In this study, we demonstrated that FF add-on therapy significantly improved the biochemical and immunological parameters in PBC patients with a suboptimal response to more than one year of UDCA treatment. Furthermore, FF add-on therapy improved the GLOBE score and UK-PBC risk score. More importantly, FF add-on therapy was associated with improved 5- and 10-year transplant-free survivals.
Our study showed that FF add-on therapy significantly improved biochemical parameters, especially the serum ALP, GGT, and TBIL levels, which is consistent with the results of previous studies[9, 13–15]. ALP and TBIL are validated biochemical surrogates of outcome and have been regarded as survival predictors in PBC patients[16]. In our study, we found that after 1 year of FF add-on treatment, the ALP normalization rate was 60.9%, and the normalization rate for both ALP and TBIL was 45.3%. These results are in line with previous studies which showed FF add-on treatment could get a ALP normalization rate of 54.2%-80% [14–16]. These efficacy results seem to be superior or at least not inferior to 1 year of OCA add-on therapy, which yielded a normalization rate of 11% for ALP, TBIL, and ALT[17]. Since no head-to-head comparative studies are available, the choice for second-line therapy between fibrate and OCA may depend on practical considerations including side-effects, cost, and availability[3].
More importantly, our study found that FF add-on therapy could improve the long-term transplant-free survival of PBC patients with suboptimal response to UDCA. Indeed, in patients receiving FF add-on therapy had significantly higher 5- and 10-year survivals than those who continued the UDCA monotherapy. This is consistent with the report of Cheung et al that adding FF for a median time of only 11 months already showed short-term survival benefits[9]. This is also in line with another recent report that adding fibrate agents lowered the risk of the cirrhosis development and further hepatic deterioration in PBC patients with suboptimal response to UDCA[18].
The survival benefit of FF add-on therapy is further supported by the finding that the GLOBE score and UK-PBC score could be improved, which in turn, lowered the predicted risk of 5-,10-, and 15-year liver-related death and liver transplantation. These results are supported by other studies including one Chinese PBC cohort study[7, 8]. Although more studies are needed to confirm these survival benefits, the favorable impact on the long-term prognosis makes adding fibrates (FF or BZF) a reasonable option for PBC patients with suboptimal biochemical responses to UDCA.
We also found that FF add-on therapy could improve the serum level of IgM, consistent with previous studies[15, 19]. In addition, serum IgG level was also reduced in our patients, which may be mediated by PPAR-α through suppressing the activation of the nuclear factor-kappa B[5, 20]. Not surprisingly, we also found that FF add-on reduced all serum levels of lipids including TG, CHOL, LDL and HDL. After one year of FF add-on treatment, the median serum level of HDL reduced to 1.7 mmol/L, which was higher than the reported hazardous threshold of 1.54 mmol/L (40mg/dl) below which there is an increased risk of coronary artery disease (CAD)[20, 21]. Therefore, whether this unfavorable HDL-lowering effect of FF could impact CAD risk in PBC patients warrants further investigation.
In our study, FF is generally well tolerated. The most common adverse effect was the elevation of liver transaminases which can be resolved upon FF withdrawal, with no case developed liver failure. Another side effect occurred in one of our patients was serum creatinine elevation, which also promptly resolved upon FF cessation. Although the musculoskeletal injury is also a common side effect of FF[21], only one case occurred in our cohort.
Our study had certain limitations. Firstly, this was a single-center study with a retrospective design. However, we hope the fair number of patients included and the longer duration of follow-up (up to 3.8 years) may still provide further evidence to cope with this unmet medical need. Secondly, liver histology was not included in the analysis due to PBC diagnosis in many patients was based on cholestatic biochemical profiles and AMA positivity. Thirdly, information on pruritus was not obtained in this study, necessitating further prospective studies.
In conclusion, FF add-on to UDCA improves not only biochemical variables and but also long-term transplant-free survival in PBC patients with suboptimal response to UDCA. Although FF is well tolerated, drug-induced liver and renal injury should be closely monitored and properly managed.