Rosiglitazone
Rosiglitazone
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Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug (Avandia) and in combination with metformin (Avandamet) or with glimepiride (Avandaryl). Annual sales peaked at approx $2.5bn in 2006. Patent expires 2012.
Some reports have suggested that rosiglitazone is associated with a statistically significant risk of heart attacks, but other reports have disagreed, and the controversy has not been resolved. Concern about adverse effects has reduced the use of rosiglitazone despite its important and sustained effects on glycemic control.[1]
Pharmacology
Like other thiazolidinediones (TZDs), the mechanism of action of rosiglitazone is through activation of the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPARγ. Rosiglitazone is a selective ligand of PPARγ, and has no PPARα-binding action.
Apart from its effect on insulin resistance, it appears to have an anti-inflammatory effect: nuclear factor kappa-B (NFκB) levels fall and inhibitor (IκB) levels increase in patients on rosiglitazone.[2]
Recent research has suggested that rosiglitazone may also be of benefit to a subset of patients with Alzheimer's disease not expressing the ApoE4 allele.[3] This is the subject of a clinical trial currently underway.[4]
The medication might also be effective in the treatment of mild to moderate Ulcerative Colitis, due to its antiinflammatory properties as a PPAR ligand.[5]
[edit] Side-effects and contraindications
A press release by GlaxoSmithKline in February 2007 noted that there is a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide.[6] The information was based on data from the ADOPT trial.[7] The same increase has been found with pioglitazone (Actos), another TZD.
A meta-analysis reported in May 2007 that the use of rosiglitazone was associated with a significantly increased risk of heart attack (43% more likely, odds ratio=1.43, (95% confidence interval, 1.03 to 1.98; P=0.03)), and an even higher risk of death from all cardiovascular diseases (64% more likely, odds ratio=1.64).[8] The FDA issued an alert on May 21, 2007.[9] 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 (including heart attacks) than a placebo, but data from several long term, prospective clinical trials showed than when rosiglitazone was compared to metformin, or sulfonylurea, there was no difference in the risk of heart attack. This data, coupled with the meta-analysis, prompted the FDA to state that the data on the association between rosiglitazone and myocardial ischemia were inconclusive. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate this, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has dramatically reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control.[1]
As early as September, 2005, both Rosiglitazone and Pioglitazone have been suspected of causing Macular Edema, which causes partial blindness in various spots of the angle of vision. While blindness is also a possible effect of diabetes, which Rosiglitazone is intended to treat, an article
in Canadian journal CMAJ
has documented several occurrences and recommends discontinuation at the first sign of vision problems. Both TZD's are contraindicated in patients with NYHA Class III and IV heart failure.
Sales
US sales of $2.2 billion in 2006.[10] Sales in 2Q 2007 down 22% compared to 2006.[11] 4Q 2007 sales down to $252 million.[12]
This page was last modified on 20 February 2009, at 15:21.
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