What is the mechanism of action of pioglitazone and its major adverse effects?

• A. Thiazolidinedione that increases insulin sensitivity via PPAR-gamma; adverse effects include weight gain, edema, heart failure risk, and potential liver toxicity
• B. Increases insulin secretion from pancreatic beta cells
• C. Delays carbohydrate absorption in the gut
• D. Inhibits hepatic glucose production

Answer: (A)

Pioglitazone is a thiazolidinedione that activates PPAR-gamma, a nuclear receptor. This activation changes the expression of genes involved in glucose and lipid metabolism, leading to increased insulin sensitivity in adipose tissue, muscle, and the liver. With tissues more responsive to insulin, glucose is taken up more effectively, and hepatic glucose production is reduced, which together improves blood sugar control without forcing more insulin to be produced.

Major adverse effects to keep in mind are weight gain and edema due to fluid retention, and a risk of heart failure in susceptible individuals. There is also a potential for liver toxicity, so liver enzymes are monitored during therapy. Other drug-class effects, such as increased insulin secretion from pancreatic beta cells, delayed carbohydrate absorption in the gut, or direct inhibition of hepatic glucose production, do not describe pioglitazone’s primary action.