Randomized Controlled Trial Evidence on Peroxisome Proliferator‐Activated Receptor (PPAR) Agonists in Primary Biliary Cholangitis: A Systematic Review and Meta‐Analysis

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Abstract
Purpose: Primary biliary cholangitis (PBC), an autoimmune liver disease, has the potential to advance to liver cirrhosis and result in fatality. Ursodeoxycholic acid (UDCA) is the first‐line treatment, while obeticholic acid (OCA) serves as a second‐line option because of moderate UDCA nonresponsiveness and cirrhosis‐related concerns. Additional therapies are necessary because of recent warnings regarding OCA usage in patients with cirrhosis. This study aimed to evaluate the efficacy and safety of peroxisome proliferator‐activated receptor (PPAR) agonists in PBC. Methods: We searched PubMed, Google Scholar, and the Cochrane Library until October 2023. We included all randomized controlled trials (RCTs) that studied the efficacy and safety of PPAR agonists in treating PBC. The primary outcome of interest was change in alkaline phosphatase (ALP) levels. In contrast, the secondary outcomes were changes in gamma‐glutamyl transferase (GGT), alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), triglyceride levels, and pruritis. We used a random‐effects model to calculate the risk ratio (RR) and standardized mean difference (SMD) with 95% CI. Results: A total of eight RCTs ( n = 515) were eligible for the analysis. Pooled data showed beneficial effects of PPAR agonists compared with placebo for change in ALP level (SMD = −2.81, 95 % CI = −4.10 to − 1.51; p < 0.0001, I 2 = 96 % ), GGT level (SMD = −1.29, 95 % CI = −2.09 to − 0.48; p = 0.002, I 2 = 92 % ), TBil level (SMD = −0.77, 95 % CI = −1.32 to − 0.22; p = 0.006, I 2 = 86 % ), and Tg level (SMD = −0.99, 95 % CI = −1.63 to − 0.35; p = 0.003, I 2 = 83 % ). There was no significant difference between PPAR agonists and placebo for ALT level (SMD = −0.93, 95 % CI = −1.94 to 0.08; p = 0.07, I 2 = 95 % ), AST level (SMD = −0.01, 95 % CI = −0.67 to 0.66; p = 0.99, I 2 = 91 % ), and pruritus (RR = 0.77, 95 % CI = 0.29 to 2.06; p = 0.60, I 2 = 34 % ). Conclusion: Our study found a superior efficacy of PPAR agonists compared with placebo for change in ALP, GGT, TBil, and Tg levels, highlighting the potentially beneficial effect of PPAR agonists on liver health.

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