Background and AimThe therapeutic landscape for primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA) is rapidly evolving. With the recent advent of peroxisome proliferator-activated receptor (PPAR) agonists and ileal bile acid transporter (IBAT) inhibitors, establishing a comparative hierarchy is urgently needed. We aimed to evaluate the relative efficacy, symptomatic relief, and safety of all second-line PBC therapies.MethodsWe systematically searched PubMed, Embase, the Cochrane Library, and recent major hepatology congresses (EASL/AASLD) up to early 2026. We included randomized controlled trials (RCTs) with durations of 12–52 weeks evaluating PPAR agonists (bezafibrate, seladelpar, elafibranor, saroglitazar), farnesoid X receptor (FXR) agonists (obeticholic acid [OCA]), and IBAT inhibitors (linerixibat) against placebo/UDCA. A frequentist network meta-analysis (NMA) was performed. Outcomes included biochemical response (POISE criteria, reflecting standard 6- to 12-month clinical evaluation timelines), complete alkaline phosphatase (ALP) normalization (≤1.0x ULN), pruritus improvement (standardized mean difference [SMD]), and safety (serious adverse events [SAEs]). Treatments were ranked using P-scores.ResultsTwelve RCTs comprising 1,540 patients (therapy lengths 12–52 weeks) were included. For POISE criteria, bezafibrate ranked highest (Odds Ratio [OR] 77.44, 95% CI 8.96–669.51; P-score 0.89). However, for the stringent endpoint of complete ALP normalization, seladelpar 10 mg was superior (OR 44.12, 95% CI 2.65–733.27; P-score 0.79). Regarding symptomatic relief, seladelpar and linerixibat significantly alleviated pruritus, whereas OCA exacerbated it (SMD +0.50, 95% CI 0.35–0.65). Bivariate cluster analyses integrating efficacy, pruritus relief, and SAEs identified seladelpar 10 mg as possessing the most optimal risk-benefit profile. OCA exhibited the highest discontinuation-free tolerability but lacked robust ALP normalization and anti-pruritic benefits.ConclusionThe treatment paradigm for UDCA-refractory PBC is shifting towards individualized care. While bezafibrate offers unparalleled potency for POISE criteria, seladelpar 10 mg provides the most advantageous clinical balance, achieving deep biochemical remission (ALP normalization) alongside profound pruritus relief and a favorable safety profile.Systematic Review Registerationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=261351, identifier 420261351426.