Avandia, Type II Diabetes, and Heart Attacks

I happened to be watching television earlier this afternoon when I noticed a trend in the commercials: at least two of the commercials during each of the breaks were asking for people who have recently experienced a cardiac event and who were taking Avandia for their type II diabetes. Now, these advertisements were to seek plaintiffs for a suit against the maker of Avandia, but they also highlight the process by which medications are scrutinized following distribution. For Avandia, a widely prescribed medication for type II diabetes, this scrutiny most recently comes from an article published in the New England Journal of Medicine on June 14, 2007.

Avandia, or by its generic name Rosiglitazone, is a member of the thiazolidinedione class of anti-diabetic drugs. It is indicated for type II diabetes, which is, basically, an acquired state of insulin insensitivity. A better description of insulin is given by my co-contributor below, but as a brief refresher this hormone regulates your blood glucose level. When you have eaten a high sugar meal, insulin is released from the pancreas and makes tissues, especially the liver and your muscles, take up glucose. This is important because a chronic high blood glucose level can cause the morbid complications of diabetes, including neuropathy, renal failure, eye damage, and damage to your circulatory system and heart, relevant to this study.

Key to understanding how thiazolinediones (TZDs) work is this idea of type II diabetes stemming from decreased tissue sensitivity to insulin. Essentially, the tissues no longer take in as much sugar from the blood when insulin is secreted. Thiazolinediones act by activating transcription of genes that would normally be activated by an insulin signal. Basically, this means that they amplify the signal to the DNA in the nucleus to make proteins, and these proteins do the actions that insulin tells the cell to do. They act on the peroxisome proliferator-activated receptor (PPAR gamma) signal pathway, which are nuclear receptors part of the insulin response that increase lipid synthesis and carbohydrate metabolism. Giving a TZD boosts a response to insulin by activating this additional route of gene transcription.

In the study published by Nissen and Wolski in the NEJM, they found that patients had a significant increase in deaths from heart attacks, or myocardial infarction, and a borderline significant increase in risk of death from other cardiovascular consequences. Already GlaxoSmithKline, the maker of Avandia, has responded to the article and cited several other studies, including the ADOPT, DREAM, and RECORD trials which followed Avandia users and all failed to find any increase in cardiac events. Moreover, the FDA issued a statement acknowledging both the previous studies and this new finding, and does not recommend drastic treatment changes or new warnings for Avandia use yet. Ironically, changing your diabetes medications can also increase your risk for cardiac events, and so discontinuing Avandia may be worse than a possible side effect.

Whether or not the drug carries an increased risk for cardiac events, the mechanism by which rosiglitazone affects the heart remains uncertain. The NEJM article highlights some of the possible ways this might occur. One is that the drug appears to be detrimental to the lipids in your serum, or blood. There is an increase in LDL cholesterol, the so-called "bad" cholesterol, by 18.6% over 26 weeks, which may contribute to a poor cardiovascular outcome, such as the increased death from heart attacks seen here. Another proposal is that Avandia, and other TZDs, have been shown to precipitate congestive heart failure, which would place greater stress on the heart wall and thereby increase oxygen demand. There is also data showing that TZDs reduce hemoglobin, the protein in your blood that holds oxygen, which could provoke the ischemia, or lack of blood supply, that causes the heart attack.

Whatever the mechanism, I think it is safe to say the jury is still out on Avandia's role in adverse cardiac events, and further investigation is certainly needed. Nonetheless, as the FDA recommends, concerns with medication should be directed to your physician, to ensure individualized treatment.