New data on possible pro-thrombotic effects of pioglitazone
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October 24, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [1]
“New York” In the aftermath of the New England Journal of Medicine meta-analysis which showed a higher rate of cardiovascular death in diabetic patients taking rosiglitazone, new research has emerged demonstrating a pro-thrombotic activity of thiazolidinediones (TZDs). Researchers at Columbia University and the NIH have used a mouse model of atherosclerosis to test the effect of pioglitazone on advanced atherosclerotic lesions. Previous research had established a beneficial effect of TZDs on insulin sensitization, which should lessen the atherosclerosis burden. This study focused on advanced lesions, and demonstrated that pioglitazone promoted macrophage apoptosis and plaque destabilization. This paradoxical effect could help explain recent clinical data about TZD safety.
The authors first examined the effect of TZDs on macrophages ex vivo. They found that pioglitazone and rosiglitazone enhanced macrophage apoptosis to free-cholesterol, the major cholesterol form found in macrophages from advanced atherosclerotic plaques. They provide evidence that the enhanced apoptosis is not due to a PPAR-gamma effect, as other PPAR-gamma agonists do not enhance apoptosis and TZDs induced apoptosis in PPAR-gamma null macrophages. Preliminary evidence suggests that effects on NF-kappaB activation might contribute, although the mechanism is not entirely worked out. Interestingly, macrophage efferocytosis, or clearing of dead neighboring cells, was improved by pioglitazone and rosiglitazone. The effect on efferocytosis would be predicted to stabilize atherosclerotic plaques. Finally, the authors asked how pioglitazone affected advanced plaques in vivo. They fed LDL-receptor deficient mice a high fat diet, allowing atherosclerotic lesions to mature, then treated mice with pioglitazone or control. The atherosclerotic lesions in mice treated with prioglitazone had less fibrous component and more regions containing apoptotic macrophages. Total lesion size was unaffected, however.
This report proposes a plausible mechanism which could contribute to the cardiovascular safety profile of TZDs. The authors propose that the TZD class effect might be two-fold: a PPAR-gamma dependent effect on insulin sensitivity which would help prevent atherogenesis, and a PPAR-gamma independent effect on macrophages that could promote destabilization of established plaques. The mechanism by which pioglitazone affects macrophage apoptosis is not entirely known, although NF-kappaB signaling appears to be involved. Also, the balance between enhanced apoptosis and enhanced efferocytosis is interesting, and why the net effect is a higher burden of apoptotic cells in atherosclerotic plaques is not clear at this time.
The current controversy regarding safety of rosiglitazone and TZDs in general will require more data to resolve. This new research is helpful in focusing future work on patient safety, drug design, and targets for insulin sensitization.
<biblio> Edward Thorp, George Kuriakose, Yatrik M. Shah, Frank J. Gonzalez, and Ira Tabas. Pioglitazone Increases Macrophage Apoptosis and Plaque Necrosis in Advanced Atherosclerotic Lesions of Nondiabetic Low-Density Lipoprotein Receptor–Null Mice. Circulation 2007: published online before print October 22, 2007 </biblio>
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