The Debate about Avandia

Thursday, July 26, 2007 - 3:02pm

By John Messmer, MD

Recent news reports have linked the diabetes drug, Avandia, to an increase in the risk of heart attack. In the study which was published in the authoritative New England Journal of Medicine1 people who took Avandia had a 43 percent higher risk of heart attack than those not on the medication. As this information was portrayed to the general public, individuals taking Avandia might conclude they would have a much lower risk of having a heart attack if they stopped taking it altogether. Unfortunately, the warnings to discuss this with one's doctor may have gone unheeded, to the potential misfortune of the patient because untreated diabetes is much more dangerous.

Avandia and other PPAR drugs

Avandia (rosiglitazone is the generic name) is one of a group of drugs called thiazolidinediones or glitazones. They stimulate a type of cell receptor called peroxisome proliferator-activated receptor (PPAR). Another PPAR drug is Actos (pioglitazone). There are two known types of PPAR, termed alpha and gamma, each having different effects. They are distributed in the liver, fat cells, immune cells, kidney, and other areas and many of their effects are not yet known. In diabetes, glitazones take advantage of the PPAR receptor effect of clearing sugar from the blood - a job they do very well while preserving the pancreas's ability to continue to make insulin. They also affect cholesterol levels--in this area pioglitazone may be more beneficial. Both glitazones can lead to fluid retention.2 Despite their shortcomings, they are considered to be very useful drugs for the treatment of type 2 diabetes.

Concerns not limited to Avandia

Any new drug is subject to review for safety before it is released, but surveillance continues after release because small effects do not become evident until millions of people use it. Another glitazone, Rezulin (troglitazone), was removed from the market years ago because of 60 cases of liver failure found after its release. Muraglitazar is another in the class of PPAR drugs that has not been released because it, too, might be associated with an increase in cardiovascular deaths.3

Putting the Avandia study into perspective

So, it seems there may indeed by a risk to some in this class of drugs, but let's look more closely at the risk for Avandia. In the New England Journal study, the author added up all the numbers from 42 different studies that were not specifically designed to determine whether Avandia had any cardiovascular effects. Out of 26,011 total people in the combined studies, there were 86 heart attacks in the Avandia-treated people and 72 in those not on Avandia; that is, 14 more heart attacks in thousands of people in the studies.

Because the studies were not specifically designed to evaluate for heart attack risk, they may not actually reflect reality. In scientific research, errors can occur when a study that is designed for one thing is used to draw another conclusion. Even if the conclusion about Avandia turns out to be true, and a study designed to evaluate this specific issue is underway, the absolute risk is 14 in over 26,000 that someone will have a heart attack caused by Avandia (or about a 1 in 1900). By comparison, a 50-year-old diabetic male with normal blood pressure and cholesterol has about a 1 in 100 chance of a heart attack in any year.4 Thus, the increased risk of heart attack is small in absolute numbers and is in a group with a higher than normal risk of heart attack in the first place.

Concerned about taking Avandia? Talk to your doctor

What should you do if you are taking Avandia? The simple answer is to ask your doctor. The problems seen are probably not due to the drug specifically. Different people have different type of PPAR receptors5; some people take better care of themselves than others, some have higher blood pressure or worse cholesterol, and so on. The decision as to whether or not to use Avandia is entirely too complicated to apply to all people but must be an individual decision between the patient and his/her physician.

[1] Nissen SE and Wolski K, Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 356(24):2457-2471 June 14, 2007.

[2] McCulloch DK, Thiazolidinediones in treatment of diabetes mellitus. UpToDate Online v. 15.2 accessed July 17, 2007.

[3] Nissen SE, et al, Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 294(20):2581-2586 November 25, 2005.

[4] Wilson PWF, et al, Prediction of Coronary Heart Disease Using Risk Factor Categories. Circulation 1998(97):1837-1847.

[5] Blank RD, Overview of Transcription Factors. UpToDate Online v. 15.2 accessed July 17, 2007.