The sordid and still-unfolding story of GlaxoSmithKline’s blockbuster drug, Avandia, highlights not just the venality of one drugmaker in regard to one drug but to fundamental flaws in the process by which drugs are approved and in the way we look at health and disease.

Recently the FDA announced new regulations to severely restrict access to the diabetes drug, Avandia, in light of studies linking the drug to increased incidence of heart failure, heart attack, stroke, and death in its users. 

A bit of background is in order here. Diabetes refers to an excess of glucose, or blood sugar. Individuals with Type I Diabetes are deficient in insulin, a naturally-occurring hormone which enables cells to take up glucose from the blood, so it can either be used as fuel or converted to fat for storage. In individuals with Type II Diabetes, insulin levels may be normal or even elevated, but the ability of cells to take up glucose is overwhelmed – a phenomenon known as insulin resistance. Physical inactivity, unhealthy diet, obesity, smoking, and excess alcohol consumption all increase the risk of developing Type II Diabetes.

90% of all diabetics have Type II Diabetes. Complications of either Type I or Type II Diabetes include heart attacks, strokes, blindness, limb amputations, and kidney failure.

Diabetes is a huge and growing problem. In 2002, one-tenth of all US health care expenditures were attributable to diabetes. Annual spending on diabetes drugs now tops 12.5 billion dollars. By 2050, the number of Americans with diabetes is expected to soar to 29 million.

There was a time within living memory in which a diagnosis of Type I Diabetes was a death sentence. By taking insulin, these individuals can have decades of productive existence. Type II Diabetes can often be managed or even cured by exercising and eating sensibly. Some individuals with this condition take insulin. In addition, in recent years a number of drugs called oral hypoglycemic agents have been introduced to help patients with Type II Diabetes control their blood glucose levels.  

One such drug is rosiglitazone, the active ingredient in Avandia as well as the combination drugs Avandemet and Avandaryl. Rosiglitazone, along with the drugs pioglitazone and troglitazone, belong to a class of drugs called peroxisome proliferator-activated receptor agonists, or PPAR-agonists. They bind to receptors in the nucleus and promote the expression of genes whose products enable cells to take up glucose from the blood. Pioglitazone is marketed by Takeda Pharmaceuticals as Actos; troglitazone was marketed by Parke-Davis as Rezulin but was withdrawn from sales after reports of acute liver toxicity among users.

Rosiglitazone has proved to be a blockbuster drug for its maker, GlaxoSmithKline. Sales receipts for rosiglitazone in 2006 exceeded 3 billion dollars.

An excellent article in Time relates the sordid story of how this drug came to market. In November of 1998, an application was submitted to the FDA for approval to market Avandia in the United States by the drug company SmithKline Beecham. (More than a year later, SmithKline Beecham would merge with Glaxo Wellcome to form the colossus GlaxoSmithKline). Right away, FDA scientists noticed a potential problem: study after study showed this drug raised the levels of LDL’s, or so-called “bad” cholesterol.

Currently, the taxpayers are made to spend billions of dollars a year underwriting drugs which lower LDL levels, often without any data that these drugs provide any meaningful clinical benefit for the patient, such as reducing the frequency of heart attacks or premature death. Why should we have to pay for drugs that produce even a small increase in these levels?

The article states, “Dr. Robert Misbin, the FDA's medical officer, said he would support approval only if the company committed to a thorough safety trial that would include monitoring for cardiovascular risks.”

I’d like you to read that last sentence again. Aren’t they supposed to determine a product is safe and effective before it is put on the market? What is going on here? Has the maxim “First do no harm” been replaced with “Shit happens?”

Even this sop to public safety was withdrawn. SmithKline Beecham offered to perform a study comparing Avandia’s ability to lower blood sugar to that of competing products, and this offer was accepted by Dr. John Jenkins, the FDA’s director of new drugs.

“It was really a marketing study,” the article quotes Dr. Misbin as saying.

That same year, Dr. John Buse of North Carolina State University, using SmithKline Beecham’s own data, calculated that Avandia produced in patients a fourfold rise in cholesterol compared to those taking a placebo. He communicated his concerns to the FDA, warning that Avandia could cause “adverse cardiac outcomes.” According to the article, officials of the newly created GlaxoSmithKline let Buse’s superiors know they were not amused.

”They threatened to sue me for something like $4 billion,” the article quotes Dr. Buse as saying.

In 2005 and 2006, GlaxoSmithKline internal reviews showed that Avandia was linked to a rise in negative heart events as high as 31%. They presented the data to the FDA, which declined to make them public right away, citing concerns with some of the research methodology. Meanwhile, as part of a settlement over the company’s failure to make public data indicating increased risk of suicides among teenagers taking the antidepressant Paxil, GlaxoSmithKline agreed to put the results of all its recent clinical trials on a website. Dr. Steven Nissen and Kathy Wolski of the Cleveland Clinic analyzed these data and in a 2007 paper in the New England Journal of Medicine reported that patients taking rosiglitazone experienced a 43% increase in heart attacks and a 64% increase in cardiac mortality compared to those taking either other drugs or placebos.

In an interview, GlaxoSmithKline spokesperson Anne Phillips defended her company’s product, stating “We feel strongly that Avandia is an important option in this horrible, progressive disease.”

On 28 July of last year, the FDA’s Dr. David Graham published a study in JAMA on 227,571 Medicare patients who were treated with either rosiglitazone or pioglitazone and found that rosiglitazone was linked to an increase in heart failure, heart attack, stroke, and death. One additional event of this nature was found for every sixty patients treated with rosiglitazone instead of pioglitazone for one year.

Over 2.84 million elderly American have taken or are taking rosiglitazone. That works out to thousands of premature deaths and tens of thousands of heart attacks linked to this drug.

In response, on 18 May the FDA announced new regulations to limit Avandia and other rosiglitazone-containing medicines to patients already being successfully treated with these medicines, or those who, after consulting with their healthcare provider, do not wish to use pioglitazone and whose blood sugar cannot be controlled with other anti-diabetic medicines. Both patients and doctors must be enrolled in the Avandia-Rosiglitazone Medicines Access Program, and doctors must agree to explain all the risks fully to patients. After 18 November of this year, Avandia and other rosiglitazone-containing medicine will be available only through certified mail-order pharmacies.

Some people might say the FDA’s actions prove the system is working. But in fact, it is working very poorly for anyone besides those who hold stock in the drug companies, or the doctors who make money prescribing these drugs.

Why was this stuff ever allowed on the market in the first place? Because it lowers blood sugar levels? So what? Contrary to what you may have been led to believe, lowering blood sugar is not, in and of itself, a benefit. It is a benefit only if it enables you to avoid a heart attack or stroke or premature death or some other hard clinical outcome.

Anyway, focusing on Avandia is missing the forest for the trees. A report by the non-profit  Institute for Safe Medication Practices states, “Drugs that lower blood sugar or increase insulin secretion have never been proven to reduce the risk of heart attack and stroke and some agents appear to increase it.”

At first glance, that seems like an astonishing assertion, on a par with saying the Emperor has no clothes. But upon reflection, why should it surprise anyone? People who exercise and eat sensibly tend to be healthier than those who do not, and they also tend to have lower blood sugar levels. It does not follow that taking a drug that lowers your blood sugar levels to that of a healthy person will make you healthy. That’s an absurdly reductionistic viewpoint. It’s like saying, healthy people are often observed wearing running shoes, therefore wearing running shoes will make me healthy. 

If, due to an individual’s inactivity and overeating, the cells’ ability to take up and use glucose is stretched to the limit, then perhaps the body in its wisdom is making the best of a lousy situation by trying to get rid of excess glucose in the urine. Why does anyone think that taking a drug that forces the cells to take up even more glucose and convert it into fat will help matters? Where does that extra fat go? Perhaps to the heart muscle, the coronary arteries, or the liver? Could this be the reason behind the cases of heart failure, cardiac arrests, and liver toxicity linked to the use of these drugs?

The PPAR-agonists, the class of drugs to which rosiglitazone belongs, have been shown to affect the expression of over a thousand different genes in the human genome. What are the functions of all these different genes? How does monkeying with their expression affect the body?

I don’t know. You don’t know. The docs prescribing these drugs don’t know.

Millions of Americans have taken or are taking these drugs. This is a gigantic uncontrolled experiment.

We know how to prevent and even cure Type II Diabetes. Exercise – as little as 150 minutes of exercise a week, or 22 minutes a day – can often do the trick. We’re talking about putting one foot in front of the other for eleven minutes, and then turning around and walking back. And if some people can’t be bothered to do that, I’d say a big part of the solution to that problem is recognizing that there is no perfect solution to this or any other problem.

People tend to live up or down to expectations. We live in a society in which expecting individuals to expend a modicum of effort to take care of their bodies is considered lunacy, but spending billions of dollars we don’t have on interventions that have not been shown to produce any clinically significant benefits is considered normal. I can imagine a society in which the reverse is true.

I recognize that if our Medical-Industrial Complex would collapse if it stopped performing all interventions which have not been shown in double-blind placebo-controlled clinical trials to produce clinically significant benefits. That’s not going to happen. But at the very least, the FDA ought to stop this business of approving drugs on the basis of surrogate outcomes (such as lowering blood sugar) without anyone demonstrating any clinically significant benefits for the patient. And people need to realize that if it takes multi-year, multimillion-dollar clinical trials just to demonstrate if a given intervention produces benefits, then any benefits it does produce are likely to be small, and we’re likely to be missing out on some toxicity to boot.

And finally: when the drug company spokespersons start talking about “horrible, progressive diseases” – hold on to your wallet.

Rosiglitazone molecule illustration via Wikimedia Commons