Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition and a leading cause of chronic liver disease worldwide. Several pharmacological agents are currently used in its clinical management. This meta-analysis assesses the comparative efficacy and safety profiles of three novel therapeutic agents-tirzepatide (a dual GIP/GLP-1 receptor agonist), lanifibranor (a pan-PPAR agonist), and resmetirom (a thyroid hormone receptor-β agonist)-in patients with MASLD/MASH.We systematically searched PubMed, Scopus, Web of Science, the Cochrane Library, and Embase from inception to December 31, 2024. Eligible randomized controlled trials (RCTs) were those that enrolled adults with MASLD/MASH and compared tirzepatide, lanifibranor, or resmetirom with placebo. Non-randomized trials, animal studies, trials using only imaging or biomarkers for diagnosis, studies without a placebo arm, and those including subjects aged < 18 years were excluded. Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool. Data synthesis was performed using RevMan 5.3. The protocol was registered with PROSPERO (CRD 42025637054). Five placebo-controlled trials met the inclusion criteria: one for tirzepatide (NCT04166773), one for lanifibranor (NCT04849728), and three for resmetirom (NCT03900429, NCT04197479, NCT04951219). The analysis included 2497 individuals (1112 [45%] male, mean age 55.6 years [SD 11.6], mean BMI 35.3 kg/m[SD 6.3], and 1385 [55%] with diabetes). All agents led to MASH resolution without worsening of fibrosis in a proportion of patients, with significant effects observed for tirzepatide and resmetirom. Tirzepatide (mean difference [MD] - 34.90% [95% CI: - 53.31 to - 16.49]) and resmetirom (MD - 31.45% [95% CI: - 35.93 to - 26.97]) significantly reduced hepatic steatosis as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Tirzepatide significantly reduced serum aminotransferase levels (ALT: MD - 30.90%, p < 0.00001; AST: MD - 20.71%, p < 0.00001). Although lanifibranor demonstrated improvements in lipid profiles (HDL-C + 9.87%, triglycerides - 26.90%), it did not achieve a statistically significant improvement in fibrosis (OR 1.26, p = 0.08). Gastrointestinal adverse events were frequently reported across all treatment arms. Tirzepatide and resmetirom significantly improved MASH resolution without worsening of fibrosis and reduced hepatic steatosis. All three agents lowered serum aminotransferase levels, while lanifibranor and resmetirom improved lipid profiles. Gastrointestinal adverse events were common, which may affect tolerability. Due to the limited number of trials for tirzepatide and lanifibranor, further large-scale studies are warranted to confirm their role in MASLD/MASH management. 2
