PPAR agonists for the treatment of primary biliary cholangitis: Old and new tales

• Published in: Journal of translational autoimmunity (Online) Vol. 6; p. 100188
• Main Authors: Colapietro, Francesca, Gershwin, M. Eric, Lleo, Ana
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2023; Elsevier
• Subjects: Elafibranor; Fibrates; PPAR agonists; Primary biliary cholangitis; Review article; Saroglitazar; Seladelpar; UDCA; FF; PAR; FXR; FDA; RCT; PPAR agonists; ALP; LT; VAS; UDCA; HR; IgM; NRS; AEs; QoL; PBC; HDL; PPAR; AMA; LDL; ULN; UK; VRS; HSC; TLR; MDR3; CKD; AIH; OR; HCC; Seladelpar; IL-1β; NASH; OCA; BZF; PC; TNF-α; GGT; SAE; Primary biliary cholangitis; PH; Fibrates; Saroglitazar; Elafibranor; TGR; LT, Liver Transplant; PBC, Primary Biliary Cholangitis; MDR3, multidrug resistance protein 3; UK, United Kingdom; AEs, adverse events; FXR, Farnesoid X Receptor; NRS, Numerical Raing Scale; TNF-α, Tumor Necrosis Factor- α; IgM, Immunoglobulin M; PPAR, peroxisome proliferator-activated receptor; OCA, Obeticholic Acid; QoL, Quality of Life; BZF, Bezafibrate; SAE, Severe Adverse Event; ULN, upper limit of normal; TLR, Toll Like Receptor; RCT, randomized controlled trial; VRS, Verbal Rating Scale; IL-1β, Interleukin-1; VAS, Visual Analogue Scale; UDCA, ursodeoxycholic acid; CKD, chronic kidney disease; HR, Hazard Ratio; PC, phosphatidylcholine; HSC, Hepatic Stellate Cells; AMA, Antimitochondrial antibodies; NASH, Non Alcoholic Steato-Hepatits; ALP, Alkaline Phosphatase; FF, Fenofibrate; LDL, low-density- lipoprotein; GGT, γ-glutamil transferase; PAR, protease-activated receptors; FDA, Food and Drug; AIH, Autoimmune Hepatitis; PH, Portal Hypertension; TGR, transmembrane G protein-coupled receptor; HCC, Hepatocellular Carcinoma; HDL, high-density lipoprotein; OR, Odds Ratio
• ISSN: 2589-9090; 2589-9090
• DOI: 10.1016/j.jtauto.2023.100188

Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed. Areas covered. Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls. Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients. •Up to 40% of PBC patients display inadequate response to standard of care with UDCA.•Among new therapeutic targets under investigation in PBC, PPARs ligands present a very promising profile due to anti-inflammatory and metabolic effects.•PPARs improve symptoms and quality of life in PBC4. Safety issues on PPAR-agonists use needs further assessment, especially in patients with advanced fibrosis.