Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French–Spanish experience

Lemoinne, Sara; Pares, A.; Reig, A.; Belkacem, Karima Ben; Fankem, Astrid Donald Kemgang; Gaouar, Farid; Poupon, Raoul; Housset, Chantal; Corpechot, Christophe; Chazouillères, Olivier

doi:10.1016/j.clinre.2018.06.009

Cited by 46 publications

(48 citation statements)

References 29 publications

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“…12 To date, there are no FDA-approved therapies for PSC, however, Lemoinne et al recently found improvement in cholestatic liver injury when patients with PSC were treated with the combination of Ursodiol and fibrates. 9 In our study, the total serum bile acid concentrations in control subjects were within the range reported for healthy adults. 10 In contrast, total bile acids in the Ursodiol monotherapy patients with PBC and PSC were significantly elevated but were reduced by 60% following combination with fenofibrate.…”

Section: Pro-inflammatory Cytokine Levelssupporting

confidence: 76%

“…Pilot studies with fenofibrate and clinical studies with bezafibrate in combination with Ursodiol reduced elevated serum liver enzymes during cholestasis for patients with PBC and a subtherapeutic response to Ursodiol (reviewed in refs. 8, 9, 14). Although bile acid toxicity is a hallmark of cholestatic liver diseases, effects of fibrates on bile acid metabolism in patients with cholestasis have not been fully reported.…”

Section: Discussionmentioning

confidence: 99%

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Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol

Ghonem

Auclair

Hemme

et al. 2020

Clin Pharma and Therapeutics

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Cholestatic liver diseases result in the hepatic retention of bile acids, causing subsequent liver toxicity. Peroxisome proliferator-activated receptor alpha (PPARα) regulates bile acid metabolism. In this retrospective observational study, we assessed the effects of fenofibrate (a PPARα agonist) therapy on bile acid metabolism when given to patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) who have had an incomplete response to Ursodiol monotherapy. When fenofibrate was added to Ursodiol therapy there was a significant reduction and in some cases normalization of serum alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase abnormalities, as well as pro-inflammatory cytokines. Combination fenofibrate treatment also reduced 7α-hydroxy-4cholesten-3-one (C4), the bile acid precursor, as well as total, primary, and conjugated bile acids. In addition, principal components analysis and heatmap analysis show that bile acid metabolites trended closer to that of healthy control subjects. These favorable effects of fenofibrate on bile acid metabolism may contribute to its beneficial clinical effects in patients with PBC and PSC experiencing a subtherapeutic response to Ursodiol monotherapy. Hepatic bile acid secretion and bile formation are essential functions of the mammalian liver. 1 Cholestatic liver diseases (i.e., primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)), result from an impairment or disruption of bile flow that causes an intracellular accumulation of toxic bile constituents, notably bile acids. Although critical for intestinal absorption of dietary cholesterol, bile acids are inherently cytotoxic, and, when accumulating in the liver, lead to inflammation, fibrosis, cirrhosis, and

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Section: Pro-inflammatory Cytokine Levelssupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol

Ghonem

Auclair

Hemme

et al. 2020

Clin Pharma and Therapeutics

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“…Patient-series indicate potential benefits from bezafibrate also in PSC [121,122], but to date no RCT has been performed. Similar reports pertain to the PPAR-a agonist fenofibrate [123]. For the PPAR-d agonist seladelpar, however, further trial activity in PSC (and NAFLD) has been suspended due to unexpected hepatic events (in the NAFLD arm).…”

Section: Fibrates and Ppar Activationmentioning

confidence: 67%

“…In a small study of eight PSC patients only published as an abstract, fenofibrate was reported to induce significant reduction in ALP and ALT but no change in Mayo risk score at 6 months [124]. The larger French-Spanish study reported that fibrates (fenofibrate 200 mg/day or bezafibrate 400 mg/day for at least 6 months) in addition to UDCA in patients with ALP [ 1.5 9 ULN on UDCA alone, reduced ALP and ALT by 41% and 39% respectively at 3 months, as well as reduced pruritus in 20 PSC patients, with 40% of patients reaching ALP \ 1.5 9 ULN [123]. A multicenter RCT regarding the effect of bezafibrate on cholestatic itch in PBC and PSC started in 2016 and is still ongoing [125].…”

Section: Fibrates and Ppar Activationmentioning

confidence: 99%

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

Vesterhus

Karlsen

2020

J Gastroenterol

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“…PPAR agonists are now established as useful "second-line therapy" for PBC patients with insufficient UDCA response as supported by the findings of the recently published BEZURSO trial as the largest RCT supporting a beneficial role for bezafibrate, a pan-PPAR agonist [5,42]. In contrast so far, there is only a limited number of studies in PSC patients [43][44][45] and most importantly no RCT. One promising prospective study with 12-week bezafibrate treatment in 11 PSC patients showed significant improvement of AP and ALT levels and an increase of these parameters after cessation of the study medication [44].…”

Section: Ppar Agonistsmentioning

confidence: 99%

Future Medical Treatment of PSC

Krones

Marschall

Fickert

2019

Curr Hepatology Rep

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Purpose of Review Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized by inflammation of intrahepatic and/or extrahepatic bile ducts leading to stricturing, biliary fibrosis, cirrhosis, and liver failure. PSC is highly associated with inflammatory bowel diseases (IBD) and bears significant risk for cholangiocellular and colorectal cancer. To date, no medical treatment has been proven in randomized controlled trials to improve transplant-free and overall patient survival. However, numerous innovative therapeutic concepts are currently tested in phase 2 to phase 3 clinical trials. Based on currently suggested pathogenetic mechanisms of PSC, such drugs target its immunopathogenesis and nuclear and membrane receptors regulating bile acid transport and metabolism, gut microbiota, and liver fibrosis. The purpose of this review is to discuss recent advances in targeted medical treatment options for PSC. Recent Findings While a large carefully designed phase 2b trial targeting fibrosis development in PSC failed (simtuzumab), another compound was promoted from phase 2a to phase 3 trial based on significant improvements of alkaline phosphatase (AP) and excellent safety profile (norursodeoxycholic acid, norUDCA). Summary Ongoing trials evaluate numerous different targets considered to be involved in PSC pathogenesis, with so far, no clear advantage of either compound. This must be attributed to the still unknown cause of PSC. It may turn out that only combination therapy may reach a breakthrough. The fact that numerous studies isochronally test the same drug or therapeutic concept like in the case of vancomycin or faecal microbiota transplantation (FMT) demands improved and coordinated international strategies for study design to develop more effective drug pipelines, which is one major target of the International PSC Study Group (IPSCSG).

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Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French–Spanish experience

Abstract: Combining UDCA with fibrates results in a significant biochemical improvement and pruritus decrease in PSC patients with incomplete response to UDCA. These results provide a rationale for larger and prospectively designed studies to establish the efficacy and safety of fibrates in PSC.

Cited by 46 publications

References 29 publications

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

Future Medical Treatment of PSC

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