Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult‐to‐treat primary biliary cholangitis

Abstract

SummaryBackgroundObeticholic acid (OCA) and fibrates are second‐line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA).AimTo know whether OCA and fibrates, administered together in combination with UDCA, have additive beneficial effects in patients with difficult‐to‐treat PBC.MethodsPBC patients treated for ≥3 months with UDCA, OCA and fibrates (bezafibrate or fenofibrate) due to failure of either second‐line therapy were included in a multicentre, uncontrolled retrospective cohort study. Changes in biochemical liver tests and pruritus were analysed using a generalised linear mixed‐effect model.ResultsAmong 58 patients included, half received OCA as second‐line and fibrates as third‐line therapy (Group OCA‐Fibrate), while the other half had the inverse therapeutic sequence (Group Fibrate‐OCA). The mean duration of triple therapy was 11 months (range 3‐26). Compared to dual therapy, triple therapy was associated with a significant gain in alkaline phosphatase (ALP) reduction: 22% per first year (95% CI 12%‐31%), an effect that was stronger in OCA‐Fibrate than in Fibrate‐OCA group. Triple therapy was associated with a 3.4 (95% CI 1.4‐8.2) odds ratio (OR) of reaching normal ALP and with a significant decrease in gamma‐glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. The ORs of achieving the Paris‐2 and Toronto criteria of adequate biochemical response were 6.8 (95% CI 2.8‐16.7) and 9.2 (95% CI 3.4‐25.1) respectively. Finally, triple therapy significantly improved pruritus in OCA‐Fibrate but not in Fibrate‐OCA group.ConclusionsTriple therapy with UDCA, OCA and fibrates is able to normalise biochemical liver tests and improve pruritus in patients with difficult‐to‐treat PBC.

Clinical characterization of patients with primary biliary cholangitis: A report from multiple Canadian centres

“…As per the typical demographics of this patient population, 90.2% of patients were female (Table S1 in the Supplementary Appendix). The median age of patients was 61.3 years at last visit: 20.5% of patients were above 70 years of age, 34.9% were between 60-69 years of age, 30.8% were between 50-59 years of age, being investigated (22). Other molecules, including non-steroidal FXR agonists (23)(24)(25) as well as other PPAR agonists (26)(27)(28) are also in development for the treatment of PBC.…”

A change of paradigm in PBC: Pursuing normal alkaline phosphatase

“…Moreover, off-label therapy with the pan-PPAR agonist bezafibrate is recognised as an alternative and triple combination therapy -including UDCA, OCA, and fibrates- can normalise biochemical liver tests in difficult-to-treat PBC. 2 Lack of response to treatment identifies patients at higher risk of poor liver related outcomes and is currently depended on Alkaline Phosphatase (ALP) levels after 1 year of treatment. ALP is indeed a well recognize surrogate marker of response and outcome.…”

Review article: therapeutic aspects of bile acid signalling in the gut‐liver axis

“…Preliminary results of the phase II RCT with the non‐steroidal FXR agonist cilofexor (formerly GS‐9674; NCT02943447) showing reduced levels of ALP, gamma‐glutamyl transferase and transaminases in PBC patients after 12 weeks of treatment were presented at an international conference in 2019. 150 Interestingly, a recent observational study indicated that the combined use of UDCA, OCA and fibrates (“triple therapy”) in patients with PBC and ineffectiveness of second‐line treatment led to an improvement of liver injury markers, 151 potentially related to complementary effects of FXR and PPAR signalling. 81 Nevertheless, further studies are needed to confirm these results.…”

“…Non‐steroidal or non‐absorbable FXR agonists will hopefully become effective and safe therapeutic options to address this question in the future. Finally, as indicated by the efficacy of cilofexor in combination with firsocostat (an acetyl‐CoA carboxylase inhibitor) in NASH, 156 and recent data on the combination of OCA and fibrates in PBC, 151 the use of combination treatment regimens may represent a promising approach to treat liver diseases. The use of human tissue or human organoids will be vital to close the gap between experimental data and human disease in future studies on BA signalling in the gut‐liver axis.…”