The New York Times (NYT) has just reported that the popular diabetes drug, Avandia, causes heart attacks. The information came from an internal FDA study in which the fate of Avandia has been argued for months. Is this a media scare or is this real?
First of all, one of the major complications of diabetes is heart disease. The tissues that make up the heart must expand and contract thousands of times a day to pump blood and anything that alters tissue flexibility will result in an increased work load for the heart and ultimately heart disease. Elevated blood glucose does this which is why diabetic patients who do not control their blood glucose are at great risk of heart complications. (To read more about why glucose does this click here). Avandia, like all of the thiazolidinedione drugs, works by promoting the expression of glucose transporters on the surface of cells. When glucose levels in the blood rise, the glucose molecules find their way into these glucose shaped holes in the cell membrane and so bring blood glucose levels down again. The specific gene that is affected is called GLUT4. Normally insulin is responsible for generating the signal for increased GLUT4 expression. Thiazolidinedione drugs target the gene which produces GLUT4 in a manner that is independent from insulin. Thus when you take Avandia, irrespective of your level of insulin resistance, you increase your ability to transport glucose out of the blood and greatly reduce the damage to the heart caused by glucose. In comparison with doing nothing, then, Avandia actually protects the type 2 diabetic person’s heart. So, if you have type 2 diabetes and are taking Avandia and then subsequently suffer a heart attack, was it because of the diabetes, the Avandia, or from some other reason? Perhaps you can now understand how difficult it has been to tease apart the variables and get to the heart (sic) of the matter.
There exist other thiazolidinedione drugs, however, and so one can compare the fate of patients on Avandia as compared to Actos for example. Additionally, one can compare thiazolidinedione treatment to other glucose lowering therapies like metfomin or the host of sulfonylurea drugs currently on the market. Apparently, patients taking Avandia were found to have more heart attacks. According to the NYT, the FDA report predicted that if every type 2 patient was switched from Avandia to Actos, 500 heart attacks and 300 heart failure events could be prevented per month. That is a strong statement. Let’s assume for the moment that it is true (we will look closely at the evidence in the next post). Why might this be so?
One reason we might have a problem here is that thiazolidinedione drugs do not target the GLUT4 gene directly. Instead, they bind to a protein called a transcription factor. This particular transcription factor has the name PPAR gamma (PPARg). Transcription factors are proteins that bind to DNA just next to the gene and nucleate the building of a large transcription machine that will copy the gene into messenger RNA and ultimately into protein. The power of this system is that transcription factors do not just bind to one gene. They bind to many genes and serve to orchestrate the expression of complex sets of genes to take care of our needs. PPARg does not just bind to the GLUT4 gene so when you take Avandia you elicit lots of changes in gene expression. Could one of these other changes explain the heart complications at issue here? Both Avandia and Actos bind to PPARg. The two drugs are different molecules, however, with subtly different shapes. When either binds to PPARg it will change the shape of PPARg such that it can now bind to DNA. One possibility is that the shape assumed by the PPARg-Actos complex is slightly different from the PPARg-Avandia complex and this will result in changes in gene expression. As it happens, when Avandia binds to PPARg it creates a complex that activates gene expression more strongly than does Actos. PPARg responsive genes in the kidney include a sodium channel that promotes sodium retention. The connection between salt and heart disease is pretty certain by now so this makes some sense. Also, the lipid profile seen with Actos treatment is superior to that seen with Avandia treatment and this also would likely contribute to the risk of cardiac events.
Another possibility to consider is that drugs are seldom absolutely specific. By this I mean that we may design a small compound to bind to a target protein; for example, PPARg. How do we know that it does not bind to other proteins? Up to a point we can do various sorts of experiments to look for this but we can never say for sure that one small molecule only binds to some other molecule or protein and never ever to anything else. Hence another reason for the cardiac effects of Avandia might be that this molecule (and not Actos) binds to something else that is involved in heart function. We would call this an off-target effect.
At present we do not have enough information to distinguish between these two possibilities. Both PPARg dependent and independent mechanisms have been implicated. Clinical trials are still coming out looking at comparisons between different thiazolidinediones as well as comparisons between thiazolidinediones and other diabetes therapies. In the next post we will look at some of them in detail.