Fenofibrate-UDCA Combination Therapy Safe and Effective for Primary Biliary Cholangitis

Hepatologists have prescribed fenofibrate off-label for years as an alternative for patients with primary biliary cholangitis who don’t respond to ursodeoxycholic acid (UDCA) therapy. Now, new research by Cleveland Clinic physicians confirms that this approach is safe and effective.

The large, retrospective study found that a combination therapy of UDCA and fenofibrate improved outcomes after both one and five years of treatment. The treatment was not associated with increased cardiovascular or liver risks, researchers say.

“I think these results are not a surprise,” says Cleveland Clinic hepatologist Dian Chiang, MD, a co-author of the study. “However, it’s reassuring to see that the benefit being shown in the study is not only short-term but also long-term.”

Investigating off-label use

Primary biliary cholangitis (PBC) is an autoimmune disease of the liver that mainly affects women. While UDCA is considered first-line therapy, as many as 40% to 50% of patients don’t respond to this treatment.

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) agonist that has long been used to treat high cholesterol. A similar medication has been used in Europe to treat patients with PBC, but that drug has not been approved for use in the United States.

As a result, hepatologists have long prescribed a combination of UDCA and fenofibrate off-label for PBC patients not responding to UDCA. However, data about its safety and effectiveness in this population were lacking, and there were concerns about whether it could increase the risk of liver injury in these patients.

Study design

Researchers used data from the TriNetX database to compare outcomes for more than 1,100 patients who received UDCA plus fenofibrate with the same number of patients who received UDCA alone. Patients who received the combination therapy had improved mortality, hospitalizations and symptoms (itchiness) at year one, with mortality and hospitalization benefits continuing after five years.

Patients who received fenofibrate had a higher cirrhosis risk at year one, likely indicating a more advanced disease stage at baseline, but after five years, this risk was comparable in both groups. The combined therapy was not associated with increased cardiovascular risks.

Reassuring results

For patients who have recently started the therapy and who have abnormal liver function tests, the results can provide encouragement that continuing therapy is unlikely to increase the risk of long-term liver damage, says Dr. Chiang.

“People can be reassured that this is a medication that not only will help reduce their liver enzymes but also has implications on their long-term outcomes,” he explains.

Dr. Chiang notes that newer, more specific PPAR agonists have since been approved for use in the PBC population.

“For those patients who are not able to receive the newer second-line agents, these results show that fenofibrate becomes a good alternative,” he says.

Researchers plan to follow up by studying additional complications of PBC to learn if fenofibrate is also helpful in those areas.

The study, “Long-Term Cardiovascular, Hepatic, and Symptom Outcomes with Ursodeoxycholic Acid Plus Fenofibrate in Primary Biliary Cholangitis: A Propensity-Matched Analysis,” was presented at the 2026 Digestive Disease Week Conference.