Thiazolidinediones (TZDs) or glitazones act by enhancing certain actions of insulin (increase insulin-dependent glucose disposal and decrease hepatic glucose output) by binding to and activating PPARs (peroxisome proliferator-activated receptors), a group of nuclear receptor proteins. Three PPARs have been identified: alpha, beta (or delta) and gamma. PPARs play a key role in the regulation of storage and catabolism of dietary fats.

TZDs can target a single PPAR or a combination. This specificity will impact the safety profile of the drug.

The first compound in this class, troglitazone (Rezulin®), was launched in 1997 by Warner-Lambert and rapidly gained market shares. Two years later, pioglitazone (Actos®) and rosiglitazone (Avandia®) were launched. In 2000, Rezulin® was withdrawn from the market after causing several deaths related to hepatotoxicity.

In August of 2007, after a review of postmarketing adverse event reports, the FDA determined that an updated label with a boxed warning on the risks of heart failure was needed for the entire thiazolidinedione class of antidiabetic drugs.

• PIOGLITAZONE

  Generic name	Actos® / Glustin®
  Company	Takeda and Lilly
  Available doses	15 mg, 30 mg and 45 mg
  Dose per day	once daily
  Side-effects	- weight gain due to fluid retention and edema - cardiac effects
  Elimination half-life	3-7 hours
  Metabolism	Metabolized by hydroxylation and oxidation (liver metabolism)
  US patent status	generic
  US FDA status	approved July 1999
  EMEA status	approved October 2000
  Indication
  Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Pioglitazone is indicated for monotherapy.Pioglitazone is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control.
  Comments
  Pioglitazone is sold under the name Actos® in the US and Glustin® in Europe Takeda and Lilly co-promoted Actos in the US until Lilly's US marketing rights expired in September 2006. Lilly continues to receive residual royalties on US Actos sales at declining rates through September 2009. Lilly also has exclusive and semi-exclusive rights in other countries. Takeda reported sales of ¥336 billion in 2006 and ¥396 billion in 2007. Lilly reported revenues (sales outside the US plus royalties from US sales) of $449 million in 2006 and $371 million in 2007. Package insert contains congestive heart failure warning In March 2007, Takeda and FDA notified healthcare professionals of recent safety data concerning pioglitazone-containing products. The results of an analysis of the manufacturer's clinical trial database of pioglitazone showed more reports of fractures in female patients taking pioglitazone than those taking a comparator (either placebo or active).

  
  

• ROSIGLITAZONE

  Generic name	Avandia®
  Company	GlaxoSmithKline
  Available doses	2 mg, 4 mg and 8 mg
  Dose per day	once or twice daily
  Side-effects	cardiac effects
  Elimination half-life	3-4 hours
  Metabolism	N-demethylation and hydroxylation
  US patent status	expires in 2012
  US FDA status	approved May 1999
  EMEA status	approved July 2000
  Indication
  Approved by US-FDA in May 1999 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
  Comments
  On July 30, 2007 an Advisory Committee of the Food and Drug Administration concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of "myocardial ischemic events". GlaxoSmithKline reported sales of £1,399 million in 2006 and £877 million in 2007. Package insert contains congestive heart failure and myocardial ischemia warning.