Bezafibrate Improves GLOBE and UK‐PBC Scores and Long‐Term Outcomes in Patients With Primary Biliary Cholangitis

Honda, Akira; Tanaka, Atsushi; Kaneko, Tetsuji; Komori, Atsumasa; Abe, Masanori; Inao, Mie; Namisaki, Tadashi; Hashimoto, Naoaki; Kawata, Kazuhito; Takahashi, Atsushi; Ninomiya, Masashi; Kang, Jae-Heon; Arakawa, Mie; Yamagiwa, Satoshi; Joshita, Satoru; Umemura, Takeji; Sato, Ken; Kaneko, Akira; Kikuchi, Kentaro; Itakura, Jun; Nomura, Takako; Kakisaka, Keisuke; Fujii, Hideki; Kawada, Norifumi; Takikawa, Yasuhiro; Masaki, Tsutomu; Ohira, Hiromasa; Mochida, Satoshi; Yoshiji, Hitoshi; Iimuro, Satoshi; Matsuzaki, Yasushi; Takikawa, Hajime

doi:10.1002/hep.30552

Cited by 87 publications

(78 citation statements)

References 47 publications

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“…There was a significant improvement of both UK‐PBC and GLOBE scores in the fibrate/UDCA group, but no improvement in the UDCA group. Recently, a Japanese retrospective study and the post hoc analysis of BEZURSO trial have shown improvement in both UK‐PBC and GLOBE scores after fibrate treatment, which is consistent with our study. Along with these studies, our current study implies that there may be a survival benefit from long‐term fibrate treatment in UDCA‐refractory PBC patients.…”

Section: Discussionsupporting

confidence: 92%

Additional fibrate treatment in UDCA‐refractory PBC patients

Chung

Lee

Kim

et al. 2019

Liver International

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Background & Aims There is no proven treatment for ursodeoxycholic acid (UDCA)‐refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long‐term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA‐refractory PBC. Methods Patients whose alkaline phosphatase (ALP) was not normalized with at least 13 mg/kg of UDCA treatment for >1 year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel‐Byar method. Results A total of 100 UDCA‐refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160 mg/d fenofibrate or 400 mg/d bezafibrate (the fibrate/UDCA group). During the follow‐up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR] = 5.00, 95% confidence interval = 2.87‐8.27, P < 0.001). Among 58 non‐cirrhotic patients (43 in the UDCA group and 15 in the fibrate/UDCA group), 19 patients (44.1%) in the UDCA group and none in the fibrate/UDCA group developed cirrhosis (HR = 0.12, P = 0.04). Hepatic deterioration (Child‐Pugh score increase or signs of decompensated cirrhosis) occurred in 17 patients (23.9%) of the UDCA group and none in the fibrate/UDCA group in which the difference was significant (HR = 0.12, P = 0.04). Conclusions In patients with UDCA‐refractory PBC, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis development and hepatic deterioration.

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Section: Discussionsupporting

confidence: 92%

Additional fibrate treatment in UDCA‐refractory PBC patients

Chung

Lee

Kim

et al. 2019

Liver International

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“…However, ADRs that include increased serum creatinine kinase levels and myalgia have been reported in a bezafibrate add‐on group . Another study from Japan did not mention the ADRs of bezafibrate add‐on as a study limitation . In the current investigation, no severe ADRs were recorded for pemafibrate.…”

Section: Discussionmentioning

confidence: 59%

“…11,12 An inadequate response to UDCA is associated with a high risk of disease progression. Bezafibrate addition to UDCA therapy, which recently showed a favorable biochemical response in refractory PBC, 13,14 has been recommended for UDCAunresponsive patients by the Japan Society of Hepatology (JSH) guidelines. 8 However, there remain patients who are resistant to alternative medicinal therapies; other options are needed to treat such cases in an effort to halt PBC progression.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis

Joshita

Umemura

Yamashita

et al. 2019

Hepatology Research

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Aim Fibrate addition to ursodeoxycholic acid (UDCA) therapy has been shown to improve both liver biochemistry and long‐term prognosis in primary biliary cholangitis (PBC) patients showing an incomplete biochemical response to UDCA alone. We herein describe the clinical outcome of seven cases of PBC that received the new selective peroxisome proliferator‐activated receptor α modulator, pemafibrate, in combination with UDCA therapy to investigate the biochemical and plasma lipid responses to the drug. Methods Of 124 initially enrolled PBC patients, 12 treated with UDCA alone and seven receiving UDCA plus bezafibrate showed alkaline phosphatase (ALP) levels above the upper limit of normal (330 U/L). Ultimately, seven patients with PBC and dyslipidemia who had agreed to biweekly visits at our hospital for UDCA plus pemafibrate combination therapy were retrospectively analyzed. Results In the four cases that switched from bezafibrate to pemafibrate, ALP became significantly decreased (0.031) and γ‐glutamyltransferase tended to decrease (0.063) over the 3 months following pemafibrate addition. Two patients showed a greater than 50% reduction in ALP. No remarkable differences were observed for plasma lipid levels, alanine aminotransferase, aspartate aminotransferase, or the liver fibrosis marker Mac‐2 binding protein glycosylation isomer between these time points. No adverse drug reactions were recorded. Conclusions Pemafibrate might be another option for PBC patients with an incomplete response to UDCA therapy.

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“…Co-administration of bezafibrate and UDCA to patients who had an incomplete response to UDCA treatment alone, significantly improved hepatic function and reduced liver fibrosis [202][203][204]. A retrospective cohort study correlated bezafibrate with UDCA combined therapy with reduced risk for liver transplantation and liver-related death [205]. Thus, the combined therapy may improve long-term prognosis of PBC patients.…”

Section: Primary Biliary Cholangitismentioning

confidence: 99%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

164

152

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

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Bezafibrate Improves GLOBE and UK‐PBC Scores and Long‐Term Outcomes in Patients With Primary Biliary Cholangitis

Cited by 87 publications

References 47 publications

Additional fibrate treatment in UDCA‐refractory PBC patients

Additional fibrate treatment in UDCA‐refractory PBC patients

Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

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