Can Pioglitazone (thiazolidinedione) be prescribed for non-alcoholic fatty liver disease (NAFLD) in non-diabetic patients?

From the Guidelines

Pioglitazone can be considered as a treatment option for non-alcoholic fatty liver disease (NAFLD) in non-diabetic patients, as it has been shown to improve liver histology and reduce liver inflammation, despite not being FDA-approved for this indication. The most recent and highest quality study, published in 2021 1, found that pioglitazone improved NASH in 34% of non-diabetic patients compared to 19% of placebo-treated patients, although it did not meet the primary endpoint of a ≥2 point reduction in the NAS. However, the resolution of steatohepatitis, a secondary outcome, was higher in the pioglitazone group than the placebo group (47% vs. 21%, P=0.001).

Some key points to consider when prescribing pioglitazone off-label for NAFLD in non-diabetic patients include:

• Typical doses range from 15-45 mg daily, with treatment duration of at least 6-12 months to see benefits
• Significant side effects include weight gain, fluid retention, increased risk of heart failure, bone fractures, and potential bladder cancer risk with long-term use
• The mechanism by which pioglitazone may help in NAFLD involves improving insulin sensitivity, reducing inflammation, and decreasing fat accumulation in the liver through activation of PPAR-gamma receptors
• First-line treatment for NAFLD should focus on lifestyle modifications including weight loss, dietary changes, and exercise, which have proven benefits without medication risks
• If medication is needed, consider consulting with a hepatologist for the most current treatment recommendations, as supported by recent guidelines 1.

It's also important to note that while pioglitazone may be effective in improving liver histology and reducing liver inflammation, it may not improve liver fibrosis, a major indicator predicting the progression of liver disease, as shown in previous studies 1. Therefore, careful consideration of the potential benefits and risks of pioglitazone treatment is necessary, and patients should be closely monitored for any adverse effects.

From the Research

Pioglitazone for Non-Alcoholic Fatty Liver Disease (NAFLD) in Non-Diabetic Patients

• The use of pioglitazone, a thiazolidinedione, for the treatment of non-alcoholic fatty liver disease (NAFLD) in non-diabetic patients has been explored in several studies 2, 3, 4, 5, 6.
• A systematic review of randomized controlled trials found that pioglitazone can exert a certain effect on alleviating NAFLD, which was consistent between non-diabetic NAFLD patients and diabetic NAFLD patients in improving histopathology, liver enzymes, and HOMA-IR and reducing blood lipids 3.
• Another study found that pioglitazone and vitamin E are effective in reducing steatosis, inflammation, and ballooning, reducing liver markers, but there seem to be conflicting data on fibrosis resolution 2.
• A review of diabetes drugs for NAFLD found that pioglitazone has benefits in liver function, liver fat, and NASH resolution, though significant increases in weight may be cause for concern 4.
• Current and potential future pharmacological approaches for NAFLD suggest that pioglitazone and vitamin E are the only drugs providing consistent benefits and are currently recommended for NASH 5.
• A review of the treatment of patients with type 2 diabetes and NAFLD found that reversal of lipotoxicity with pioglitazone is associated with significant histological improvement, which occurs within 6 months and persists with continued treatment, holding potential to modify the natural history of the disease, and that benefit has also been reported in non-diabetic patients 6.

Key Findings

• Pioglitazone can be effective in improving histopathology, liver enzymes, and HOMA-IR and reducing blood lipids in non-diabetic NAFLD patients 3.
• Pioglitazone has benefits in liver function, liver fat, and NASH resolution, though significant increases in weight may be cause for concern 4.
• Pioglitazone and vitamin E are the only drugs providing consistent benefits and are currently recommended for NASH 5.
• Reversal of lipotoxicity with pioglitazone is associated with significant histological improvement, which occurs within 6 months and persists with continued treatment, holding potential to modify the natural history of the disease, and that benefit has also been reported in non-diabetic patients 6.