Pioglitazone

Pioglitazone is an orally administered insulin sensitising thiazolidinedion e agent that has been developed for the treatment of type 2 diabetes mellit us. Pioglitazone activates the nuclear peroxisome proliferator activated recept or-gamma (PPAR-gamma), which leads to the increased transcription of variou s proteins regulating glucose and lipid metabolism. These proteins amplify the post-receptor actions of insulin in the liver and peripheral tissues, w hich leads to improved glycaemic control with no increase in the endogenous secretion of insulin. In placebo-controlled clinical trials, monotherapy with pioglitazone 15 to 45 mg/day has been shown to decrease blood glycosylated haemoglobin (HbA(1c )) levels in patients with type 2 diabetes mellitus. The addition of pioglitazone 30 mg/day to preexisting therapy with metformi n, or of pioglitazone 15 or 30 mg/day to sulphonylurea, insulin or voglibos e therapy, has been shown to decrease HbA(1c) and fasting blood glucose lev els significantly in patients with poorly controlled type 2 diabetes mellit us. Pioglitazone has also been associated with improvements in serum lipid prof iles in randomised placebo-controlled clinical studies. The drug has been well tolerated by adult patients of all ages in clinical studies. Oedema has been reported with monotherapy, and pooled data have sh own hypoglycaemia in 2 to 15% of patients after the addition of pioglitazon e to sulphonylurea or insulin treatment. There have been no reports of hepa totoxicity. Pioglitazone is a member of the thiazolidine-dione group of drugs developed for the treatment of type 2 (non-insulin-dependent) diabetes mellitus, a d isorder associated with a number of metabolic abnormalities that include im paired insulin secretion and insulin resistance. Insulin resistance leads t o decreased glucose utilisation by the peripheral tissues and increased hep atic glucose output, and is an important underlying metabolic abnormality i n many patients with type 2 diabetes mellitus. It is believed to be a key c omponent of the metabolic syndrome ('syndrome X'), which is characterised b y dyslipidaemia, hypertension, atherosclerosis, central obesity and impaire d glucose metabolism (reviewed by Saltiel and Olefskyl([1]) and Granberry a nd Fonseca([2])). The thiazolidinediones act by sensitising the liver and p eripheral tissues to the effects of insulin, which results in improved insu lin-mediated glucose disposal. Pioglitazone was administered orally in all animal and human studies discus sed in this profile.