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Effectiveness of Fenofibrate in Treatment Naive.18
Effectiveness of Fenofibrate in Treatment Naive.18
Effectiveness of Fenofibrate in Treatment Naive.18
LIVER
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Yansheng Liu, MD1,*, Guanya Guo, MD1,*, Linhua Zheng, MM1,*, Ruiqing Sun, MM1, Xiufang Wang, MM1, Juan Deng, MM1,
Gui Jia, MM1, Chunmei Yang, MM1, Lina Cui, MD1, Changcun Guo, MD1, Yulong Shang, MD1 and Ying Han, MD1
INTRODUCTION: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease, and patients with
inadequate response to ursodeoxycholic acid (UDCA) treatment show reduced long-term survival.
Recent studies have shown that fenofibrate is an effective off-label therapy for PBC. However,
prospective studies on biochemical response including the timing of fenofibrate administration are
lacking. This study is aimed to evaluate the efficacy and safety of fenofibrate in UDCA treatment-naive
patients with PBC.
METHODS: A total of 117 treatment-naive patients with PBC were recruited from the Xijing Hospital for a 12-month
randomized, parallel, and open-label clinical trial. Study participants were assigned to receive either
UDCA standard dose (UDCA-only group) or fenofibrate at a daily dose of 200 mg in addition to UDCA
(UDCA-Fenofibrate group).
1
National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi’an,
China. Correspondence: Ying Han, MD. Email: hanying1@fmmu.edu.cn. Yulong Shang, MD. E-mail: shangyul870222@163.com. Changcun Guo, MD.
E-mail: guochc@sina.com.
*Yansheng Liu, Guanya Guo, and Linhua Zheng contributed equally to this article.
Received February 12, 2023; accepted February 28, 2023; published online March 9, 2023
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
1974 Liu et al
RESULTS: The primary outcome was biochemical response percentage in patients according to the Barcelona
criterion at 12 months. In the UDCA-Fenofibrate group, 81.4% (69.9%–92.9%) of patients achieved
the primary outcome and 64.3% (51.9%–76.8%) in the UDCA-only group achieved the primary
LIVER
outcome (P 5 0.048). There was no difference between the 2 groups in noninvasive measures of liver
fibrosis and biochemical markers other than alkaline phosphatase at 12 months. Creatinine and
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transaminases levels in the UDCA-Fenofibrate group increased within the first month, then returned to
normal, and remained stable thereafter until the end of the study, even in patients with cirrhosis.
DISCUSSION: In this randomized clinical trial in treatment-naive patients with PBC, the combination of fenofibrate
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and UDCA resulted in a significantly higher biochemical response rate. Fenofibrate seemed to be well-
tolerated in patients.
KEYWORDS: primary biliary cholangitis; fenofibrate; efficacy; safety
INTRODUCTION METHODS
Primary biliary cholangitis (PBC) is a progressive autoimmune Participants
liver disease that predominantly affects female individuals. It is Patients diagnosed with PBC (3,4) were recruited from Xijing
characterized by chronic inflammation of the liver manifested as Hospital based on the presence of 2 of the following 3 criteria:
nonsuppurative destructive cholangitis of small bile ducts and presence of antimitochondrial antibody or other PBC-associated
progressive cholestasis and eventually cirrhosis of the liver. High autoantibodies, including sp100 or gp210; elevation of ALP; and
levels of alkaline phosphatase (ALP) and total bilirubin (TBIL) compatible or diagnostic liver histology. All patients were en-
are correlated with poor prognosis (1,2). rolled at initial diagnosis and had never received UDCA before.
Ursodeoxycholic acid (UDCA) is currently the standard Patients with the presence of other liver diseases were excluded.
first-line treatment for PBC (3,4). Treatment with UDCA at Written informed consent was obtained from all patients. This
13–15 mg/kg/d can decrease the levels of cholestasis markers, study was approved by the Ethics Committee of Xijing Hospital
ALP and g-glutamyltransferase (GGT) (5), and extend according to the ethical guidelines of the 2013 declaration of
transplant-free survival (6). However, approximately 30%–40% Helsinki.
of patients show inadequate responses to UDCA and have im-
paired long-term survival (7–10). Hence, additional therapeutic
options are required for such patients. Obeticholic acid (OCA), Trial oversight and design
a selective agonist of the farnesoid X receptor, has been ap- This was a randomized, parallel-group, open-label trial per-
proved as a second-line therapy for UDCA in patients with formed over a 12-month period. The protocol is provided in
incomplete responses (3,4). Although patients treated with Supplement 1 (see Supplementary Digital Content 1, http://links.
OCA had improved levels of ALP, TBIL, and other biochemical lww.com/AJG/C902). All study subjects were randomized 1:1 by
markers (11), OCA can also be associated with severe pruritus, computer to receive either UDCA alone or a combination of oral
and its effects on long-term outcomes remain unclear (12). fenofibrate at a dose of 200 mg once-daily and UDCA at a dose of
Peroxisome proliferator–activated receptor (PPAR) ago- 13–15 mg/kg/d. Follow-up assessments were performed every 3
nists are recognized as candidate therapeutics for PBC. As the months until 12 months after the start of treatment. Liver stiffness
off-label treatment, fibrates are the most widely used PPAR measurements were performed at baseline, month 6, and month
agonists in PBC, which include bezafibrate (a pan-PPAR ag- 12. Liver stiffness was assessed using the Fibrotouch system. Liver
onist) and fenofibrate (a PPAR-a agonist). Some other non- biopsy was performed at baseline.
fibrate PPAR agonists are also in study (13–15). Randomized
clinical trials have shown that combination therapy with Outcomes
UDCA and bezafibrates can reduce the levels of biochemical The primary outcome was defined as biochemical response per-
markers of patients with PBC with inadequate responses to centage in patients at 12 months according to the Barcelona
UDCA (16,17). Several retrospective studies have shown that criterion (8). The secondary outcomes included the biochemical
fenofibrate treatment is associated with a significant decrease response percentage as defined earlier and percentage of ALP
in ALP, but there was controversy about the safety of fenofi- normalization at various time points; changes in serum levels of
brate (18–21). Evidence from prospective studies is lacking ALP, GGT, TBIL, aspartate aminotransferase (AST), alanine
(22). Furthermore, the starting time for second-line therapy in aminotransferase (ALT), platelet, albumin, and total cholesterol;
these studies was at least 1 year after the initiation of UDCA, and the biochemical response percentage in patients at 12 months
which raises the concern that patients with incomplete UDCA as defined by the Paris I (7), Paris II (23), and Toronto (24)
responses were exposed to higher risks of delayed alternative criteria. The secondary outcomes also included changes in liver
therapy. Therefore, the objective of this study was to assess the stiffness, AST to Platelet Ratio Index score (25), and Fibrosis-4
efficacy and safety of fenofibrate on treatment-naive patients score (26). Safety outcomes included changes in serum levels of
with PBC. creatinine and urea nitrogen and percentages of adverse events.
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Effectiveness of Fenofibrate 1975
LIVER
UDCA-only UDCA-fenofibrate
(n 5 60) (n 5 57)
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Age (yr) 52 6 8 52 6 9
Sex (female, %) 50 (83.3) 51 (89.5)
AMA (1, %) 51 (85.0) 47 (82.5)
Sp100 (1, %) 4 (6.7) 6 (10.5)
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Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
1976 Liu et al
whole study (Figure 3). GGT level had a similar rapid reduction,
while TBIL and ALT levels progressively decreased in both groups
(see eFigure 3A–C, Supplementary Digital Content 2, http://links.
lww.com/AJG/C903).
Noninvasive measures of fibrosis. Liver stiffness at 12 months
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UDCA-only UDCA-Fenofibrate
Missing data Response Missing data Response
n (%) n (%) [95% CI] n (%) n (%) [95% CI] P
Paris-I 7 (12) 34 (64.2) [50.7%–75.7%] 12 (21) 36 (80.0) [66.2%–89.1%] 0.083
Paris-II 7 (12) 25 (47.2) [34.4%–60.3%] 12 (21) 33 (73.3) [59.0%–84.0%] 0.009
Barcelona 7 (12) 35 (66.0) [52.6%–77.3%] 12 (21) 37 (82.2) [68.7%–90.7%] 0.107
Toronto 7 (12) 39 (73.6) [60.4%–83.6%] 12 (21) 42 (93.3) [82.1%–97.7%] 0.015
Results are expressed as the n (%) of patients with an adequate biochemical response. The x2 or Fisher exact test was used to determine the differences in response
percentages.
CI, confidence interval; UDCA, ursodesoxycholic acid.
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Effectiveness of Fenofibrate 1977
LIVER
(n 5 60) (n 5 57) (n 5 117)
n (%) n (%) n (%)
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Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
1978 Liu et al
DISCUSSION remained stable thereafter until the end of the study. Simulta-
In this study, we conducted a randomized, parallel, open-label neously, it is critical to determine whether fenofibrate use in pa-
clinical trial to explore the efficacy and safety between standard tients with cirrhosis is safe and reliable. The prevailing view is that
UDCA treatment and the combination of UDCA and fenofibrate fenofibrate should be used with caution in such patients (4).
LIVER
on treatment-naive patients with PBC. Analysis of our data Therefore, we analyzed changes of biochemical markers in pa-
demonstrated that UDCA combined with fenofibrate signifi- tients with cirrhosis after treatment. We noticed the same trends
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cantly increased the biochemical response rate, especially in as the analysis in all patients, and no obvious elevation of ami-
normalization of ALP. notransaminases, TBIL, and SCr was observed. In this study, 5
Consistent with previous studies, our results confirmed that patients with cirrhosis developed 7 events including gastroin-
fenofibrate showed good efficacy at normalizing ALP levels, testinal hemorrhage and ascites during the study, with no sig-
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which is the most important prognostic indicator of PBC (2). No nificant difference observed in the incidence of these events
increase in TBIL level was observed in patients treated with between 2 groups. Admittedly, the number of patients with cir-
fenofibrate during the study. Biochemical response rates were rhosis was small, and more randomized and blind studies should
also significantly higher in the UDCA-Fenofibrate group, except be initiated to explore the safety of fenofibrate treatment in pa-
for Paris-I criterion. One possible reason may be that Paris-I tients with cirrhosis.
criterion, which is usually used in patients with late-stage PBC, To date, this is the first randomized clinical trial of fenofibrate
was not suitable for our participants because most of our study in treatment-naive patients with PBC. Our results complemented
population was in the early stage of disease. previous retrospective studies and confirmed the favorable effi-
Our study was a 12-month trial, and it was therefore not cacy of fenofibrate combination therapy in patients with PBC.
suitable to perform repeated liver biopsies. We used liver stiffness Furthermore, our study targeting treatment-naive patients also
as a surrogate and found it to be significantly decreased in the sheds light on the fact that the evaluation and timing of adding
UDCA-Fenofibrate group, although with no differences between second-line drugs could be advanced.
groups. This is probably due to the short-term nature of our Our study had several limitations. First, this was a single-
study, given that previous long-term studies have shown that center design, and the sample size was relatively small. The lack of
fibrates prevented the progression of cirrhosis (28). We will a placebo control and the open-label design might limit the
continue to follow-up this cohort to define the effects of fenofi- objectivity of the results. Second, we did not analyze the long-
brate on liver pathology and the long-term survival of these pa- term survival of the patients, and only prognostic biochemical
tients, although the objectivity of this study would be markers were used to predict the outcomes. Third, because our
compromised due to the open-label design. patients did not undergo paired liver biopsy at baseline and after
Although fibrates have been used as an off-label treatment for fenofibrate treatment, the effect of fibrates on liver histology
PBC in recent years, the underlying mechanisms are still unclear. remained unclear.
Various mechanisms may be involved in the therapeutic effects. It In conclusion, in treatment-naive patients with PBC, combi-
has been found that bile acid metabolism was altered after nation therapy with UDCA and fenofibrate for 12 months
treatment with fenofibrate in patients with cholestasis (29,30) resulted in a higher biochemical response rate than UDCA
through the PPAR-a pathway. The PPAR-a isoform transcrip- monotherapy. Fenofibrate was associated with increased SCr,
tionally activates gene expression of many bile acid–metabolizing BUN, and AST levels, but these markers returned to the normal
enzymes (31). Therefore, its anticholestatic properties may be due range at the end of the study. Further studies are required to assess
to the detoxification of hepatic-toxic bile acid and inhibition of the long-term effects and safety of fenofibrate in patients
bile acid synthesis. In addition, previous studies have suggested with PBC.
that fenofibrate can suppress the immune response (30,32). Our
study also confirmed the lower IgG levels in the UDCA- ACKNOWLEDGMENT
Fenofibrate group than in the UDCA-only group. We are sincerely grateful to all the patients who participated in this
In this trial, fenofibrate was found to be associated with rapid study and M. Eric Gershwin and Patrick S.C. Leung, University of
and sustained decreases in ALP levels. Specifically, biochemical California at Davis, for their great suggestions in manuscript editing
markers and response rate rapidly reached a plateau after 1 month and organizations.
of combination therapy. Of interest, the UDCA-only group
showed a similar trend. For a long time, PBC has been considered CONFLICTS OF INTEREST
a chronic slow-progressing disease. Almost all response criteria Guarantor of the article: Ying Han, MD.
were designed to be used after a 1-year treatment of UDCA, and Specific author contributions: Y.H., Y.S., and C.G.: designed the
second-line drugs were added at 1 year. However, our study study. Y.L. and G.G.: performed the research. L.Z., R.S., X.W., J.D.,
showed that the biochemical indicators of the patients changed G.J., C.Y., and L.C.: collected data. Y.L.: analyzed data and wrote the
drastically within 3 months of receiving treatment. It re-enforced paper. All authors read and approved the final manuscript.
retrospective analysis from our cohort, which indicated the Financial support: The study was funded by the National Natural
treatment effect could be assessed in advance (33). Science Foundation of China (Nos. 81820108005 and 81900502) and
This study was aimed to evaluate the safety of fenofibrate in Key Research and Development Program of Shaanxi (No.
PBC. Recent evidence demonstrated that fenofibrates were well- 2021ZDLSF02-07). The funder had no role in the design and conduct
tolerated in PBC, with slight elevations in transaminases and SCr of the study; collection, management, analysis, and interpretation of
levels being the most common side effects (18–21,28,30). Con- the data; preparation, review, or approval of the manuscript; and
sistent with previous studies, our study also indicated that SCr decision to submit the manuscript for publication.
and aminotransaminase levels in the UDCA-Fenofibrate group Potential competing interests: None to report.
increased within the first month, then returned to normal, and Trial registration: ClinicalTrials.gov, NCT02823353.
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Effectiveness of Fenofibrate 1979
14. Bowlus CL, Galambos MR, Aspinall RJ, et al. A phase II, randomized,
Study Highlights open-label, 52-week study of seladelpar in patients with primary biliary
cholangitis. J Hepatol 2022;77(2):353–64.
WHAT IS KNOWN 15. Schattenberg JM, Pares A, Kowdley KV, et al. A randomized placebo-
controlled trial of elafibranor in patients with primary biliary cholangitis
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3 Approximately 30%–40% patients with primary biliary and incomplete response to UDCA. J Hepatol 2021;74(6):1344–54.
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3 Fibrates have been used in off-label drugs for PBC in years.
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17. de Vries E, Bolier R, Goet J, et al. Fibrates for itch (FITCH) in fibrosing
3 Solid evidence from randomized clinical trial of fenofibrate in cholangiopathies: A double-blind, randomized, placebo-controlled trial.
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