Pioglitazone

Pioglitazone is a prescription drug of the class thiazolidinedione (TZD) with hypoglycemic (antihyperglycemic, antidiabetic) action. Pioglitazone is marketed as trademarks Actos in the USA, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda Pharmaceuticals. Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion. Its cardiovascular safety profile compares favorably with rosiglitazone (Avandia), which was withdrawn after concerns about an increased risk of cardiac events, but pioglitazone has subsequently been found to be associated with bladder tumors and has been withdrawn in some countries.

Pharmacology
Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. It modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. As a result, pioglitazone reduces insulin resistance in the liver and peripheral tissues; increases the expense of insulin-dependent glucose; decreases withdrawal of glucose from the liver; reduces quantity of glucose, insulin and glycated hemoglobin in the bloodstream. Although not clinically significant, pioglitazone decreases the level of triglycerides and increases that of high-density lipoproteins (HDL) without changing low-density lipoproteins (LDL) and total cholesterol in patients with disorders of lipid metabolism, although statins are the drug of choice for this.

More recently, pioglitazone and other active TZDs have been shown to bind to the outer mitochondrial membrane protein mitoNEET with affinity comparable to that of pioglitazone for PPARγ.

Indications and usage
Pioglitazone is used for the treatment of diabetes mellitus type 2 (previously known as non-insulin-dependent diabetes mellitus, NIDDM) in monotherapy and in combination with a sulfonylurea, metformin, or insulin. Pioglitazone has also been used to treat non-alcoholic steatohepatitis (fatty liver), but this use is presently considered experimental. Pioglitazone has also been found to reduce the risk of conversion from prediabetes to diabetes mellitus type 2 by 72%.

Contraindication
Pioglitazone cannot be used in patients with a known hypersensitivity to pioglitazone, other thiazolidinediones or any of components of its pharmaceutical forms. It is ineffective and possibly harmful in diabetes mellitus type 1 and diabetic ketoacidosis. Its safety in pregnancy, lactation (breastfeeding) and people under 18 is not established.

Given previous experiences with the related drug troglitazone, acute diseases of the liver are regarded as a contraindication for pioglitazone.

Pioglitazone and all other drugs of its class (Thiazolidinediones) are absolutely contraindicated in patients with heart failure.

Side effects
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. The information was based on data from the ADOPT trial. Following release of this statement, Takeda also admitted that pioglitazone has similar implications for female patients.

The risk of hypoglycemia is low in the absence of other drugs that lower blood glucose.

Pioglitazone can cause fluid retention and peripheral edema. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia. Mild weight gain is common due to increase in subcutaneous adipose tissue. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.

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" when compared to placebo, but when compared to other diabetes drugs, there was no increased risk. Pioglitazone is currently being reviewed. A meta-analysis released subsequently showed that pioglitazone reduced the number of ischemic cardiac events rather than increase the risk, but increases CHF. The PERISCOPE study compared pioglitazone with glimepiride in diabetics; atherosclerotic plaque volume was measured and followed over time. Glimepiride therapy had highly significant progression of plaque volume over time of 0.73 percent. In comparison, pioglitazone had a -0.16 percent regression in plaque volume. This is the first study to show that diabetic therapy slowed progression of atherosclerosis. Therapy with pioglitazone raised HDL, and lowered triglyceride and hsCRP; these are all beneficial effects on risk factors for coronary artery disease, however to date, no oral anti-diabetic drug has been shown to reduce the risk of cardiovascular complications. Chronic administration of the drug has led to occasional instances of cholestatic hepatitis, reversible upon drug discontinuation.

On June 9, 2011 the French Agency for the Safety of Health Products decided to withdraw pioglitazone in regards to high risk of bladder cancer On June 10, 2011 Germany's Federal Institute for Drugs and Medical Devices also advised doctors not to prescribe the medication until further investigation of the cancer risk had been conducted.

On June 15, 2011 the U.S. FDA announced that pioglitazone use for more than one year may be associated with an increased risk of bladder cancer, and that the information about this risk will be added to the Warnings and Precautions section of the label for pioglitazone-containing medicines. The patient Medication Guide for these medicines will also be revised to include information on the risk of bladder cancer.

Drug interactions
Combination with sulfonylureas or insulin reciprocally exponentiate risk of hypoglycemia. Therapy with pioglitazone increased risk for pregnancy in those taking oral contraception.

Formulations
Pioglitazone as Actos is supplied in oral tablets containing 15, 30 or 45 mg of pioglitazone base. It is also available in combination with metformin as ActoplusMet (tablets containing 15 mg pioglitazone and either 500 or 850 mg of metformin), Competact (tablets containing 15 mg pioglitazone and 850 mg of metformin) or in combination with glimepiride as Duetact (tablets containing 30 mg pioglitazone and either 2 or 4 mg of glimepiride).