglitazone showed no heart attack risk.
As mentioned above, the one study designed to definitively show whether or not Avandia led to cardiovascular risk (RECORD, which showed that Avandia did not cause cardiovascular risk, and in fact surpasses the FDA's standard for cardiovascular safety) was harshly criticized by those within the FDA that wanted to see Avandia pulled from the market. Specifically, the FDA found that GSK had some errors in reporting the results of RECORD. Though these types of errors are not uncommon in very large trials, and likely won't affect the overall results of the study, nonetheless, they deserve looking into. However, the FDA promised to do a complete independent analysis of the RECORD results; a promise it has yet to deliver on.
The main issue here is #3: Actos appears to be safe, so let's dump Avandia. (Interestingly, independent cardiologists analyzed all the data and did not find a conclusive difference in cardiovascular risk between Actos and Avandia).
Here is the full transcript of the advisory board. Since it is a very difficult document to read through, I have pasted some of the direct quotes below from some of the advisers who voted to either remove Avandia from the market or severely restrict its use. Based on these quotes, I feel pretty strongly that had the advisers known about Actos' bladder cancer risk, that they may have voted very, very differently. However, the FDA did know about the association between Actos and bladder cancer. They just chose not to mention it! In fact, when one adviser brought up the question at the July advisory board, the FDA only briefly mentioned this and discussed it more as a class effect also seen with dual PPAR agonists.
Avandia and Actos help diabetics use their own insulin better by hitting a receptor called PPAR. There are three main PPAR receptors: alpha, gamma and delta. We don't know a whole lot about delta, but PPAR gamma works on glucose, and PPAR alpha affects cholesterol. Fibrates like gemfibrozil, which lower triglycerides and raise HDL, or good cholesterol, are PPAR alpha agonists. Dual PPAR agonists were drugs that pharma were trying to develop that hit both alpha and gamma in order to help both with lipids and glucose. They have not been able to make it to market due to safety concerns (raised by, guess who, Dr. Nissen). One of the differences between Actos and Avandia, is that Actos has a higher affinity for the PPAR alpha receptor, which is why it likely does a better job on raising HDL and lowering triglycerides than Avandia. Some have hypothesized that this might be the reason why Actos might not have the same cardiovascular issues as Avandia (though this has yet to be shown). If in fact, as stated during the FDA meeting (I am not aware that this data is published) that the bladder cancer risk was seen in both Actos and the dual PPAR agonists. Bladder cancer has not been seen with Avandia. In other words, the evidence (both available and suggested by FDA quotes that are public record) suggest that Actos may have more of a bladder cancer risk than Avandia.
Why the FDA in discussing to keep Avandia on the market would not extensively discuss the concerns of bladder cancer with Actos, paired with the weak and controversial data showing Avandia's cardiovascular risk and effort to discredit GSK's study proving Avandia's safety, leads me to believe that the FDA's attack on Avandia was very much politically motivated. Scientists look at all the available data and weigh the risks and benefits of all options before making a conclusion. It is clear to me that the FDA's decision on severely restricting Avandia was more political then science. Based on the currently available data, which now include bladder cancer risk, Avandia may actually be a better choice than Actos, but the FDA's restriction will essentially prevent any doctor from being able to prescribe Avandia after November.
Select quotes from advisers who voted to voted to either remove Avandia from the market or severely restrict its use:
DR. SCHAMBELAN: This is Morrie Schambelan. I voted E. (remove Avandia from the market). I was one of the brain-dead kangaroos last time (meeting in 2007) who was on the fence, largely because I did see a signal for harm. I was led at that time by the comparison to active comparators, which I think is much more relevant to me than placebo. I wasn't swayed by the pioglitazone data that were presented at that time because they were pretty preliminary. I was much more persuaded this time, including Dr. Graham's analysis. I feel that pioglitazone is a perfectly acceptable alternative.
DR. SAVAGE: Peter Savage. I voted D (keep on the market with restrictions). I was also oscillating between D and E because I think that the evidence of potential harm associated with rosiglitazone is stronger now than it was in 2007. And very importantly, the evidence about pioglitazone is substantially greater than what we saw treat [sic] in 2007.
DR. FLEMING: Fleming. I voted E. My main sense about this is really explained in my answer to question number 7. There's very concerning data about safety with rosiglitazone. It's not definitive, but if TIDE is to provide that, we have many years before we're going to get that insight. We do have an alternative, pioglitazone, for which there is considerably strong safety experience. So I come down to, then, what is the continued role for rosiglitazone?
DR. THOMAS: Abraham Thomas. I voted E. The scientist in me says we should always seek the truth. But this isn't an NIH study section. This isn't the review of a journal for publication. Really, what this is, is an intersection, as someone mentioned at lunch, between public policy and science. And when we look at it that way, we can't always have the absolute truth to make a decision. We have other classes that are available that we never had before for the treatment of diabetes. And if rosiglitazone was removed from the market, we still have another TZD, what has had a trial that does demonstrate no increased cardiovascular mortality, no increased cardiovascular events, in PROactive. 
Matthew Mintz, MD, is a Fellow of the American College of Physicians. He is board certified in internal medicine and has been practicing for more than a decade. He is also an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients. This post originally appeared at Dr. Mintz' Blog. Conflict-of-interest disclosures are available here.
Labels: cancer, Diabetes, Dr. Mintz' Blog, drug interactions, evidence-based medicine, FDA, guest post, Matthew Mintz
posted by Matthew Mintz, MD at
11:00 AM
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7 Comments:
I see you received research support from GSK, maker of Avandia. I feel that your musings are well written but ultimately tainted with the unmistakable stench of bias, and ultimately lack objectivity. Have a nice day!
Dr. Bones, there is no question that my work with GSK (as well as work with other companies involved in diabetes products) has some influence my opinion. This is why there I have provided a link to all my potential conflicts of interest for full disclosure. While the pharmaceutical industry is certainly not without blemishes in recent years, collaboration between academia and industry has led to many scientific advances. As a physician, I try to be as objective as possible. If there is anything in this post (or others) that you feel is not based on scientific evidence, I invite you to point this out.
I am aware of the risks involved on taking Actos. However, I'd like to know which medication is the the safest to use.
Carol,
Tough question. Each diabetes medicine has risks and benefits. As long as your kidney and heart function are fine, metformin is probably the safest and most effective agent to use because it is well studied and does not cause hypoglycemia. Most guidelines and experts recommend this as first line. The problem is that most patient will not do well on metformin alone and need a second or 3rd agent. Currently available second line options include sulfonylureas (glipizide), TZD's (Actos/Avandia), DDP4's (Januvia/Onglyza) and GLP-1's (Byetta/Victoza). I am not big fan of SU's because they burn out the pancrease and cause hypoglycemia. TZD's are the only agents that have shown long term durability. However, in addition to the Actos bladder cancer risk, there is CHF and osteoporosis. DPP4's are probably the safest drugs, but they are still relatively new so there is no long term data. GLP-1's similarly seem pretty safe. One beneficial side effect is weight loss, but the other is nausea which many people don't do well with. There is a potential concern about thyroid tumors, but I don't think this will pan out for humans at normal doses.
In other words, each medicine has pros and cons when it comes to safety/side effect and how well it works.
Rhea,
True, but it's also very uncommon and not entirely clear that it's caused by Actos. Recent data suggests that most of bladder cancer can be linked to smoking. Would like to know the smoking status of the few patients in the Actos studies that wound up with bladder cancer.
Dr. Mintz, for patients who are or had been on Actos with urinary concerns (which maybe just BPH) how aggressive do you recommend working this up?
The concerns due Actos (of which clear causation has not been determined) are for bladder cancer. Though some symptoms of bladder cancer (urinary urgency and frequency) can overlap with BPH, they are uncommon presenting symptoms for bladder cancer.
However, there are no real great ways to screen for bladder cancer and there has been no guidance from the FDA. For my patients on Actos, in addition to the microalbumin test I do each year for routine diabetes care, I am now ordering urinalysis (UA), and for those diabetics on Actos who have hematuria, I am sending them to urology for further workup. In an older male patient who has common signs and symptoms associated with BPH, I believe my work up would be the same-get a UA and if positive send to urology. However, males on Actos with new urinary symptoms where BPH seems less likely (younger age, small prostate on exam, other symtomps, etc.), I might be more aggressive even with a negative UA.
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