Rosiglitazone binding to PPARγ causes a conformational change within the complex that causes the dissociation of the endogenous ligand and the recruitment of a nuclear receptor coactivator 2, NCoA-2. This similarly occurs in the other half of the complex: RXRα Receptor
A type II nuclear receptor as well, RXR-α heterodimerizes with PPARγ. The ligand that activates RXR-α is the ligand 9-cis retinoic acid that results in dissociation of corepressor and recruitment of coactivator protein, also called NCoA (Vikas et.al 2008)
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Figure 6. NCoA-2
Transcriptional coregulatory protein proteins interact with transcription …show more content…
However, in May 2007, Dr. Steven Nissen, cardiologist at Cleveland Clinic, conducted analysis of clinical trials and concluded that the data showed rosiglitazone increases heart attacked by 43% (Ratziu et al. 2008). Subsequently, FDA requires warning label for Avandia in November of 2007 and it is withdrawn from market in UK and India in September 2010, under heavy pressure from consumers and advocacy groups who link cardiovascular problems to this drug. From November 2011 to November 2013 the FDA continues to allow this drug on the market but mandates a doctor’s prescription to purchase Avandia. However, at the end of 2013 the government removed all restrictions after a new RECORD clinical trial was published by GlaxoSmithKline. They conducted a six-year, open label randomized control trial that evaluated cardiac outcomes and failed to show correlation between rosiglitazone and cardiac failure. New information also revealed that the clinical trial analysis conducted by Dr. Nissen was flawed due to lack of heterogeneity in the meta-analysis, meaning that not all the studies were undertaken the same way (Nissen et al.