Thiazolidinediones

Thiazolidinediones (sometimes termed glitazones) are a novel class of drugs that were initially identified for their insulin-sensitizing properties. They all act to decrease insulin resistance and enhance insulin action in target tissues. Thiazolidinediones activate the nuclear peroxisome proliferator-activated receptor (PPAR) 7, a nuclear orphan receptor that is predominantly expressed in adipose tissue and to a lesser extent in muscle, liver, and other tissues. The endogenous ligand for the PPAR-7 receptor is postulated to be prostaglandin J2, and it appears to work by heterodimerizing with other nuclear receptors to modulate the expression of insulin-sensitive genes.

Thiazolidinediones are readily absorbed from the gastrointestinal tract following oral administration and are rapidly metabolized by the liver. Plasma elimination half-life is 2 to 3 hours for rosiglitazone (Avandia) and slightly longer for pioglitazone (Actos). About two-thirds of conjugated metabolites appear in the urine and the remainder in the feces. The biological effect of these drugs takes several weeks to develop, although patients may see some benefit within a few days to a week. Generally, however, the insulin-sensitizing action of the thiazolidinediones takes a while to develop. For that reason, upward adjustments in dosage are made gradually to avoid hypoglycemia.

The patient who would benefit the most from a thi-azolidinedione is a type II diabetic with a substantial amount of insulin resistance (e.g., one who does not respond to other oral therapies or who requires excessive amounts of insulin [>100 units/day]). Improvements in diabetic control are variable, ranging from a 1% reduction in hemoglobin A1c when used as monotherapy to greater reductions (>2% reduction in hemoglobin A1c) when used in combinations with other agents, such as sulfonylureas or metformin.

Rosiglitazone is approved for use as monotherapy and in conjunction with metformin, though it is sometimes combined with a sulfonylurea or insulin. It is usually taken once or twice a day with or without food. Rosiglitazone may cause a modest increase in low-density lipoprotein and triglyceride concentrations, but it is unclear whether this effect has any clinical significance or persists in the long term.

Pioglitazone is approved for use as monotherapy and in conjunction with metformin, sulfonylureas, and insulin. It is taken once a day with or without food. Though pioglitazone may also cause a small increase in low-density lipoprotein concentrations, there is usually a modest decrease in triglyceride levels, but it unclear whether this has any clinical significance or persists in the long term.

The original prototype of this class of drugs, trogli-tazone (Rezulin), was taken off the U.S. market in 2000 because of increasing concerns about idiosyncratic hepatic toxicity that resulted in several deaths worldwide. Consequently, frequent monitoring of liver transami-nases is recommended for rosiglitazone and pioglita-zone, and these drugs should be stopped if transami-nases rise to more than two to three times the upper limit of normal. To date, rosiglitazone and pioglitazone seem to be associated with far fewer incidents of hepatic toxicity.

Thiazolidinediones commonly cause edema that can be quite severe, sometimes requiring cessation of the drug, but mild cases of lower extremity edema can be treated with a low dose of a diuretic. There is often a modest amount of weight gain that is independent of water-retaining effects. In laboratory animals, thiazo-lidinediones at high doses are associated with ultrastructural histopathological changes in cardiac tissue; therefore, thiazolidinedione use is contraindicated in patients with significant heart failure. Thiazolidinediones can also cause mild anemia. Safety in pregnancy is not established.

Hypoglycemia is rare with thiazolidinedione monotherapy; however, these drugs may potentiate the hypo-glycemic effects of concurrent sulfonylurea or insulin therapy. If a thiazolidinedione is to be added to a diabetic's regimen, the sulfonylurea or insulin dosage should be decreased to compensate for any enhanced insulin sensitivity. Occasionally a small portion of insulin-treated type II diabetics may be capable of coming off their insulin altogether, depending on their responsiveness to thiazolidinedione action.

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