Rosiglitazone (Avandia) - Hooray for heart attacks!

I read the news today, oh boy. First rofecoxib (Vioxx), now this. A paper has been published in a prestigious scientific journal claiming that being on rosiglitazone, a drug used to treat diabetes, considerably increases one's risk of having a heart attack. Awesome. Diabetics rejoice.

This is the second strike against this drug. A study released earlier this year by the manufacturer reported that female diabetics taking rosiglitazone had an increased incidence of limb fractures compared to those on other antidiabetic medications. So it may soften up bones by promoting osteoporosis or something.

Rosiglitazone is a member of the thiazolidinedione (TZD) class of antidiabetic drugs, which are employed to treat type 2 (insulin-independent, adult onset) diabetes mellitus. TZDs bind to peroxisome proliferator-activated receptors (PPARs), a group of nuclear (intracellular) receptors that control the expression of a bunch of genes (i.e. function as transcription factors) and are normally activated by fatty acids and eicosanoids (e.g. prostaglandins). In particular, the activation of PPARγ results in a number of significant physiological effects. These include:

• reduced insulin resistance (take that, diabetes!) due to the re-sensitization of adipose (fat) tissue to insulin, resulting in improved glucose utilization and lowered blood glucose levels
• altered differentiation of adipocytes (fat cells) such that they are smaller and more responsive to insulin
• decreased levels of leptin, a hormone released from fat cells that signals the brain that you have had enough to eat, resulting in the munchies
• decreased levels of certain interleukins, which modulate the immune system, producing an anti-inflammatory effect
• increased levels of adiponectin, a hormone that controls insulin and blood glucose levels
  

TZDs are often used in combination with other classes of antidiabetic drugs such as sulfonylurea derivatives and biguanides. Troglitazone, another TZD, was withdrawn from the market due to it being linked to drug-induced hepatitis (inflammation of the liver). So there's been some problems with these compounds.

Interestingly, rosiglitazone is currently under investigation as a possible treatment for Alzheimer's disease, specifically for those afflicted individuals who possess the ApoE4 allele of the ApoE gene. This gene encodes Apolipoprotein E (APOE), an apoprotein that has important roles in lipoprotein metabolism, cardiovascular disease, Alzheimer's disease, regulation of the immune system, and cognition. ApoE4 encodes a dysfunctional form of APOE that somehow increases one's susceptibility to Alzheimer's disease.

Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.
http://en.wikipedia.org/wiki/Apolipoprotein_E
http://en.wikipedia.org/wiki/Rosiglitazone