What is the use of pioglitazone (thiazolidinedione)?

From the Guidelines

Pioglitazone is recommended for the treatment of nonalcoholic steatohepatitis (NASH) in patients with type 2 diabetes, as it has been shown to improve glucose and lipid metabolism, reverse steatohepatitis, and potentially slow fibrosis progression 1. The medication works by activating peroxisome proliferator-activated receptor gamma (PPAR-γ), which enhances insulin sensitivity in fat, muscle, and liver tissues, thereby lowering blood glucose levels without increasing insulin production. Some key points to consider when using pioglitazone include:

• It can be used alone or in combination with other diabetes medications such as metformin or insulin
• Common side effects include weight gain, fluid retention, and potential bone fracture risk, particularly in women
• It should be used cautiously in patients with heart failure, as it may worsen fluid retention
• Liver function should be monitored before and during treatment
• The medication typically takes 2-3 months to reach its full glucose-lowering effect, so patience is needed when evaluating its effectiveness
• Unlike some diabetes medications, pioglitazone has a low risk of causing hypoglycemia when used alone Additionally, pioglitazone may also have benefits in reducing cardiovascular disease in patients with or without type 2 diabetes, although this is not an approved indication by the U.S. Food and Drug Administration 1. It is essential to weigh the potential benefits and risks of pioglitazone in individual patients, particularly those with a history of heart failure or bladder cancer, and to monitor them closely for any adverse effects 1. Overall, pioglitazone is a valuable treatment option for patients with NASH and type 2 diabetes, and its use should be considered in the context of a comprehensive treatment plan that includes lifestyle modifications and other medications as needed 1.

From the FDA Drug Label

ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

The primary mechanism of action of pioglitazone is to decrease insulin resistance in the periphery and liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. It works by activating PPARγ receptors, which are found in tissues important for insulin action. Pioglitazone is not an insulin secretagogue and requires the presence of insulin to be effective 2.

• Key points:
  • Mechanism of action: decreases insulin resistance
  • Requires insulin: to be effective
  • Not an insulin secretagogue: does not stimulate insulin release
  • Activates PPARγ receptors: to increase insulin sensitivity
• Main use: management of type 2 diabetes mellitus 2

From the Research

Overview of Pioglitazone

• Pioglitazone is a thiazolidinedione used in the treatment of type 2 diabetes mellitus, approved for use as monotherapy and in combination with other antidiabetic agents 3.
• It increases hepatic and peripheral insulin sensitivity, inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake 4.

Efficacy of Pioglitazone

• Pioglitazone has been shown to reduce blood glucose levels, with decreases in glycosylated hemoglobin (up to 2.6%) and blood glucose levels (up to 95 mg/dL) 3.
• It also reduces triglyceride levels and increases high-density lipoprotein cholesterol (HDL-C) levels, which could lead to a reduction in cardiovascular risk 3, 4.
• Pioglitazone improves glycemic control, serum lipid profiles, and reduces some measures of cardiovascular risk and arteriosclerosis 4, 5.

Safety and Adverse Effects

• Common adverse effects of pioglitazone include weight gain, mild edema, and a clinically nonsignificant decrease in hemoglobin concentrations 3, 4.
• Abnormal results on liver function testing are no more common in treated patients than in control groups 3.
• Pioglitazone may cause fluid retention, fractures, and other adverse effects, but these can be diminished with lower doses 5.

Clinical Use and Recommendations

• Pioglitazone is a valuable component of combination therapy for type 2 diabetes mellitus, particularly for patients whose condition is not well controlled with monotherapy 6.
• It can be administered in combination with metformin, sulfonylureas, exenatide, dipeptidyl peptidase 4 (DPP-4) inhibitors, or insulin 6.
• Patients should be appropriately selected, especially to avoid those with heart failure, to minimize adverse events attributable to water retention 6, 7.