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Thiazolidinediones in the treatment of diabetes mellitus

David K McCulloch, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD


Two classes of oral hypoglycemic drugs improve insulin action as their primary effect: biguanides and thiazolidinediones (table 1). Two thiazolidinediones (rosiglitazone [Avandia] and pioglitazone [Actos]) are currently available in the United States. In 2010, the European Medicines Agency suspended sales of rosiglitazone, and in June 2011, the French and German Medicines Agencies also suspended the use of pioglitazone, owing to concerns that the overall risks of rosiglitazone and pioglitazone exceed their benefits. A third, troglitazone (Rezulin), was the first drug in this class to be marketed, but was removed from the market in both the United States and United Kingdom because it caused liver dysfunction and, in some patients, liver failure.

Rosiglitazone and pioglitazone are used as monotherapy or with a sulfonylurea, metformin, or insulin. However, there are concerns with combined thiazolidinedione and insulin therapy because of an increased incidence of heart failure (HF). In addition, thiazolidinediones have several other potential side effects, which make them less appealing as initial or second step therapy. (See 'Cardiovascular effects' below and 'Safety' below.)

The pharmacology and use of thiazolidinediones will be reviewed here. Biguanides (only metformin is currently available) and other oral hypoglycemic drugs are discussed separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus" and "Sulfonylureas and meglitinides in the treatment of diabetes mellitus" and "Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus".)


Insulin sensitivity — The thiazolidinediones increase insulin sensitivity by acting on adipose, muscle, and liver to increase glucose utilization and decrease glucose production [1-3]. The mechanism by which the thiazolidinediones exert their effect is not fully understood. They bind to and activate one or more peroxisome proliferator-activated receptors (PPARs), which regulate gene expression in response to ligand binding [3,4].

PPAR-gamma is found predominantly in adipose tissue, pancreatic beta-cells, vascular endothelium, macrophages, and the central nervous system. PPAR-alpha is expressed mostly in liver, heart, skeletal muscle, and vascular walls. The various thiazolidinediones have differential effects on PPAR-gamma and PPAR-alpha. Troglitazone and rosiglitazone are purely PPAR-gamma agonists, while pioglitazone also exerts some PPAR-alpha effects. This may account for the different effects that pioglitazone and rosiglitazone have on lipids. (See 'Lipids' below.)


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Literature review current through: Sep 2016. | This topic last updated: Sep 16, 2016.
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