From the Guidelines
Fenofibrate is not currently recommended as a primary treatment for patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD, formerly known as NAFLD). While fenofibrate effectively treats hypertriglyceridemia by activating peroxisome proliferator-activated receptor alpha (PPAR-α), its benefits specifically for MASLD remain limited, as noted in the recent guidelines 1. Patients with MASLD who also have significant hypertriglyceridemia (typically >500 mg/dL) may be appropriate candidates for fenofibrate therapy at standard doses (typically 145 mg daily), but the medication should be prescribed primarily to address the lipid abnormality rather than as a direct MASLD treatment.
Key Considerations for Fenofibrate Use in MASLD
- When prescribing fenofibrate to MASLD patients, liver function should be monitored regularly, with baseline testing before initiation and follow-up testing at 3 months, then periodically thereafter, as suggested by general clinical practice guidelines.
- The primary approach for MASLD management should focus on lifestyle modifications including weight loss of 7-10% through dietary changes and increased physical activity, along with optimal management of associated metabolic conditions such as diabetes and dyslipidemia, as emphasized in the guidelines 1.
- Fenofibrate works by enhancing fatty acid oxidation and reducing triglyceride synthesis, which theoretically could benefit fatty liver, but clinical evidence supporting its use specifically for improving liver histology in MASLD remains insufficient compared to other interventions, such as resmetirom for non-cirrhotic MASH with significant liver fibrosis 1.
Management of MASLD
- The management of MASLD involves a stepwise approach using non-invasive tests to identify individuals with liver fibrosis, particularly in those with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis 1.
- Lifestyle modification, including weight loss, dietary changes, physical exercise, and discouraging alcohol consumption, as well as optimal management of comorbidities, is advised for adults with MASLD 1.
- Bariatric surgery is also an option in individuals with MASLD and obesity, and certain pharmacotherapies like resmetirom may be considered for non-cirrhotic MASH with significant liver fibrosis, if locally approved and dependent on the label 1.
From the Research
Fenofibrate Use in Patients with MASLD
- Fenofibrate is contraindicated in patients with advanced hepatic fibrosis due to limited clinical data 2.
- A study evaluated the pharmacokinetics and safety of fenofibrate in participants with mild hepatic impairment or with advanced fibrosis due to metabolic-associated fatty liver disease (MAFLD) 2.
- The results showed that fenofibrate was well tolerated, and modest differences were observed in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD 2.
Mechanisms and Treatment Options
- Metabolic-associated fatty liver disease (MAFLD) is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes, and is closely related to disturbances in systemic energy metabolism, including insulin resistance and atherogenic dyslipidemia 3.
- Lifestyle changes, including diet, physical exercise, and weight loss, should be the main basis for any treatment for MAFLD 4.
- Therapies to potentially treat MAFLD-induced cardiovascular disease include statins and lipid-lowering drugs, glucose-lowering agents, antihypertensive drugs, and antioxidant therapy 5.
Pharmacological Treatment
- The pharmacotherapy scenario of MAFLD is rapidly evolving, with several molecules targeting diverse biological mechanisms being tested in preclinical and clinical settings 6.
- Fenofibrate, a lipid-lowering drug, has been studied in patients with MAFLD, and has been shown to be well tolerated, with modest differences in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD 2.