UDCA and primary biliary cirrhosis

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Open Access Full Text Article

http://dx.doi.org/10.2147/DDDT.S79837

Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis

Yan Zhang1,2,*Sainan Li1,*Lei He1

Fan wang1

Kan Chen1

Jingjing Li1

Tong Liu1

Yuanyuan Zheng1

Jianrong wang1,3

wenxia Lu1,3

Yuqing Zhou1,4

Qin Yin1,4

Yujing Xia1

Yingqun Zhou1

Jie Lu1

Chuanyong Guo1

1Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 2Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 3The First Clinical Medical College of Nanjing Medical University, Nanjing, 4The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China

*These authors contributed equally to this work

Background: Although the effectiveness of treatment with ursodeoxycholic acid (UDCA) and

fenofibrate for primary biliary cirrhosis (PBC) has been suggested by small trials, a systematic

review to summarize the evidence has not yet been carried out.

Methods: A meta-analysis of all long-term randomized controlled trials comparing the combination

of UDCA and fenofibrate with UDCA monotherapy was performed via electronic searches.

Results: Six trials, which included 84 patients, were assessed. Combination therapy with

UDCA and fenofibrate was more effective than UDCA monotherapy in improving alkaline

phosphatase (mean difference [MD]: -90.44 IU/L; 95% confidence interval [CI]: -119.95

to -60.92; P,0.00001), gamma-glutamyl transferase (MD: -61.58 IU/L; 95% CI: -122.80

to -0.35; P=0.05), immunoglobulin M (MD: -38.45 mg/dL; 95% CI: -64.38 to -12.51; P=0.004),

and triglycerides (MD: -0.41 mg/dL; 95% CI: -0.82 to -0.01; P=0.05). However, their effects on

pruritus (odds ratio [OR]: 0.39; 95% CI: 0.09–1.78; P=0.23), total bilirubin (MD: -0.05 mg/dL;

95% CI: -0.21 to 0.12; P=0.58), and alanine aminotransferase (MD: -3.31 IU/L; 95% CI: -14.60

to 7.97; P=0.56) did not differ significantly. This meta-analysis revealed no significant differences

in the incidence of adverse events (OR: 0.21; 95% CI: 0.03–1.25; P=0.09) between patients

treated with combination therapy and those treated with monotherapy.

Conclusion: In this meta-analysis, combination therapy with UDCA and fenofibrate was more

effective in reducing alkaline phosphatase than UDCA monotherapy, but it did not improve

clinical symptoms. There did not appear to be an increase in adverse events with combination

therapy.

Keywords: randomized controlled trials, combination therapy, monotherapy, fibrates, odds

ratio, risk difference

IntroductionPrimary biliary cirrhosis (PBC) is a chronic progressive inflammatory autoimmune-

mediated cholestatic disease that mainly occurs in elderly women and is character-

ized by progressive inflammatory destruction of the interlobular bile duct, and the

subsequent development of liver fibrosis and cirrhosis, eventually leading to liver

failure.1 The etiology and exact pathogenesis of PBC are still not entirely clear, and

may be related to genetic factors, viral and bacterial infections, autoimmune status,

and environmental factors.2 Ursodeoxycholic acid (UDCA) is currently the only

United States Food and Drug Administration (FDA)-approved and the 2009 American

Association for the Study of Liver Diseases Practice Guidelines-recommended drug

for the treatment of PBC.3 UDCA therapy for PBC is very safe, and it can improve

Correspondences: Chuanyong Guo; Jie LuDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of Chinaemail [email protected]; [email protected]

Journal name: Drug Design, Development and TherapyArticle Designation: ReviewYear: 2015Volume: 9Running head verso: Zhang et alRunning head recto: UDCA and primary biliary cirrhosisDOI: http://dx.doi.org/10.2147/DDDT.S79837

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Zhang et al

clinical symptoms and liver function abnormality indicators,

delay histologic progression, improve quality of life, prolong

survival, and prolong transplant-free survival.4 However, up

to 40% of patients treated with UDCA monotherapy have

a suboptimal response (no significant decrease in alkaline

phosphatase [ALP], alanine aminotransferase [ALT], or

immunoglobulin [Ig]M), and 10% will subsequently die

or require liver transplantation, indicating a clear need for

additional therapies.4,5

Fenofibrate, a peroxisome proliferator-activated receptor

(PPAR)-α-selective agonist, is a fibric acid derivative that is

US FDA approved and clinically used for the treatment of

hypercholesterolemia and hypertriglyceridemia.6–8 Recent

pilot studies in patients with PBC refractory to UDCA

monotherapy demonstrated that fenofibrate can also improve

biochemical and immunological indicators to normal levels,

and significantly improve clinical symptoms without side

effects.9,10 Therefore, we conducted this meta-analysis to

evaluate the clinical outcomes of the combination of UDCA

and fenofibrate compared with UDCA monotherapy in

patients with PBC.

MethodsStudy identificationRelevant studies were searched and selected by searching

the PubMed, the Cochrane Library, Embase, and CINAHL

databases, as well as the Science Citation Index (updated to

September 2013) using the search terms “ursodeoxycholic

acid”, “fenofibrate”, “PBC”, and “randomized controlled

trial”. We also carried out a full manual search of all review

articles, and retrieved original studies and abstracts.11

inclusion criteriaThe studies included in this study fit the following three cri-

teria. First, in terms of study design, randomized controlled

trials (RCTs) comparing combination therapy with UDCA/

fenofibrate and monotherapy with UDCA were included.

Second, with respect to study population, the diagnosis of

PBC was made on the basis of any two of the following

criteria: 1) positive test for antimitochondrial antibody;

2) biochemical evidence of cholestasis; and 3) liver biopsy

compatible with the diagnosis.12 Parés et al4 suggested that

patients who show a drop of .40% in serum ALP levels from

baseline or normalization have similar survival rates when

compared with the general age- and sex-matched population.

Therefore, we defined a complete biochemical response to

treatment as an ALP level decrease of more than 40% of the

baseline values or normal range after 1 year of UDCA treat-

ment. Third, duplicated publications were excluded and no

language or date limitations were imposed. There was also

no limitation on the form of publication.

Data extractionData were independently collected from each study by two

researchers (Yan Zhang and Sainan Li) to confirm the accu-

racy of the data. The following data were extracted from each

included article: name of the first author, year of publication,

number of patients, daily dose of oral therapy, duration of

treatment, method used to deal with missing data, liver bio-

chemistry, symptoms, death, and adverse events.

Assessment of risk of bias in included studiesThere are a lot of tools available to assess the method-

ological quality of clinical trials. According to the Cochrane

Handbook 5.0.2, the Cochrane Collaboration recommends

a specific tool for assessing the risk of bias in each included

study.13–15 This consists of a description of and a judgment

for each entry in a “Risk of bias” table, where each entry

addresses a specific feature of the study. The judgment for

each entry involves answering a question, with answers

“Yes” indicating low risk of bias, “No” indicating high risk

of bias, and “Unclear” indicating either a lack of information

or uncertainty over the potential for bias. For parallel group

trials, the features of interest in a standard “Risk of bias”

table of a Cochrane review are allocation sequence genera-

tion, allocation concealment, blinding, incomplete outcome

data, selective outcome reporting, and other potential sources

of bias (Table 1).

Statistical analysesThe data collected were processed by RevMan 5.2 (The Nor-

dic Cochrane Centre, Copenhagen, Denmark; The Cochrane

Collaboration, 2012). We calculated the odds ratio (OR) and/

or risk difference for dichotomous outcomes, and the mean

difference (MD) for continuous outcomes, all with 95%

confidence intervals (CIs). We tested heterogeneity using the

χ2 test and the I2 test, and a P-value of ,0.10 or an I2 value

of .50% was considered as substantial heterogeneity.

A fixed-effects model was used when the heterogeneity test

showed a P-value of .0.10 and an I2 value of ,50%; other-

wise, a random-effect model was used. We also constructed

funnel plots to evaluate the presence of publication bias.

ResultsDescriptive and qualitative assessmentsThis meta-analysis included 84 patients (Figure 1). The

general characteristics of the six trials are shown in Table 2.

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UDCA and primary biliary cirrhosis

The mean ages ranged from 51 to 61 years and the mean

follow-up intervals ranged from 3 to 24 months. The daily

dose of UDCA ranged from 600 to 900 mg/day, and the daily

dose of fenofibrate was 134–200 mg/day. Not all studies were

published as full-text articles.16–21 One trial was published as

an abstract and one as a letter to the editor.17,18 The results

of the meta-analysis are shown in Table 3. The six included

trials were evaluated with the help of the “assessing risk of

bias” table and the outcome is summarized in Figure 2. Risk

of bias was assessed according to six components: alloca-

tion sequence generation, allocation concealment, blinding,

handling of incomplete outcome data, selective outcome

reporting, and other potential sources of bias. All trials

were assessed as having a high risk of bias. Our statistical

analyses are, therefore, based only on trials with a high risk

of bias (Figure 3). Figure 4 shows the funnel plots of the

meta-analysis. The funnel plots for clinical events showed

slight asymmetry, suggesting possible publication bias.

evaluation of the effects of therapyFour studies17,19–21 reported the clinical outcome of the treatments

on patients’ symptoms, and found improvement in pruritus.

The combination therapy significantly improved liver function

and reduced serum ALP levels in all the included studies. Five

studies16,17,19–21 also reported adverse effects (heartburn, nausea,

aggravated pruritus, and fatigue) and yet, no serious adverse events

were reported. There were no deaths in the five studies.16,17,19–21

Meta-analysisALP levelsSix trials,16–21 which included 84 patients, reported data

regarding this endpoint. Combination therapy with UDCA

Table 1 Criteria used to assess the risk of bias in the included studies

Trials assessed as having a “low risk of bias” in all the specified individual domains were considered as “trials with low risk of bias”. Trials assessed as having an “uncertain risk of bias” or a “high risk of bias” in one or more of the specified individual domains were considered “trials with high risk of bias”.Allocation sequence generation- Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing

a coin, shuffling cards, and throwing dice are adequate if performed by an independent adjudicator.- Uncertain risk of bias: the trial is described as randomized, but the method of sequence generation was not specified.- High risk of bias: the sequence generation method is not, or may not be, random. Quasi-randomized studies – those using dates, names, or admittance

numbers in order to allocate patients – are inadequate and will be excluded for the assessment of benefits, but not for harms.Allocation concealment- Low risk of bias: allocation was controlled by a central and independent randomization unit, sequentially numbered, and in opaque and sealed envelopes

or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.- Uncertain risk of bias: the trial was described as randomized, but the method used to conceal the allocation was not described, so that intervention

allocations may have been foreseen in advance of, or during, enrolment.- High risk of bias: if the allocation sequence was known to the investigators who assigned patients or if the study was quasi-randomized.

Quasi-randomized studies will be excluded for the assessment of benefits, but not for harms.Blinding- Low risk of bias: the trial was described as blinded; the parties that were blinded, and the method of blinding were described, so that knowledge

of allocation was adequately prevented during the trial.- Uncertain risk of bias: the trial was described as blind, but the method of blinding was not described, so that knowledge of allocation was possible

during the trial.- High risk of bias: the trial was not blinded, so that the allocation was known during the trial.Incomplete outcome data- Low risk of bias: the numbers and reasons for dropouts and withdrawals in all intervention groups were described, or if it was specified, that there

were no dropouts or withdrawals.- Uncertain risk of bias: the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.- High risk of bias: the number or reasons for dropouts and withdrawals were not described.Selective outcome reporting- Low risk of bias: predefined or clinically relevant and reasonably expected outcomes are reported on.- Uncertain risk of bias: not all predefined or clinically relevant and reasonably expected outcomes are reported on, or they are not reported fully,

or it is unclear whether data on these outcomes were recorded or not.- High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely

to have been recorded.Other bias- Low risk of bias: the trial appears to be free of other components that could increase risk of bias.- Uncertain risk of bias: the trial may or may not be free of other components that could increase the risk of bias.- High risk of bias: there are other factors in the trial that could increase the risk of bias – eg, for-profit involvement, the authors have conducted trials

on the same topic, etc.

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27 identified studies from thedatabases

19 potentially relevant studies

Ten articles reviewed

Six articles included in themeta-analysis

Two case reportsOne combined with other therapies

One no controls

Nine excluded titles and abstract werenot relevant for the endpoint of

the study

Eight excluded for duplication

Figure 1 Flow diagram of the studies included in the meta-analysis.

Table 2 Baseline characteristics of the trials included in the meta-analysis

References Mean age (years)

Patients (n)

UDCA dose (mg/day)

Fenofibrate dose (mg/day)

Duration of treatment Publication typeUDCA COM

Ohira et al17 61 7 600–900 150–200 8 years 6 months LetterDohmen et al16 53 9 600 100–150 6 months 3 months Full textwalker et al18 55 16 600–900 134–200 23 months 23 months LetterLiberopoulos et al19 57 10 600 200 8 months 2 months Full textLevy et al20 56 20 600–900 160 12 months 12 months Full textHan et al21 51 22 600–900 200 18 months 6 months Full text

Abbreviations: n, number; UDCA, ursodeoxycholic acid; COM, combination treatment.

Table 3 Meta-analysis of clinical events and biochemical parameter changes in the included studies

Outcome title Number of studies

Number of participants

Statistical method Effect size P-value

Pruritus 4 59 Odds ratio (M–H, fixed, 95% CI)

0.39 (0.09–1.78) 0.23

Adverse events 5 68 Odds ratio (M–H, fixed, 95% CI)

0.21 (0.03–1.25) 0.09

Alkaline phosphatase

6 84 Mean difference (IV, fixed, 95% CI)

-90.44 (-119.95 to -60.92) ,0.00001

Gamma-glutamyl transferase

4 48 Mean difference (IV, fixed, 95% CI)

-61.58 (-122.80 to -0.35) 0.05

immunoglobulin M 5 62 Mean difference (IV, fixed, 95% CI)

-38.45 (-64.38 to -12.51) 0.004

Alanine aminotransferase

4 61 Mean difference (IV, fixed, 95% CI)

-3.31 (-14.60 to 7.97) 0.56

Total bilirubin 4 61 Mean difference (IV, fixed, 95% CI)

-0.05 (-0.21 to 0.12) 0.58

Triglycerides 4 61 Mean difference (IV, fixed, 95% CI)

-0.41 (-0.82 to -0.01) 0.05

Abbreviations: M–H, Mantel–Haenszel; CI, confidence interval; IV, inverse-variance.

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UDCA and primary biliary cirrhosis

and fenofibrate was more effective than UDCA monotherapy

in decreasing serum ALP (MD: -90.44 IU/L; 95%

CI: -119.95 to -60.92; P,0.00001; Figure 5). There was no

significant heterogeneity (P=0.11; I2=45%).

PruritusFour trials,17,19–21 which included 59 patients, reported data

regarding this endpoint. Symptoms improved in one of

53 patients in the monotherapy groups and in one of 55

patients in the combination therapy groups. There was no sig-

nificant heterogeneity (P=0.77; I2=0%) and no significant dif-

ferences between the groups (OR: 0.39; 95% CI: 0.09–1.78;

P=0.23; Figure 6).

Gamma-glutamyl transferase (γ-GT) levelsFour trials,16,17,20,21 which included 48 patients, reported

data regarding this endpoint. The combination therapy

significantly decreased serum γ-GT compared with UDCA

monotherapy (MD: -61.58 IU/L; 95% CI: -122.80 to -0.35;

P=0.05; Figure 7). There was no significant heterogeneity

(P=0.38; I2=2%).

igM levelsFive trials,16–20 which included 62 patients, reported data

regarding this endpoint. The combination therapy signifi-

cantly decreased serum IgM levels compared with UDCA

monotherapy (MD: -38.45 mg/dL; 95% CI: -64.38 to

Dohmen et al16

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Figure 2 Risk of bias in the included studies.

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

Figure 3 Risk of bias graph: review of the authors’ judgments regarding each risk of bias item presented as percentages across all included studies.

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Zhang et al

–200 –100 0 100 200

–1,000 –500

0

20

40

60

80

100

0SE (log [OR])

OR

OR

SE (log [OR])

SE (MD)

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Figure 4 Funnel plots for the meta-analysis.Notes: (A) Symptoms of pruritus. (B) Alkaline phosphatase. (C) Immunoglobulin M. (D) Adverse events.Abbreviations: Se, standard error; OR, odds ratio; MD, mean difference.

UDCA COM

UDCA COM

Mean differenceStudy orsubgroup Mean SD Total Mean SD Total

WeightIV, fixed, 95% Cl

Mean differenceIV, fixed, 95% Cl

Dohmen et al16 12 90.5 9 98.1 95.5 9 11.8% –86.10 (–172.06 to –0.14)Han et al21 66 101 22 179.73 106.255 22 23.2% –113.73 (–174.99 to –52.47)Levy et al20 86 96 20 174 92 20 25.7% –88.00 (–146.27 to –29.73)Liberopoulos et al19 7 75.5 4 63 71.5 6 10.0% –56.00 (–149.53 to 37.53)Ohira et al17 32 110.5 7 275 120 7 6.0% –243.00 (–363.84 to –122.16)Walker et al18 62 89 16 110 87 16 23.4% –48.00 (–108.98 to 12.98)

–1,000 –500 5000 1,000

Total (95% Cl) 78 80 100.0% –90.44 (–119.95 to –60.92)

Heterogeneity: χ 2=9.08, df=5 (P=0.11); I 2=45%Test for overall effect: Z=6.01 (P<0.00001)

Figure 5 ALP levels in PBC patients treated with monotherapy versus COM.Abbreviations: ALP, alkaline phosphatase; UDCA, ursodeoxycholic acid; COM, combination therapy; SD, standard deviation; IV, inverse-variance; CI, confidence interval; df, degrees of freedom; PBC, primary biliary cirrhosis.

-12.51; P=0.004; Figure 8). There was no significant

heterogeneity (P=0.14; I2=42%).

ALT levelsFour trials,16,19–21 which included 61 patients, reported data

regarding this endpoint. The combination therapy compared

with monotherapy had no significant effect on serum ALT

levels (MD: -3.31 IU/L; 95% CI: -14.60 to 7.97; P=0.56;

Figure 9). There was no significant heterogeneity (P=0.99;

I2=0%).

Triglyceride levelsFour trials,16,19–21 which included 61 patients, reported

data regarding this endpoint. Combination therapy signifi-

cantly decreased triglyceride levels compared with UDCA

monotherapy (MD: -0.41 mg/dL; 95% CI: -0.82 to -0.01;

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UDCA and primary biliary cirrhosis

UDCA COM

Study orsubgroup Total

Odds ratioM–H, fixed, 95% Cl

Han et al21 22Levy et al20 20Liberopoulos et al19 4Ohira et al17

UDCAEvents

0010 7

COMEvents

1211

0.01 0.1 101 100

Total (95% Cl)Total events

531

Total

222067

5

55

Weight

24.8%41.3%10.1%23.8%

100.0%

Odds ratioM–H, fixed, 95% Cl

0.32 (0.01–8.25)0.18 (0.01–4.01)1.67 (0.07–37.73)0.29 (0.01–8.39)

0.39 (0.09–1.78)

Heterogeneity: χ 2=1.11, df=3 (P=0.77); I 2=0%Test for overall effect: Z=1.21 (P=0.23)

Figure 6 effects of monotherapy versus COM on pruritus in patients with PBC.Abbreviations: UDCA, ursodeoxycholic acid; COM, combination therapy; M–H, Mantel–Haenszel; CI, confidence interval; df, degrees of freedom; PBC, primary biliary cirrhosis.

UDCA COM

UDCA COM Mean differenceStudy orsubgroup Mean SD Total Mean SD Total

WeightIV, fixed, 95% Cl

Mean differenceIV, fixed, 95% Cl

Dohmen et al16 12 112 9 24.4 126.65 9 30.7% –12.40 (–122.86 to 98.06)Han et al21 110 201.42 22 278.38 277.38 22 18.3% –168.38 (–311.62 to –25.14)Liberopoulos et al19 8 98 4 42 112 6 21.7% –34.00 (–165.36 to 97.36)Ohira et al17 15 106 7 82 110 7 29.3% –67.00 (–180.17 to 46.17)

–100 –50 500 100

Total (95% Cl) 42 44 100.0% –61.58 (–122.80, –0.35)

Heterogeneity: χ 2=3.08, df=3 (P=0.38); I 2=2%Test for overall effect: Z=1.97 (P=0.05)

Figure 7 γ-GT levels in PBC patients treated with monotherapy versus COM.Abbreviations: UDCA, ursodeoxycholic acid; COM, combination therapy; SD, standard deviation; IV, inverse-variance; CI, confidence interval; df, degrees of freedom; γ-GT, gamma-glutamyl transferase; PBC, primary biliary cirrhosis.

UDCA COM

UDCA COM Mean differenceStudy orsubgroup Mean SD Total Mean SD Total

WeightIV, fixed, 95% Cl

Mean differenceIV, fixed, 95% Cl

Dohmen et al16 8 78.6 9 62.9 76.7 9 13.1% –54.90 (–126.65 to 16.85)Levy et al20 6 54 20 13 65 20 49.1% –7.00 (–44.04 to 30.04)Liberopoulos et al19 12 64 4 65 68 6 9.8% –53.00 (–136.03 to 30.03)Ohira et al17 102 78 7 218 87 7 9.0% –116.00 (–202.56 to –29.44)Walker et al18 76 82 16 140 89 16 19.1% –64.00 (–123.30 to –4.70)

–200 –100 1000 200

Total (95% Cl) 56 58 100.0% –38.45 (–64.38, –12.51)

Heterogeneity: χ 2=6.89, df=4 (P=0.14); I 2=42%Test for overall effect: Z=2.90 (P=0.004)

Figure 8 igM levels in PBC patients treated with monotherapy versus COM.Abbreviations: UDCA, ursodeoxycholic acid; COM, combination therapy; SD, standard deviation; IV, inverse-variance; CI, confidence interval; df, degrees of freedom; igM, immunoglobulin M; PBC, primary biliary cirrhosis.

UDCA COM

UDCA COM Mean differenceStudy orsubgroup Mean SD Total Mean SD Total

WeightIV, fixed, 95% Cl

Mean differenceIV, fixed, 95% Cl

Dohmen et al16 16 26 9 17.3 27.85 9 20.5% –1.30 (–26.19 to 23.59)Han et al21 16 41 22 21.24 46.075 22 19.2% –5.24 (–31.01 to 20.53)Levy et al20 8 28 20 10 30 20 39.4% –2.00 (–19.98 to 15.98)Liberopoulos et al19 2 13.5 4 8 26 6 20.9% –6.00 (–30.65 to 18.65)

–100 –50 500 100

Total (95% Cl) 55 57 100.0% –3.31 (–14.60, 7.97)

Heterogeneity: χ 2=0.11, df=3 (P=0.99); I 2=0%Test for overall effect: Z=0.58 (P=0.56)

Figure 9 ALT levels in PBC patients treated with monotherapy versus COM.Abbreviations: UDCA, ursodeoxycholic acid; COM, combination therapy; SD, standard deviation; IV, inverse-variance; CI, confidence interval; df, degrees of freedom; ALT, alanine aminotransferase; PBC, primary biliary cirrhosis.

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P=0.05; Figure 10). There was no significant heterogeneity

(P=0.81; I2=0%).

Total bilirubinFour trials,16,19–21 which included 61 patients, reported data

regarding this endpoint. There was no significant heterogene-

ity (P=0.18; I2=39%), and there were no significant differ-

ences between the groups (MD: -0.05 IU/L; 95% CI: -0.21

to 0.12; P=0.58; Figure 11).

Adverse eventsFive trials,16,17,19–21 which included 68 patients, reported data

regarding this endpoint. The incidence of adverse events

was one of 62 patients in the monotherapy groups and six of

64 patients in the combination therapy groups. There was no

significant heterogeneity (P=0.19; I2=41%), and there were

no significant differences between the groups (OR: 0.21;

95% CI: 0.03–1.25; P=0.09; Figure 12).

DiscussionPBC is a chronic autoimmune cholestatic liver disease, and

it can cause progressive liver fibrosis and eventually liver

failure.22,23 Fenofibrate and bezafibrate are members of the

fibrate class of hypolipidemic agents used clinically to treat

hypertriglyceridemia and mixed hyperlipidemia.24 Unlike

bezafibrate, fenofibrate is effective when taken only once a

day, as it has a longer half-life (18 hours), and it reduces total

cholesterol, similar to the effects of statin drugs.25 The activ-

ity of fenofibrate toward the PPAR is strong when compared

with that of bezafibrate.26

Although many observational studies have been pub-

lished, the mechanism by which fibrates reduce biochemical

markers of cholestasis, and whether fibrate therapy improves

survival in patients with these disorders, remain unclear.

There are some hypotheses that have been postulated:27–30

1) As PPAR-α agonists, fibrates improve the homeostasis

of lipid concentrations in serum through PPAR systems.

PPAR also acts to control inflammation through the regula-

tion of leukotriene B4 by suppressing nuclear factor-kappa

B systems and activating I-κB systems; fibrates then indi-

rectly affect inflammation. 2) Fibrates induce MDR3 gene

expression and upregulate P-glycoprotein expression, thus

facilitating the production of biliary phospholipids. This,

in turn, results in a reduction in the cytotoxic effects of

these phospholipids on the biliary epithelia. However, the

mechanism of action of UDCA is different. The main effects

UDCA COM

UDCA COM

Mean differenceIV, fixed, 95% Cl

Study orsubgroup Mean SD Total Mean SD Total

Weight Mean differenceIV, fixed, 95% Cl

Dohmen et al16 10 52 9 22.41 51.6 9 0.0% –12.41 (–60.27 to 35.45)Han et al21 0.2 0.65 22 0.61 0.72 22 100.0% –0.41 (–0.82 to –0.00)Levy et al20 16 50 20 24 52 20 0.0% –8.00 (–39.62 to 23.62)Liberopoulos et al19 14 48 4 37 51 6 0.0% –23.00 (–85.27 to 39.27)

–100 –50 500 100

Total (95% Cl) 55 57 100.0% –0.41 (–0.82 to –0.01)

Heterogeneity: χ 2=0.97, df=3 (P=0.81); I 2=0%Test for overall effect: Z=2.00 (P=0.05)

Figure 10 Triglyceride levels in PBC patients treated with monotherapy versus COM.Abbreviations: UDCA, ursodeoxycholic acid; COM, combination therapy; SD, standard deviation; IV, inverse-variance; CI, confidence interval; df, degrees of freedom; PBC, primary biliary cirrhosis.

UDCA COM

UDCA COM

Mean differenceIV, fixed, 95% Cl

Study orsubgroup Mean SD Total Mean SD Total

Weight Mean differenceIV, fixed, 95% Cl

Dohmen et al16 0.5 0.5 9 0.1 0.6 9 10.0% 0.40 (–0.11 to 0.91)Han et al21 8 24 22 10.01 25.26 22 0.0% –2.01 (–16.57 to –12.55)Levy et al20 0.3 0.5 20 0.5 0.2 20 47.0% –0.20 (–0.44 to 0.04)Liberopoulos et al19 0.08 0.21 4 0.06 0.17 6 43.0% 0.02 (–0.23 to 0.27)

–100 –50 500 100

Total (95% Cl) 55 57 100.0% –0.05 (–0.21 to 0.12)

Heterogeneity: χ 2=4.92, df=3 (P=0.18); I 2=39%Test for overall effect: Z=0.55 (P=0.58)

Figure 11 Total bilirubin levels in PBC patients treated with monotherapy versus COM.Abbreviations: UDCA, ursodeoxycholic acid; COM, combination therapy; SD, standard deviation; IV, inverse-variance; CI, confidence interval; df, degrees of freedom; PBC, primary biliary cirrhosis.

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UDCA and primary biliary cirrhosis

UDCA COM

Study orsubgroup

Odds ratioM–H, fixed, 95% Cl

Han et al21

Dohmen et al16

Levy et al20

Liberopoulos et al19

Ohira et al17

UDCAEvents

10

000

0.01 0.1 101 100

Total (95% Cl)Total events

Total

229

2047

621

COMEvents

10

500

6

Total

229

2067

64

Weight

15.1%84.9%

100.0%

Odds ratioM–H, fixed, 95% Cl

1.00 (0.06–17.07)Not estimated

0.07 (0.00–1.34)Not estimatedNot estimated

0.21 (0.03–1.25)

Heterogeneity: χ 2=1.71, df=1 (P=0.19); I 2=41%Test for overall effect: Z=1.71 (P=0.09)

Figure 12 Adverse events in PBC patients treated with monotherapy versus COM.Abbreviations: UDCA, ursodeoxycholic acid; COM, combination therapy; M–H, Mantel–Haenszel; CI, confidence interval; df, degrees of freedom; PBC, primary biliary cirrhosis.

of UDCA are to improve the balance between toxic and

nontoxic hydrophobic bile acids, and to activate the secre-

tion of bile acids, phospholipids, and cholesterol. Thus, it

does not overlap with the fibrate-affected systems, and the

combination therapy of fenofibrate and UDCA may be more

effective than UDCA monotherapy.

There are some limitations in this study. All six trials

included in this meta-analysis had a small sample size, with

an average of 14 PBC patients, which means that there is less

chance of detecting a small, but true effect as statistically

significant.14 The risk of random error would be higher when

data are obtained from a small sample size; thus, sample sizes

need to be large enough in order to reduce the risk of random

error and increase the chance of observing a true intervention

effect.11,31,32 Also, we did not achieve pathological results

when comparing the histologic changes before and after

combination therapy. Thus, we would recommend larger

controlled multicenter studies to further evaluate the clinical

and laboratory outcomes of this combination therapy.

ConclusionIn summary, combination therapy with UDCA and fenofi-

brate provided satisfactory clinical outcomes, which may be

a promising alternative for PBC patients refractory to UDCA.

We suggest that more animal research about the pathogenesis

of autoimmune liver diseases needs to be done to develop

more specific and sensitive immunological parameters and

genetic diagnostic techniques,33–38 which would be significant

to the early diagnosis and prognostic evaluation of PBC.

AcknowledgmentsThis study was supported by the National Natural Science

Foundation of China (grant number: 81270515), the Chinese

Foundation for Hepatitis Prevention and Control (grant

numbers: WBN20100021 and CFHPC20131011), and the

Shanghai Municipal Health Bureau Foundation (grant num-

bers: 2011287 and 2012107).

Author contributionsAll of the authors conceived the study, performed the litera-

ture search, quality assessment and performed the statistical

analysis. All of the authors were involved in manuscript

writing and preparation. All of the authors have read and

approved of the final manuscript.

DisclosureThe authors report no conflicts of interest in this work.

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