Much Ado about Avandia

Recently (for anyone who hasn’t picked up a newspaper, watched TV, or checked their favorite online news sites), the safety of the diabetes drug Avandia has been questioned by Steven Nissen, M.D., President of the American College of Cardiology, in a meta-analysis to be published in the June 14, 2007 issue of the New England Journal of Medicine. The publication of this study has elicited a strong response from the popular media, the medical community of bloggers, and even a “calm-down” editorial from the Lancet. From what I’ve read, it seems that the bottomline messages are as follows:

1. Avandia (rosiglitazone) may have cardiovascular risks as suggested by Nissen’s analysis, but no conclusions can be made at this time. Further studies should follow – fast.

Despite the extensive ranting by various bloggers and editorialists, including those at the Wall Street Journal, Nissen and the accompanying NEJM editorial by Psaty and Furberg do clearly list and explain the weaknesses of Nissen’s study. Meta-analyses are not replacement for randomized clinical trials. Sometimes I wonder if people actually read the studies and articles they comment on.

What I find problematic (and what many have identified as being problematic) is the media response to a study such as Nissen’s study. Nissen, whether or not one considers him a “crusader” (carried over from his days as an anti-Vietnam war activist), has previously spearheaded the efforts to bring down Vioxx (rofecoxib) and Pargluva (muraglitazar). Is he on the right track this time? Either way, the popular media, intentionally or not, has generated hype over this story, perhaps ultimately leading to the interruption of a needed clinical trial to better assess the drug’s safety. Unfortunately, diabetes mellitus is a disease that develops slowly, and treatments that might stall the progression of the long-term complications of diabetes (peripheral neuropathy, diabetic retinopathy, microvascular damage, macrovascular damage, etc.) may not show an effect for as much as a year or two after treatments begins.

2. Sources matter.

I enjoy blogging, but at the same time, I understand that it is a very problematic medium. When anyone is given the chance to express their opinions and perspectives, how can you tell whether or not someone is writing with an even hand? How can you assess qualifications when someone is presenting themselves as an expert on a subject (when they might not have any qualifications or experience to speak of)? Since few bloggers cite sources for all of their claims (at best, because it would be tedious and blogs are not peer-reviewed journals), how can you tell which claims have valid evidence backing them?

There have been many attacks on Nissen in the past several days. There have been, moreover, high-profile attacks on the New England Journal of Medicine for allegedly not providing as rigorous an editorial process as one would desire from the most influential of medical journals.

While I do perhaps have bias in favor of NEJM (having worked with the Editors and the Editorial Staff for a few years), I look upon my friends as critically (if not more so) than others. After reading through Nissen’s study, the accompanying editorial, dozens of blog posts, and several popular media articles and editorials, I believe that the NEJM presented the paper and the editorial in the appropriate manner, and Nissen and the editorialists adequately presented the weaknesses of the study. There is always “more” that one can do, but at some point one is flogging a dead horse. The main problem was the hypersensitive reaction from the popular media. It seems to me that most medical bloggers are responding with a knee-jerk reaction to the popular media interpretation of Nissen’s study, and they are taking out their frustration at (almost) all levels: at the popular media, at Nissen, at NEJM, and most especially, at the lawyers preparing to launch lawsuits against GlaxoSmithKline, the maker of Avandia. I heard it mentioned on a blog somewhere that a doctor expressed frustration about the popular media’s health reporting, and that no one without “Doctor” in front of their name (physicians and researchers) should be allowed to publicly comment on drug safety issues. Despite my tendencies toward favoring free speech and the preservations of freedom, I don’t entirely disagree: improper (”hype”) portrayal of drug safety news may have severe, negative impacts on the process of assessing and handling drug safety, including reducing our supply of medications that are imperfect but may be useful for some patients (not all medications work for all patients, and many of our oldest, most useful medications may have severe side effects). In some ways, it feels like a fight between siblings: at some point, one will make a public outcry and bring in the parents to settle the dispute. In this case, it seems that physicians and researchers seeking to protect patients from bad drugs have to (intentionally or unintentionally) call upon the media to bring in the power of public opinion to bring the pharmaceutical industry to its news. This obviously isn’t an ideal situation; hopefully, new reforms at the FDA will strengthen and streamline the drug safety testing process and appease both the desire to make a profit from new drugs and the desire to keep patients safe from bad drugs or the improper use of good drugs with bad side effects.

Some speculations of mine: (but I’m not a physician yet, so this isn’t medical advice – not that I would give medical advice on a blog anyways)

1. It’s trendy to be skeptical. You’re even more trendy if you can find some clever way of picking apart someone else’s published claim.

Skepticism is an important part of science. However, a lot of people don’t know what it means to be skeptical and analytical in a meaningful way. Everyone wants to be Gregory House, but few bloggers (at least, that I know of) can consistently make a sound argument. Most go for sensationalism, catharsis through complaint, and self-indulgence. Many people complain about the popular media, but many bloggers are just as bad, if not worse.

2. Simply stating that diabetes is a risk factor for cardiovascular disease is not a meaningful criticism for Nissen’s study.

Cardiovascular disease (CVD) is a primary outcome for diabetics: diabetics have the same risk of having a myocardial infarction (ischemic heart attack) as someone who has previously already had a heart attack (high risk!). Notably, the controls in Nissen’s analysis were also diabetics. Since Nissen’s analysis suggests a greater CVD/MI risk for patients taking Avandia than patients “receiving any drug regimen other than rosiglitazone”, the study is only comparing diabetics. Again, some people simply don’t do their reading.

3. Given that Avandia (rosiglitazone) increases LDL (low-density lipoproteins) by almost 20%, it seems that physicians should generally be careful about prescribing Avandia even without Nissen’s meta-analysis.

A 20% increase in LDL is a lot. Considering that CVD is one of the greatest risks for diabetics (more so than non-diabetics), it would seem that any diabetes drug that increases CVD risk factors would be of questionable value.

On this line of thought, I think the NEJM editorialists have the right idea:

Physicians who chose to prescribe rosiglitazone perhaps focused on the single dimension of glycemic control. The underlying assumption represents a kind of linear “physiological” argument: high levels of glycated hemoglobin increase risk, so a reduction in glycated hemoglobin will automatically translate into improved health outcomes for patients. This perspective ignores the many actions of the genes activated by PPAR-gamma agonists, only some of which are currently known. Many physicians did not require proof of health benefits as a criterion for selecting rosiglitazone as a therapy for type 2 diabetes.

Had practicing physicians required this higher standard, they would have been at a loss for evidence from large, long-term trials. Rosiglitazone was approved on the basis of short-term studies of the surrogate end point of glycemic control. The use of surrogate end points in the drug-approval process has been problematic… Indeed, at the time of approval of rosiglitazone, the evidence from 26-week studies of expected health benefits was at best mixed. For a lifelong condition such as diabetes, how do the risks of weight gain, edema, and adverse changes in lipids play out against the benefits of improved glycemic control? For a drug that activates a large set of genes, what is the overall balance of risks and benefits?

In other words, Avandia may help reduce blood glucose, but it might not improve a patient’s overall diabetic condition. One step forwards, one step backwards (or perhaps even two). If I’m not mistaken, the general consensus is that exercise and weight loss are still the best means by which to control diabetes and halt the progression of its long-term complications (the unpleasant and sometimes lethal parts of the disease). Even though it is often hard for patients to adhere to these regimens, should we allow the use of a drug such as Avandia in light of virtually-no-risk alternatives? It seems that diabetes drugs should have a higher safety standard than many others, especially since diabetes is a slow-moving disease that can sometimes be managed without medications.

On a side note related to the issue of sources, it’s interesting to note that the WSJ editorial accusing NEJM of “journalistic malpractice” was written by Scott Gottlieb, M.D., former Deputy Commissioner for Medical and Scientific Affairs. I really wish medical bloggers would pay more attention to who writers are when they express criticism. While some have questioned Nissen’s ties to the pharmaceutical industry, no one has (recently) bothered to take a closer look at Gottlieb, formerly a Wall Street pharmaceutical industry golden boy (who would point out pharmaceutical company stocks to invest in) and a Bush administration recruit to the FDA. It’s surprising that a non-career FDA scientist or expert in a particular field would get the second highest position at the FDA. The words of a former FDA commissioner: “The appointment comes out of nowhere. I’ve never seen anything like that.” During his time at the FDA, Gottlieb did everything in his power to break down barriers to quicken approval of drugs, possibly at the expense of properly determining the safety of drugs before they go to the market (arguing instead that drug safety cannot be determined meaningfully until they are on the market and in use by many patients for some time). Is it at all possible to take this guy seriously? I wish I could have faith in all people with M.D.’s after their names, but sadly that isn’t the case.

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