What is the safety of pioglitazone (thiazolidinedione) in patients with hepatitis?

From the Guidelines

Pioglitazone may be beneficial in certain patients with nonalcoholic steatohepatitis (NASH), a form of liver disease, but is not generally recommended for viral hepatitis. For patients with NASH, particularly those with type 2 diabetes or insulin resistance, pioglitazone can be considered at doses of 15-45 mg daily, as suggested by the most recent study 1. Treatment duration typically ranges from 6-24 months, with ongoing monitoring of liver enzymes every 3-6 months. Pioglitazone works by activating peroxisome proliferator-activated receptor gamma (PPAR-γ), which improves insulin sensitivity, reduces inflammation, and may decrease liver fat accumulation and fibrosis. Some key points to consider when using pioglitazone for NASH include:

• Potential side effects, such as weight gain, fluid retention, heart failure exacerbation, and increased fracture risk, as noted in several studies 1
• Contraindication in patients with active bladder cancer or history of bladder cancer
• Lack of established role in the management of viral hepatitis (hepatitis B or C), where standard antiviral medications remain the treatment of choice
• Importance of consultation with both hepatology and endocrinology specialists when considering pioglitazone for liver disease Additionally, the most recent study 1 highlights the importance of comprehensive management of cardiovascular risk factors in patients with type 2 diabetes and NAFLD, and suggests that pioglitazone may be beneficial in reducing the risk of cardiovascular events. However, it is essential to weigh the potential benefits and risks of pioglitazone in each individual patient, taking into account their specific clinical context and medical history.

From the FDA Drug Label

Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal.

Pioglitazone use in hepatitis:

• Pioglitazone should not be initiated in patients with active liver disease or ALT levels exceeding 2.5 times the upper limit of normal.
• Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) should be evaluated to determine the cause of the liver enzyme elevation and therapy with pioglitazone should proceed with caution and include appropriate clinical follow-up.
• Liver function tests should be performed prior to initiation of therapy and periodically thereafter.
• If jaundice is observed, drug therapy should be discontinued 2.

From the Research

Pioglitazone and Hepatitis

• Pioglitazone is an oral hypoglycemic agent in the thiazolidinedione class that has been associated with hepatotoxicity in some cases 3.
• A case report published in 2002 described a patient who developed mixed hepatocellular-cholestatic liver injury after taking pioglitazone for 6 months 3.
• However, a 3-year randomized controlled study published in 2009 found that pioglitazone had a similar hepatic safety profile to glibenclamide in patients with type 2 diabetes 4.
• Another study published in 2005 found that pioglitazone caused reductions in mean levels of hepatic enzymes and had a lower incidence of liver test abnormalities compared to metformin and gliclazide 5.

Liver Safety and Pioglitazone

• A study published in 2018 found that pioglitazone was effective in treating nonalcoholic steatohepatitis (NASH) in patients with and without type 2 diabetes, with significant reductions in liver fibrosis and improvements in insulin sensitivity in patients with type 2 diabetes 6.
• A retrospective analysis published in 2005 found no evidence of increased risk of liver failure or hepatitis associated with pioglitazone compared to other oral antidiabetic agents 7.
• The available evidence suggests that pioglitazone is generally safe for the liver, but patients should be monitored for signs of hepatotoxicity, particularly during the initial stages of treatment 3, 4, 5, 6, 7.

Key Findings

• Pioglitazone has been associated with hepatotoxicity in some cases, but the overall risk is considered low 3, 4, 5, 6, 7.
• Pioglitazone may have beneficial effects on the liver, including reductions in liver enzyme levels and improvements in insulin sensitivity 5, 6.
• Patients taking pioglitazone should be monitored for signs of hepatotoxicity, particularly during the initial stages of treatment 3, 4, 5, 6, 7.