Thiazolidinediones

Thiazolidinediones (TZDs) are drugs that are prescribed in type 2 diabetes to decrease insulin resistance and help lower blood sugar levels. There are currently two drugs in this class available in the United States: rosiglitazone (marketed as Avandia) and pioglitazone (marketed as Actos). Troglitazone, previously marketed as Rezulin, was withdrawn from the market due to an increased incidence of drug-induced hepatitis. Compounds in development include MCC-555, rivoglitazone^[1], and ciglitazone.

Uses

TZDs are only approved for use in patients with type 2 diabetes; they are not appropriate for type 1 diabetics. Rosiglitazone and pioglitazone can lower hemoglobin A1c levels (a measure of blood sugar) by 1% to 1.5% in people with type 2 diabetes. They can be combined with insulin or other classes of oral glucose-lowering drugs.

TZDs are also being investigated for use in polycystic ovary syndrome^[2], non-alcoholic steatohepatitis^[3], psoriasis^[4], and other, less prevalent conditions such as Waldenstrom's macroglobulinemia^[5].

How Thiazolidinediones Work

TZDs act by binding to receptors in the nucleus of cells in muscle, fat, and liver tissues. The receptors, called peroxisome proliferator-activated receptors (PPARs) migrate to the DNA in the nucleus when activated by TZDs. They initiate the synthesis of specific proteins from genes, a process called transcription. These proteins help the body regulate carbohydrate and fat metabolism and use the available insulin more efficiently. Besides decreasing insulin resistance, TZDs alter levels of some hormones related to fat cell (adipocyte) behavior.

Side Effects and Contraindications

The withdrawal of troglitazone from the market has raised concerns about an association between other TZDs and hepatitis. To address this risk, guidelines now include periodic monitoring of the liver for signs of damage. This can be done by measuring the amount of specific enzymes in the blood.

The main side effects of all TZDs are fluid retention and accumulation edema. Edema is morel likely to occur when the drugs are given in combination with insulin. Complications of this retention include weight gain and worsening of heart failure. Therefore, TZDs are generally not used in people with preexisting heart failure. Heart problems are most likely to occur within the first six months of starting treatment (see video below).

The potential cardiovascular risks associated with pioglitazone have been examined in several clinical trials, and a recently-completed meta-analysis concluded that "pioglitazone does not appear to be harmful in terms of cardiovascular events."^[6]

The use of TDZs have also been associated with an increased risk of bone fractures in women (see video below).

History

The first TZD, troglitazone, was developed by the Japanese pharmaceutical company Sankyo. Parke-Davis obtained the U.S. license and began clinical trials in the 1990s. The Food and Drug Administration (FDA) approved the drug for use in the United States in 1997 after the results of the trials showed the drug to be effective and relatively safe. Some cases of liver toxicity began to surface after Troglitazone was used in millions of people. The FDA recommended to physicians that liver function tests be performed periodically in patients prescribed troglitazone. Only about 5% of physicians complied, and some people treated with the drug required liver transplantations. Parke-Davis voluntarily removed troglitazone from the market in March 2000 after FDA approval of other TZDs.

References

1. ↑ Schimke K, Davis TM. Drug evaluation: rivoglitazone, a new oral therapy for the treatment of type 2 diabetes. Curr Opin Investig Drugs. 2007 Apr;8(4):338-44. Abstract
2. ↑ Lanham MS, Lebovic DI, Domino SE. Contemporary medical therapy for polycystic ovary syndrome. Int J Gynaecol Obstet. 2006 Dec;95(3):236-41. Abstract
3. ↑ Belfort R et. al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355(22): 2297-307. Abstract | Full Text | PDF
4. ↑ Krentz AJ, Friedmann PS. Type 2 diabetes, psoriasis and thiazolidinediones. Int J Clin Pract 2006;60:362-3. Abstract
5. ↑ Mitsiades CS, Mitsiades N, Richardson PG, Treon SP, Anderson KC. Novel biologically based therapies for Waldenstrom's macroglobulinemia. Semin Oncol. 2003 Apr;30(2):309-12. Abstract
6. ↑ Mannucci E, Monami M, Lamanna C, Gensini GF, Marchionni N. Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2008 May 26. Abstract

External Links

Actos home page (pioglitazone)

Avandia home page (rosiglitazone)