ARTICLE 1973

Effectiveness of Fenofibrate in Treatment-Naive Patients

LIVER
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With Primary Biliary Cholangitis: A Randomized

Clinical Trial
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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

© 2023 by The American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 11/06/2023

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

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/C902; http://links.lww.com/AJG/C903

Am J Gastroenterol 2023;118:1973–1979. https://doi.org/10.14309/ajg.0000000000002238

INTRODUCTION
Primary biliary cholangitis (PBC) is a progressive autoimmune
liver disease that predominantly affects female individuals. It is
characterized by chronic inflammation of the liver manifested as
nonsuppurative destructive cholangitis of small bile ducts and
progressive cholestasis and eventually cirrhosis of the liver. High
levels of alkaline phosphatase (ALP) and total bilirubin (TBIL)
are correlated with poor prognosis (1,2).
Ursodeoxycholic acid (UDCA) is currently the standard
first-line treatment for PBC (3,4). Treatment with UDCA at
13–15 mg/kg/d can decrease the levels of cholestasis markers,
ALP and g-glutamyltransferase (GGT) (5), and extend
transplant-free survival (6). However, approximately 30%–40%
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),
a selective agonist of the farnesoid X receptor, has been ap-
proved as a second-line therapy for UDCA in patients with
incomplete responses (3,4). Although patients treated with
OCA had improved levels of ALP, TBIL, and other biochemical
markers (11), OCA can also be associated with severe pruritus,
and its effects on long-term outcomes remain unclear (12).
Peroxisome proliferator–activated receptor (PPAR) ago-
nists are recognized as candidate therapeutics for PBC. As the
off-label treatment, fibrates are the most widely used PPAR
agonists in PBC, which include bezafibrate (a pan-PPAR ag-
onist) and fenofibrate (a PPAR-a agonist). Some other non-
fibrate PPAR agonists are also in study (13–15). Randomized
clinical trials have shown that combination therapy with
UDCA and bezafibrates can reduce the levels of biochemical
markers of patients with PBC with inadequate responses to
UDCA (16,17). Several retrospective studies have shown that
fenofibrate treatment is associated with a significant decrease
in ALP, but there was controversy about the safety of fenofi-
brate (18–21). Evidence from prospective studies is lacking
(22). Furthermore, the starting time for second-line therapy in
these studies was at least 1 year after the initiation of UDCA,
which raises the concern that patients with incomplete UDCA
responses were exposed to higher risks of delayed alternative
therapy. Therefore, the objective of this study was to assess the
efficacy and safety of fenofibrate on treatment-naive patients
with PBC.
METHODS
Participants
Patients diagnosed with PBC (3,4) were recruited from Xijing
Hospital based on the presence of 2 of the following 3 criteria:
presence of antimitochondrial antibody or other PBC-associated
autoantibodies, including sp100 or gp210; elevation of ALP; and
compatible or diagnostic liver histology. All patients were en-
rolled at initial diagnosis and had never received UDCA before.
Patients with the presence of other liver diseases were excluded.
Written informed consent was obtained from all patients. This
study was approved by the Ethics Committee of Xijing Hospital
according to the ethical guidelines of the 2013 declaration of
Helsinki.
Trial oversight and design
This was a randomized, parallel-group, open-label trial per-
formed over a 12-month period. The protocol is provided in
Supplement 1 (see Supplementary Digital Content 1, http://links.
lww.com/AJG/C902). All study subjects were randomized 1:1 by
computer to receive either UDCA alone or a combination of oral
fenofibrate at a dose of 200 mg once-daily and UDCA at a dose of
13–15 mg/kg/d. Follow-up assessments were performed every 3
months until 12 months after the start of treatment. Liver stiffness
measurements were performed at baseline, month 6, and month
12. Liver stiffness was assessed using the Fibrotouch system. Liver
biopsy was performed at baseline.
Outcomes
The primary outcome was defined as biochemical response per-
centage in patients at 12 months according to the Barcelona
criterion (8). The secondary outcomes included the biochemical
response percentage as defined earlier and percentage of ALP
normalization at various time points; changes in serum levels of
ALP, GGT, TBIL, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), platelet, albumin, and total cholesterol;
and the biochemical response percentage in patients at 12 months
as defined by the Paris I (7), Paris II (23), and Toronto (24)
criteria. The secondary outcomes also included changes in liver
stiffness, AST to Platelet Ratio Index score (25), and Fibrosis-4
score (26). Safety outcomes included changes in serum levels of
creatinine and urea nitrogen and percentages of adverse events.

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 Effectiveness of Fenofibrate 1975

Table 1. Demographic and clinical characteristics of the

participants at baseline

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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gp210 (1, %) 20 (33.3) 19 (33.3)

WBC (310E9/L) 4.6 6 1.8 4.6 6 1.3
RBC (310E9/L) 4.0 6 0.5 4.2 6 0.5
HB (g/L) 119 6 17 123 6 18 Figure 1. Percentage of Barcelona biochemical response in patients. Data
PLT (310E9/L) 150 6 85 164 6 72 are shown as the Barcelona biochemical response percentages in patients
with available data. UDCA, ursodeoxycholic acid.
ALT (U/L) 63 (38–98) 54 (40–77)
AST (U/L) 66 (46–93) 59 (43–95)
15% loss to follow-up, we calculated that 61 patients would need
ALB (g/L) 39.3 6 3.8 40.5 6 3.8 to be enrolled for the study to have 80% power, at a 2-sided
GLB (g/L) 34.0 6 6.2 33.4 6 5.4 significance level of 5%.
Multiple imputation was performed to replace missing data on
TBIL (mmol/L) 18.4 (11.7–26.0) 15.7 (11.5–25.6)
biochemical measure that were used to assess the primary out-
ALP (U/L) 303 (218–503) 277 (202–426) come. The intention-to-treat population was analyzed at the end
GGT (U/L) 327 (201–476) 343 (176–591) of the trial, including all patients who underwent randomization.
CHO (mmol/L) 4.2 (3.8–5.1) 4.8 (3.9–5.7) The x2 test or Fisher exact test was used to determine the differ-
ences in response percentages and adverse events percentages.
TG (mmol/L) 1.1 (0.8–1.5) 1.2 (0.8–1.6)
Sensitivity analyses were performed with no imputation, the last
BUN (mmol/L) 4.9 6 1.5 4.8 6 1.4 observation carried forward method, and the worst-case scenario
SCr (mmol/L) 71.7 6 18.0 70.4 6 22.7 method. Continuous variables were expressed as medians
IgG (g/L) 16.0 6 3.8 15.1 6 3.4
(interquartile ranges) or mean 6 SD when appropriate. The
Student t test or Mann-Whitney U test was used to compare the
IgM (g/L) 3.7 (2.4–6.0) 3.5 (2.3–5.6)
secondary outcomes, as appropriate. All tests were 2-sided, and P
Liver stiffness (kPa) 12.3 (8.6–16.7) 12.0 (7.5–18.3) values #0.05 were considered statistically significant. All analyses
Histological stages (n, %) were performed using GraphPad Prism 8.0 (GraphPad software)
and SAS 9.4 (SAS Institute).
I–II 51 (80.7) 46 (85.0)
III–IV 9 (19.3) 11 (15.0) RESULTS
Continuous data are presented as mean values 6 SD and tested by the Student Trial population
t test or as medians with interquartile range and tested by the Mann-Whitney A total of 117 patients with PBC (57 in the UDCA-Fenofibrate
U test, as appropriate. Categorical data are shown as number with percentage group and 60 in the UDCA-only group) were enrolled between
and tested by the Pearson x2 test or Fisher exact test, as appropriate.
April 2016 and May 2021 (see eFigure 1, Supplementary Digital
ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; BUN, blood urea nitrogen; CHO, total cholesterol;
Content 2, http://links.lww.com/AJG/C903). Overall, 101/117
GGT, g-glutamyltranspeptidase; GLB, globulin; HB, hemoglobin; IgG, (86%) of the patients were female with a mean age of 52 6 8 years.
immunoglobulin G; IgM, immunoglobulin M; PLT, platelet; RBC, red blood cell; 20/117 (17%) of the patients were at an advanced stage of the
SCr, serum creatinine; TBIL, total bilirubin; TG, triglyceride; UDCA, disease (Ludwig stage 3 or 4) (Table 1).
ursodesoxycholic acid; WBC, white blood cell.
Primary outcome
Based on the Barcelona criteria, 81.4% (69.9%–92.9%) of patients
Post hoc exploratory analysis consisted of changes in serum total
in the UDCA-Fenofibrate group achieved the primary outcome,
bile acids levels, immunoglobulin M, and immunoglobulin G (IgG)
whereas 64.3% (51.9%–76.8%) in the UDCA-only group achieved
levels; total cholesterol; and triglyceride levels. Furthermore, a
the primary outcome (P 5 0.048). In the analysis with last ob-
model that predicted UDCA response before treatment (27) was
servation carried forward imputation, 86.0% (74.4%–92.7%) of
used at baseline to identify patients who were more likely not to
patients in the UDCA-Fenofibrate group achieved the primary
respond to UDCA. The difference in the actual UDCA response
outcome, whereas 63.3% (50.7%–74.4%) of patients in UDCA-
rates of these patients was compared between the 2 groups.
only group achieved (P 5 0.005, see eTable 1, Supplementary
Digital Content 2, http://links.lww.com/AJG/C903). Biochemical
Statistical analysis response rates gradually increased in the UDCA-only group until
We expected a rate of biochemical response of 85% in the UDCA- reaching a plateau of 65% at month 9, whereas the response rate in
Fenofibrate group and 60% in the UDCA-only group. Assuming a the UDCA-Fenofibrate group reached above 80% at month 1

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 1976 Liu et al
LIVER
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Figure 2. Percentage of patients with normalization of ALP. Data are shown
as the percentage of patients with available data who had normalization
ALP. ALP, alkaline phosphatase; UDCA, ursodeoxycholic acid.
(88.5% vs 45.3%, P , 0.001) and remained stable throughout the
study (Figure 1).
Secondary outcomes
ALP normalization. At month 12, 62% (48%–75%) of patients in
the UDCA-Fenofibrate group had normal ALP level, whereas
40% (28%–53%) in the UDCA-only group had normal ALP level
(P 5 0.042, Figure 2). The changes of percentage of patients with
normal ALP were consistent with the results of the primary
outcome. In addition, we also evaluated the biochemical re-
sponses using ALP ,200 U/L as a criterion. As shown in eFigure 2
(Supplementary Digital Content 2, http://links.lww.com/AJG/
C903), the percentage of patients with ALP less than 200 U/L
reached above 60% at month 1 in UDCA-Fenofibrate group,
while the percentages progressively increased to 60% in UDCA-
only group. At month 12, 84.4% (71.2%–92.3%) of patients in
UDCA-Fenofibrate group had ALP less than 200 U/L, whereas
64.2% (50.7%–75.7%) of patients in the UDCA-only group met
this criterion (P 5 0.038).
Prespecified biochemical responses. Biochemical response rates
according to established criteria (Paris II, 73.3% vs 47.2%, P 5
0.009 and Toronto, 93.3% vs 73.6%, P 5 0.015) were significantly
higher in the UDCA-Fenofibrate group than those in the UDCA-
only group (Table 2).
Biochemical measures. The specific changes in ALP levels were
consistent with the primary outcome, and the changes of ALP,
GGT, TBIL, ALT, AST, platelet, albumin, and total cholesterol
Table 2. The biochemical response and prognostic scores at end point
UDCA-only
Missing data Response
n (%) n (%) [95% CI]
Paris-I 7 (12) 34 (64.2) [50.7%–75.7%]
Paris-II 7 (12) 25 (47.2) [34.4%–60.3%]
Barcelona 7 (12) 35 (66.0) [52.6%–77.3%]
Toronto 7 (12) 39 (73.6) [60.4%–83.6%]
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.
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levels are summarized in eTable 2 (see Supplementary Digital
Content 2, http://links.lww.com/AJG/C903). A 36% median re-
duction in ALP level from baseline was observed in the UDCA-
Fenofibrate group at 1 month. In addition, a significantly lower
level of ALP was found in patients treated with UDCA-
Fenofibrate than in those treated with UDCA only during the
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
decreased by 11% from baseline in the UDCA-Fenofibrate group
and 15% in the UDCA-only group (difference 23%, 95% confi-
dence interval 222% to 16%, eFigure 4A, Supplementary Digital
Content 2, http://links.lww.com/AJG/C903). Liver fibrosis and
AST to Platelet Ratio Index scores decreased progressively during
the trial, although not significantly, while the Fibrosis-4 score
remained stable (see eFigure 4B and C, Supplementary Digital
Content 2, http://links.lww.com/AJG/C903).
Post hoc analyses
At baseline, the serum levels of total bile acids did not differ
significantly between groups. Although levels fluctuated during
the trial, there was no difference between the groups at month 12
(see eFigure 5, Supplementary Digital Content 2, http://links.lww.
com/AJG/C903).
In post hoc analyses of immune and inflammatory markers in
patient subgroups with available data, there was no significant
difference in serum immunoglobulin M levels between groups at
month 12. However, IgG levels were higher in the UDCA-only
group than in the UDCA-Fenofibrate group (see eFigure 6,
Supplementary Digital Content 2, http://links.lww.com/AJG/
C903).
In a post hoc analysis of serum lipids, the levels of total cho-
lesterol in both groups fluctuated during the trial and remained
within the normal range. Levels of triglycerides in the UDCA-
only group progressively increased in the middle of study,
whereas levels in the UDCA-Fenofibrate group remained stable
within the normal range (see eFigure 7, Supplementary Digital
Content 2, http://links.lww.com/AJG/C903).
As summarized in eTable 3 (see Supplementary Digital
Content 2, http://links.lww.com/AJG/C903), in patients
whose predicted probability of response before UDCA treat-
ment was lower than 85% and 80%, the actual UDCA response
at 12 months was significantly higher in the UDCA-
Fenofibrate group than that in the UDCA-only group (89%
UDCA-Fenofibrate
Missing data Response
n (%) n (%) [95% CI] P
12 (21) 36 (80.0) [66.2%–89.1%] 0.083
12 (21) 33 (73.3) [59.0%–84.0%] 0.009
12 (21) 37 (82.2) [68.7%–90.7%] 0.107
12 (21) 42 (93.3) [82.1%–97.7%] 0.015
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 Effectiveness of Fenofibrate 1977

Table 3. Incidence of adverse events in any treatment group

UDCA-only UDCA-Fenofibrate Overall

LIVER
(n 5 60) (n 5 57) (n 5 117)
n (%) n (%) n (%)
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Patients with at least 1 AE 17 (28) 19 (33) 36 (31)

Patients with at least 1 AE 0 (0) 1 (2) 1 (1)
leading to withdrawal of
study drug
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Pruritus 0 (0) 1 (2) 1 (1)

Jaundice 0 (0) 1 (2) 1 (1)
Nausea 0 (0) 1 (2) 1 (1)
Figure 3. Changes in ALP levels. The median and interquartile ranges Gastrointestinal 3 (5) 1 (2) 4 (3)
values of ALP are shown. ALP, alkaline phosphatase; UDCA, ursodeox- hemorrhage
ycholic acid; ULN, upper limit of the normal range. ***P , 0.001, Mann-
Ascites 2 (3) 1 (2) 3 (3)
Whitney U test.
Grade 1 laboratory 12 (20) 26 (46) 38 (32)
abnormalities
[74%–96%] vs 61% [46%–74%], P 5 0.005; 93% [79%–99%] vs
61% [45%–74%], P 5 0.002). ALT 4 (7) 8 (14) 12 (10)
AST 0 (0) 11 (19) 11 (9)

Safety and adverse events TBIL 7 (12) 1 (2) 8 (7)

Overall, 36 patients reported 67 adverse events (52% in the SCr 1 (2) 6 (11) 7 (6)
UDCA-only group and 48% in the UDCA-Fenofibrate group, Grade 2 laboratory 3 (5) 7 (12) 10 (9)
respectively). One patient in the UDCA-Fenofibrate group abnormalities
withdrew from the study because of pruritus. Pruritus, jaundice,
ALT 1 (2) 3 (6) 4 (3)
and nausea were reported in 2% of patients in the UDCA-
Fenofibrate group. Gastrointestinal hemorrhage developed in 1 AST 2 (3) 1 (2) 3 (3)
patient in the UDCA-Fenofibrate group and in 3 patients in the TBIL 0 (0) 0 (0) 0 (0)
UDCA-only group. A further 1 patient in the UDCA-Fenofibrate SCr 0 (0) 3 (6) 3 (3)
group and 2 patients in the UDCA-only group developed ascites.
Grade 3 laboratory 2 (3) 0 (0) 2 (2)
Both gastrointestinal hemorrhage and ascites developed in pa-
abnormalities
tients with cirrhosis. No death was reported (Table 3).
Serum creatinine (SCr) levels in the UDCA-Fenofibrate group AST 1 (2) 0 (0) 1 (1)
fluctuated during the trial, and the difference between the 2 TBIL 1 (2) 0 (0) 1 (1)
groups was noticeable at month 6. However, the mean SCr level
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate
returned to normal after 12 months (see eFigure 8A, Supple- aminotransferase; SCr, serum creatinine; TBIL, total bilirubin; UDCA,
mentary Digital Content 2, http://links.lww.com/AJG/C903). ursodesoxycholic acid.
During the trial, 1 patient in the UDCA-only group and 6 patients
in the UDCA-Fenofibrate group had grade 1 SCr abnormalities,
and 3 patients in the UDCA-Fenofibrate group had grade 2 ab- elevation of aminotransferase levels in the UDCA-Fenofibrate
normalities. Blood urea nitrogen (BUN) levels in the UDCA- group resolved spontaneously within 3 months.
Fenofibrate group increased at 12 months. However, the BUN Aminotransferases, TBIL, and renal function in patients with
level remained within the normal range throughout the trial (see cirrhosis were analyzed to further observe the safety of fenofibrate
eFigure 8B, Supplementary Digital Content 2, http://links.lww. (see eFigure 10, Supplementary Digital Content 2, http://links.
com/AJG/C903). lww.com/AJG/C903). The ALT and AST levels in the UDCA-
Twelve patients had a grade 1 increase in ALT levels (8 patients Fenofibrate group increased by 40% at 1 month and then de-
in the UDCA-Fenofibrate group and 4 in the UDCA-only group). creased gradually thereafter (see eFigure 10A and B, Supple-
Three patients in the UDCA-Fenofibrate group and 1 patient in mentary Digital Content 2, http://links.lww.com/AJG/C903).
the UDCA-only group showed grade 2 abnormalities in ALT BUN levels fluctuated during the study in both groups, and it
levels (Table 3). Overall, the AST levels in the UDCA-Fenofibrate remained within the normal range throughout the trial in UDCA-
group increased at month 1 and then progressively decreased Fenofibrate group (see eFigure 10C, Supplementary Digital
during the rest of the trial (see eFigure 9, Supplementary Digital Content 2, http://links.lww.com/AJG/C903). SCr levels fluctu-
Content 2, http://links.lww.com/AJG/C903). Eleven patients in ated during the study in the UDCA-Fenofibrate group (see
the UDCA-Fenofibrate group had a grade 1 increase in AST eFigure 10D, Supplementary Digital Content 2, http://links.lww.
levels. One patient in the UDCA-Fenofibrate group and 2 patients com/AJG/C903). TBIL levels did not increase in either group
in the UDCA-only group had grade 2 abnormality. One patient in during the study (see eFigure 10E, Supplementary Digital Con-
the UDCA-only group had grade 3 abnormality (Table 3). The tent 2, http://links.lww.com/AJG/C903).

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 1978 Liu et al
DISCUSSION
In this study, we conducted a randomized, parallel, open-label
clinical trial to explore the efficacy and safety between standard
UDCA treatment and the combination of UDCA and fenofibrate
LIVER
on treatment-naive patients with PBC. Analysis of our data
demonstrated that UDCA combined with fenofibrate signifi-
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cantly increased the biochemical response rate, especially in
normalization of ALP.
Consistent with previous studies, our results confirmed that
fenofibrate showed good efficacy at normalizing ALP levels,
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which is the most important prognostic indicator of PBC (2). No
increase in TBIL level was observed in patients treated with
fenofibrate during the study. Biochemical response rates were
also significantly higher in the UDCA-Fenofibrate group, except
for Paris-I criterion. One possible reason may be that Paris-I
criterion, which is usually used in patients with late-stage PBC,
was not suitable for our participants because most of our study
population was in the early stage of disease.
Our study was a 12-month trial, and it was therefore not
suitable to perform repeated liver biopsies. We used liver stiffness
as a surrogate and found it to be significantly decreased in the
UDCA-Fenofibrate group, although with no differences between
groups. This is probably due to the short-term nature of our
study, given that previous long-term studies have shown that
fibrates prevented the progression of cirrhosis (28). We will
continue to follow-up this cohort to define the effects of fenofi-
brate on liver pathology and the long-term survival of these pa-
tients, although the objectivity of this study would be
compromised due to the open-label design.
Although fibrates have been used as an off-label treatment for
PBC in recent years, the underlying mechanisms are still unclear.
Various mechanisms may be involved in the therapeutic effects. It
has been found that bile acid metabolism was altered after
treatment with fenofibrate in patients with cholestasis (29,30)
through the PPAR-a pathway. The PPAR-a isoform transcrip-
tionally activates gene expression of many bile acid–metabolizing
enzymes (31). Therefore, its anticholestatic properties may be due
to the detoxification of hepatic-toxic bile acid and inhibition of
bile acid synthesis. In addition, previous studies have suggested
that fenofibrate can suppress the immune response (30,32). Our
study also confirmed the lower IgG levels in the UDCA-
Fenofibrate group than in the UDCA-only group.
In this trial, fenofibrate was found to be associated with rapid
and sustained decreases in ALP levels. Specifically, biochemical
markers and response rate rapidly reached a plateau after 1 month
of combination therapy. Of interest, the UDCA-only group
showed a similar trend. For a long time, PBC has been considered
a chronic slow-progressing disease. Almost all response criteria
were designed to be used after a 1-year treatment of UDCA, and
second-line drugs were added at 1 year. However, our study
showed that the biochemical indicators of the patients changed
drastically within 3 months of receiving treatment. It re-enforced
retrospective analysis from our cohort, which indicated the
treatment effect could be assessed in advance (33).
This study was aimed to evaluate the safety of fenofibrate in
PBC. Recent evidence demonstrated that fenofibrates were well-
tolerated in PBC, with slight elevations in transaminases and SCr
levels being the most common side effects (18–21,28,30). Con-
sistent with previous studies, our study also indicated that SCr
and aminotransaminase levels in the UDCA-Fenofibrate group
increased within the first month, then returned to normal, and
The American Journal of GASTROENTEROLOGY
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
remained stable thereafter until the end of the study. Simulta-
neously, it is critical to determine whether fenofibrate use in pa-
tients with cirrhosis is safe and reliable. The prevailing view is that
fenofibrate should be used with caution in such patients (4).
Therefore, we analyzed changes of biochemical markers in pa-
tients with cirrhosis after treatment. We noticed the same trends
as the analysis in all patients, and no obvious elevation of ami-
notransaminases, TBIL, and SCr was observed. In this study, 5
patients with cirrhosis developed 7 events including gastroin-
testinal hemorrhage and ascites during the study, with no sig-
nificant difference observed in the incidence of these events
between 2 groups. Admittedly, the number of patients with cir-
rhosis was small, and more randomized and blind studies should
be initiated to explore the safety of fenofibrate treatment in pa-
tients with cirrhosis.
To date, this is the first randomized clinical trial of fenofibrate
in treatment-naive patients with PBC. Our results complemented
previous retrospective studies and confirmed the favorable effi-
cacy of fenofibrate combination therapy in patients with PBC.
Furthermore, our study targeting treatment-naive patients also
sheds light on the fact that the evaluation and timing of adding
second-line drugs could be advanced.
Our study had several limitations. First, this was a single-
center design, and the sample size was relatively small. The lack of
a placebo control and the open-label design might limit the
objectivity of the results. Second, we did not analyze the long-
term survival of the patients, and only prognostic biochemical
markers were used to predict the outcomes. Third, because our
patients did not undergo paired liver biopsy at baseline and after
fenofibrate treatment, the effect of fibrates on liver histology
remained unclear.
In conclusion, in treatment-naive patients with PBC, combi-
nation therapy with UDCA and fenofibrate for 12 months
resulted in a higher biochemical response rate than UDCA
monotherapy. Fenofibrate was associated with increased SCr,
BUN, and AST levels, but these markers returned to the normal
range at the end of the study. Further studies are required to assess
the long-term effects and safety of fenofibrate in patients
with PBC.
ACKNOWLEDGMENT
We are sincerely grateful to all the patients who participated in this
study and M. Eric Gershwin and Patrick S.C. Leung, University of
California at Davis, for their great suggestions in manuscript editing
and organizations.
CONFLICTS OF INTEREST
Guarantor of the article: Ying Han, MD.
Specific author contributions: Y.H., Y.S., and C.G.: designed the
study. Y.L. and G.G.: performed the research. L.Z., R.S., X.W., J.D.,
G.J., C.Y., and L.C.: collected data. Y.L.: analyzed data and wrote the
paper. All authors read and approved the final manuscript.
Financial support: The study was funded by the National Natural
Science Foundation of China (Nos. 81820108005 and 81900502) and
Key Research and Development Program of Shaanxi (No.
2021ZDLSF02-07). The funder had no role in the design and conduct
of the study; collection, management, analysis, and interpretation of
the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Potential competing interests: None to report.
Trial registration: ClinicalTrials.gov, NCT02823353.
VOLUME 118 | NOVEMBER 2023 www.amjgastro.com

Study Highlights
WHAT IS KNOWN
3 Approximately 30%–40% patients with primary biliary
cholangitis (PBC) have inadequate response to
Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn
ursodeoxycholic acid (UDCA).
3 Fibrates have been used in off-label drugs for PBC in years.
3 Solid evidence from randomized clinical trial of fenofibrate in
PBC treatment is still lacking.
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 11/06/2023
WHAT IS NEW HERE
3 Fenofibrate can significantly increase the biochemical
response rate in treatment-naive patients with PBC.
3 Patients can have rapid biochemical response after 1 month
of combination treatment of fenofibrate and UDCA.
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