Hope that thiazolidinedione agonists of PPARγ (Peroxisome Proliferator Activated Receptor-γ) will prove beneficial for Alzheimer's patients (see ARF recent live discussion) may be tempered slightly by a report in this week's Mayo Clinic Proceedings.
Asra Kermani and Abhimanyu Garg, at the Department of Veterans Affairs Medical Center, Dallas, Texas, report that pioglitazone and rosiglitazone, which have been used for some time now to treat type II diabetes, can contribute to cardiac and renal failure. Kermani and Garg reviewed records of six elderly patients with symptoms of congestive heart failure and pulmonary edema, and who had just started treatment with, or had just had their dose of thiazolidinedione increased. Five of the patients had no prior history of congestive heart failure, though four of these had a history of poor kidney function. On admission to the center, all of the patients were placed on diuretics to reduce plasma volume and in five cases thiazolidinedione treatment was immediately stopped. Over the next three days to four weeks, these patients' symptoms disappeared. The sixth patient was also given diuretics but thiazolidinedione treatment continued. Thirteen months later, he returned with the same symptoms, was again given diuretics and this time the thiazolidinedione treatment was halted. The patient fully recovered after about 10 weeks.
This study builds on earlier reports that a small number of patients on troglitazone develop pulmonary edema as a result of fluid retention. This drug, which had been sold under the name Rezulin, was withdrawn from the market in March 2000 following FDA concerns about liver toxicity. Because the second generation of thiazolidinediones, including pioglitazone and rosiglitazone, were milder on the liver, it was hoped that they would have fewer, less serious side effects. In the present study, the six patients represent less than one percent of patients treated with the drugs at the Veterans Center. Nevertheless, the authors conclude that "thiazolidinediones can cause pulmonary edema or exacerbate heart failure," and recommend that "further study is needed to identify patient groups at risk of this complication."
Suzanne Craft, University of Washington, Seattle, who is currently directing clinical trials of pioglitazone and rosiglitazone in 30 AD patients (see ARF related news story) does not see this as a major setback. "It indicates some potential guidelines that will need to be followed," she ventured, adding that "chronic renal insufficiency or cardiomyopathy may be exclusionary conditions for prescribing these drugs." This suggests that only a small fraction of glitazone candidates would be denied potential benefits.
This study comes on the heels of a recent paper in Science by Ronald Evans and colleagues at the Salk Institute for Biological Studies, La Jolla, California, and the Brigham and Women's Hospital, Boston, Massachusetts, which showed the importance of another isoform of PPAR, namely PPARδ, in promoting the growth of atherosclerotic plaques.
First author Chih-Hao Lee and coworkers showed that deleting the PPARδ gene from foam cells-lipid-laden macrophages that advance atherosclerosis by promoting an inflammatory response-reduces atherosclerotic lesions by about 50 percent. This raises the possibility of using PPARδ inhibitors to regulate cardiovascular disease.—Tom Fagan
No Available Further Reading
- Kermani A, Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc. 2003 Sep;78(9):1088-91. PubMed.
- Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, Curtiss LK. Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science. 2003 Oct 17;302(5644):453-7. PubMed.