NEW YORK -- Experiments in mice suggest that the type 2 diabetes drugs rosiglitazone (Avandia) and pioglitazone (Actos) increase uptake of both glucose and triglycerides in cardiac tissue, causing or exacerbating heart failure.
NEW YORK, Sept. 6 -- Experiments in mice suggest that the type 2 diabetes drugs rosiglitazone (Avandia) and pioglitazone (Actos) increase uptake of both glucose and triglycerides in cardiac tissue, causing or exacerbating heart failure.
Transgenic mice bred to over-express the nuclear receptor targeted by the drugs (peroxisome proliferator-activated receptor-gamma, or PPARg), developed dilated cardiomyopathy associated with increased lipid and glycogen stores, reported Ira J. Goldberg, M.D., of the Columbia College of Physicians and Surgeons, here, and colleagues.
What's more, signs of heart failure worsened when mice bred for low-level overexpression were exposed to rosiglitazone, the authors wrote in a study published online today by the Journal of Clinical Investigation.
"While PPAR? agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function," they wrote.
Rosiglitazone and pioglitazone, two of the most widely prescribed drugs for type 2 diabetes, are PPARg agonists. Both carry black-box warnings about the potential for the drugs to cause or exacerbate congestive heart failure. The drugs are not recommended in patients with symptomatic heart failure, and are contraindicated in patients with established New York Heart Association Class III or IV heart failure.
"In some rodent models of lipotoxic dilated cardiomyopathy, PPAR? agonist treatment improves heart function," the investigators wrote. "It has been postulated that PPAR? agonists have salutary effects due to direct actions on the heart; this is surprising, since PPAR? causes lipid accumulation in other tissue."
Since one of the actions of PPAR? agonists is to channel plasma triglycerides and fatty acids to adipose tissue, it's possible that doing so might reduce lipid uptake by cardiac myocytes, thereby reducing lipotoxicity, the authors speculated.
To evaluate the cardiac effects of PPARg agonists, the authors bred two strains of mice that overexpress PPARg at either low or high levels. They found that both lines of mice had increased cardiac expression of genes that encode for fatty acid oxidation, as well as increased uptake of triglycerides compared with wild-type animals,
The hearts of the transgenic mice also had dilated left ventricles, impaired systolic function, and increased heart-to-body ratios at four months in the high-PPARg expression animals, and at eight months in the low-expression mice, with the high expression mice having more severe cardiac dysfunction, greater left ventricular systolic dimension (P < 0.001) and a greater reduction in fractional shortening (P < 0.001).
The expression of genes for brain-type natriuretic peptide and atrial natriuretic factor, both markers for heart failure, was increased in the high-expression mice by four months, and in the low expression mice by eight months.
When the authors exposed eight-month-old low-expression mice to rosiglitazone, the treatment caused further deterioration of cardiac function, including increased lipid accumulation, larger hearts, and decreased fractional shortening.
In addition, when they compared PPARg expression levels in the hearts of wild-type mice, mice with streptozocin-induced diabetes, and human hearts, they found that the diabetic mice had two-fold greater expression of the receptor than the wild-type mice, and the expression in human hearts was about eight to 14 times higher than in wild-type mice, suggesting that PPARg has greater physiologic effect in human hearts, the authors wrote.
"It is possible that cardiotoxic effects of PPAR? agonists in humans occur due to glucolipotoxocity," they wrote in their conclusion. "Fortunately, this is seen in only a minority of patients whose diabetes and perhaps genetic variation make them unusually sensitive to what is otherwise a useful form of therapy."