Introduction

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct damage and cholestasis. While ursodeoxycholic acid (UDCA) is the first-line therapy, about 40% of patients have incomplete responses, necessitating alternative treatments.

Aims & Methods

This meta-analysis evaluates the efficacy and safety of novel oral anti-cholestatic agents for PBC, focusing on key biochemical and symptomatic outcomes. A systematic literature search was conducted across electronic databases. Eligible studies included randomized controlled, retrospective, and open-label trials investigating novel oral anti-cholestatic agents in PBC patients. Data on efficacy (e.g., alkaline phosphatase [ALP] reduction) and safety outcomes were extracted and analyzed using meta-analytic techniques.

Results

Ten studies involving 878 patients were analyzed. Investigated therapies included seladelpar, fenofibrate, saroglitazar, bezafibrate, elafibranor, and budesonide. Novel anti-cholestatic agents significantly lowered ALP levels compared to controls (SMD -2.80; 95% CI [-3.56, -2.03]; p<0.00001), with saroglitazar showing the largest effect size (SMD -4.62; 95% CI [-5.54, -3.70]). Subgroup analysis revealed that fibrates (fenofibrate, bezafibrate, and saroglitazar) demonstrated the most consistent ALP reduction across studies (SMD -3.15; 95% CI [-3.89, -2.41]; p<0.00001).
In addition to ALP reduction, several agents showed improvements in other liver function tests. Bilirubin levels decreased significantly with novel therapies (MD -0.22 mg/dL; 95% CI [-0.35, -0.09]; p=0.001). Gamma-glutamyl transferase (GGT) also showed substantial reduction (SMD -1.98; 95% CI [-2.56, -1.40]; p<0.00001).
Symptomatic improvements were observed, particularly for pruritus. Bezafibrate and seladelpar demonstrated the most promising results, with mean reductions in visual analog scale scores for pruritus of 30% and 35%, respectively. Fatigue scores also improved, though to a lesser extent (SMD -0.42; 95% CI [-0.68, -0.16]; p=0.002).
Safety profiles were comparable to controls, with no significant increase in serious adverse events (OR 1.21; 95% CI [0.81, 1.83]; p=0.35). The most common adverse events were mild gastrointestinal symptoms (10-15% of patients) and transient elevations in creatinine (5-8% of patients). No significant hepatotoxicity was observed across the studies.

Conclusion

Novel oral anti-cholestatic agents show promise in managing PBC patients with suboptimal UDCA responses, demonstrating significant improvements in biochemical markers and some symptomatic relief. However, study heterogeneity, small sample sizes, and limited follow-up durations restrict direct comparisons and generalizability. Further research is needed to confirm long-term efficacy and safety.

References

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