Fenofibrates in the Treatment of Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) represents a chronic autoimmune condition that causes progressive nonsuppurative bile duct injury and cholestasis, resulting in advanced fibrosis in up to 50% of cases in the absence of treatment.¹ Although ursodiol (UDCA) remains standard first-line therapy, an estimated 40% of patients will be considered biochemical ‘non-responders’ at one year,² associated with worsened histologic progression and transplant-free survival.¹ For this population, fibrates have been explored as an adjunctive second line treatment, with an AASLD conditional recommendation to ‘consider fibrates as an off-label treatment in this context. However, no prospective data previously existed exploring the possible role of fibrates in first-line therapy for PBC.

Liu et al sought to close this gap through a single center randomized parallel-group, open label clinical trial conducted over a 12-month period at Xijing Hospital in China conducted among 117 treatment naïve patients with PBC.³ Patients were randomized on a 1:1 basis to receive either standard ursodiol monotherapy (13-15 mg/kg; n = 60) or ursodiol in combination with fenofibrate (200 mg daily; n = 57). PBC was diagnosed by meeting 2 of the standard criteria: presence of PBC associated autoantibodies; alkaline phosphatase (ALP) elevation; or compatible liver histology. Patients with previous ursodiol exposure or concomitant alternate etiology of liver disease were excluded.

Liver histology was obtained at baseline, serologic response was monitored at 3-month intervals and liver stiffness was assessed non-invasively at 6-month intervals using transient elastography. The primary outcome was biochemical response defined by the Barcelona criteria: either normalization of alkaline phosphatase, or 40% reduction from baseline at 12 months. Multiple secondary outcomes were evaluated including earlier change in alkaline phosphatase, improvement in other liver function tests, or change in elastography. Sub-population analysis was performed examining those patients with the highest pre-test risk of inadequate treatment response, as identified by modeling from prior literature.⁴

Overall, there was a significantly higher rate of occurrence of the primary outcome with combination treatment cohort compared to ursodiol monotherapy with rates of treatment response per Barcelona criteria of 81.4% and 64.3%, respectively (P = .048). Significantly, no meaningful difference in these trends was observed among patients identified as being at highest risk of non-response to treatment, with response rates of 89% and 61% in the 2 arms, respectively.

Interestingly, combination therapy was also associated with earlier treatment response, with 80% of patients responding within 1 month of treatment initiation compared to the 9 months in the control cohort. There was a corresponding higher rate of alkaline phosphatase normalization with combination therapy, although no significant different was seen in bilirubin, ALT or hepatic fibrosis change between the 2 groups.

Both treatment regimens were well tolerated, with only 1 patient withdrawing from the fibrate treatment arm due to pruritus and no difference in adverse event rates between the 2 groups. There was a transient worsening of renal function in the fibrate arm within the first 6 months of treatment in 6 patients; however, this normalized at the 1-year mark. Among patients with cirrhosis, fibrate therapy was associated with only transient aminotransferase increase without any higher incidence of decompensating events including hemorrhage or ascites.

Overall, this study suggested that the addition of fibrate therapy to first-line PBC treatment was associated with earlier and higher rates of biochemical response. It additionally showed that even if fibrates are not utilized first line, full effect of ursodiol monotherapy plateaued at 9 months rather than 1 year, suggesting that earlier identification of non-responsiveness and subsequent escalation in therapy is feasible. Additionally, heightened concerns regarding risks of fibrates in advanced disease, which culminated in a revised American Association for the Study of Liver Disease (AASLD) guideline against their use in decompensated cirrhotic patients,5 did not manifest during this study. This suggests the possible expanded role of fibrate therapy in later stage patients.

It is important to note, however, that the proportion of even stage III-IV fibrosis was less than 20% in both study arms and future studies with a larger cirrhotic cohort will be essential. Additionally, patients were only followed for 12 months, restricting the insight this study could offer in terms longitudinal disease progression and the histological impact of fibrate therapy, which ultimately will drive clinical outcomes for patients with PBC. Similarly, longer-follow up during future studies will be beneficial for ascertaining whether abnormalities in aminotransferases and renal function were truly transient or can recur with chronic therapy.

Furthermore, while this study validated first line fibrate initiation in patients at risk of non-response to fibrate therapy, it also reinforced the necessity of better prognostication in identifying these individuals, as evidenced by the similar treatment response in the ‘high risk’ cohort to the overall study population.

Cumulatively, however, in spite of these directions for future research, this study shows significant promise for earlier and expanded use of fibrate therapy in management of PBC.