Rosiglitazone

Products

Rosiglitazone was commercially available in tablet form (Avandia). It had been approved since 1999 and was also commercially available in fixed combination with the biguanide metformin (Avandamet). The combination with the sulfonylurea glimepiride (Avaglim, EU, off-label) was not approved in many countries. A publication in on possible cardiovascular risks led to a controversy about the safety of the drug starting in 2007 (Nissen & Wolski, 2007 Pubmed). The study showed a slightly increased risk of myocardial infarction and a non-significant increase in the risk of cardiovascular death. Based on new data, the European Medicines Agency (EMA) decided in September 2010 to withdraw approval for the active ingredient and remove all products containing rosiglitazone from the market. Swissmedic followed this decision in October and cancelled the approval in many countries. The glitazone pioglitazone remains on the market.

Structure and properties

Rosiglitazone (C18H19N3O3S, Mr = 357.43 g/mol) is a racemate and is present in drugs as rosiglitazone maleate, a white solid that is readily soluble in acidic water. Solubility decreases with increasing pH. Glitazones such as rosiglitazone are also called thiazolidinediones because of the thiazolidinedione ring.

Effects

Rosiglitazone (ATC A10BG02) is antidiabetic, antihyperglycemic, normalizes blood glucose, and lowers HbA1c. It is a high-affinity agonist at the nuclear receptor PPAR-γ, which controls the regulation of genes involved in glucose and lipid metabolism. Its effects are primarily due to increased sensitivity of adipose tissue, muscle, and liver to insulin, thus decreasing insulin resistance and increasing uptake of blood glucose into tissues. Unlike the sulfonylureas, rosiglitazone does not promote insulin secretion.

Indications

Rosiglitazone was approved as a 2nd-line agent for the treatment of type 2 diabetes mellitus.

Dosage

The prescribed dose is taken in 1-2 doses per day, independent of meals. The maximum daily dose is 8 mg.

Contraindications

Rosiglitazone is contraindicated in hypersensitivity, heart failure (NYHA classes III and IV), and acute coronary syndrome. For complete precautions, see the drug label.

Interactions

Rosiglitazone is fully biotransformed to active and inactive metabolites via CYP2C8 and to a lesser extent via CYP2C9. Inducers such as rifampicin may therefore reduce bioavailability, and inhibitors of CYP2C8 such as trimethoprim or gemfibrozil may increase exposure to rosiglitazone. Methotrexate may also increase maximum plasma concentration and AUC. Rosiglitazone should not be combined with insulins because more adverse effects can be expected.

Adverse effects

Rosiglitazone has come under criticism in recent years because of the potential for cardiovascular adverse effects. These include the development or worsening of heart failure, fluid retention, oedema, weight gain due to water retention, and cardiac ischemia (impaired blood flow to the heart). The risk for adverse effects is increased when combined with other antidiabetic agents, especially insulins. The question of whether significantly more cases of myocardial infarction and more deaths occur with rosiglitazone is controversial and the subject of investigation. Rosiglitazone has also been criticized for other side effects. These include anemia (common), bone fractures (common), macular edema (very rare), hypercholesterolemia, increased appetite, hypoglycemia, constipation, and very rarely anaphylactic reactions, pancreatitis, fulminant hepatitis, hepatocellular necrosis, and an increase in bilirubin.