Rosiglitazone

Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5 billion in 2006; however, following a meta-analysis in 2007 that linked the drug's use to an increased risk of heart attack,[1] sales plummeted to just $9.5 million in 2012. The drug's patent expired in 2012.[2]

It was patented in 1987 and approved for medical use in 1999.[3] Despite rosiglitazone's effectiveness at decreasing blood sugar in type 2 diabetes mellitus, its use decreased dramatically as studies showed apparent associations with increased risks of heart attacks and death.[4] Adverse effects alleged to be caused by rosiglitazone were the subject of over 13,000 lawsuits against GSK;[5] as of July 2010, GSK had agreed to settlements on more than 11,500 of these suits.

Some reviewers recommended rosiglitazone be taken off the market, but an FDA panel disagreed, and it remains available in the US.[6] From November 2011 until November 2013, the US federal government did not allow Avandia to be sold without a prescription from a certified doctor; moreover, patients were required to be informed of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.[7] In 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of a 2009 trial which failed to show increased heart attack risk.[8][9]

In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended because the benefits no longer outweighed the risks.[10][11] It was withdrawn from the market in the UK, Spain and India in 2010,[12] and in New Zealand and South Africa in 2011.[13]

Medical uses

Rosiglitazone was approved for glycemic control in people with type 2 diabetes, as measured by glycated haemoglobin A1c (HbA1c) as a surrogate endpoint, similar to that of other oral antidiabetic drugs.[14][15] The controversy over adverse effects has dramatically reduced the use of rosiglitazone.[16]

Published studies did not provide evidence that outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by rosiglitazone.[14]

Adverse effects

Pharmacology

Rosiglitazone is a member of the thiazolidinedione class of drugs. Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the peroxisome proliferator-activated receptors (PPARs). PPARs are transcription factors that reside in the nucleus and become activated by ligands such as thiazolidinediones. Thiazolidinediones enter the cell, bind to the nuclear receptors, and alter the expression of genes. The several PPARs include PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to PPARγ.

PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPARγ is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. It is also found in pancreatic beta cells, vascular endothelium, and macrophages[45] Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action. Other drugs bind to PPARα.

Rosiglitazone also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance. Nuclear factor kappa-B (NF-κB), a signaling molecule, stimulates the inflammatory pathways. NF-κB inhibitor (IκB) downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.[46]

History

Rosiglitazone was approved by the US FDA in 1999 and by the EMA in 2000; the EMA however required two postmarketing studies on longterm adverse effects, one for chronic heart failure and the other for cardiovascular effects.[10]

Society and culture

Research

Rosiglitazone was thought to be able to benefit patients with Alzheimer's disease who do not express the ApoE4 allele,[84] but the phase III trial designed to test this showed that rosiglitazone was ineffective in all patients, including ApoE4-negative patients.[85]

Rosiglitazone may also treat mild to moderate ulcerative colitis, due to its anti-inflammatory properties as a PPAR ligand.[86]

Rosiglitazone has been investigated as an agent that may expedite body fat redistribution into a more feminine shape in trans women who have had little fat redistribution from hormone replacement therapy, due to thiozolidinediones' effects on body fat metabolism.[87]

Synthesis

External links