Pharmacotherapy for adults with metabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH): a systematic review and network meta analysis.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) have risen substantially in prevalence over recent decades, driven by a growing global burden of obesity, diabetes mellitus, and other cardiometabolic risk factors. In response, researchers have intensified efforts to evaluate novel and re-purposed therapies that may prevent or reverse disease progression. Although several pharmacological therapies are under investigation, robust comparative evidence on their relative effectiveness and safety remains limited. We will therefore conduct a systematic review and network meta-analysis (SRNMA) of randomized controlled trials (RCTs) evaluating pharmacological therapies for adults with MASLD or MASH. Methods: We will search four electronic databases (Ovid MEDLINE, Embase, CINAHL and Cochrane CENTRAL) from inception to August 2025 without language and other restrictions. Eligible studies will include parallel-arm RCTs enrolling ≥10 adults per arm with MASLD or MASH; comparing any pharmacological therapy to standard care, no treatment, lifestyle modifications, placebo or alternative pharmacotherapies; and having a minimum follow-up duration of 12 weeks. Primary clinical outcomes are all-cause mortality, cardiovascular mortality, hospitalization, progression to cirrhosis, hepatic decompensation, hepatocellular carcinoma, and serious treatment-related adverse events. Surrogate outcomes include histological, imaging, biochemical, and metabolic markers of disease activity. Paired reviewers will independently screen identified hits for eligibility, extract data from eligible studies, and assess risk of bias using the Risk Of Bias instrument for Use in SysTematic reviews-for Randomised Controlled Trials (ROBUST-RCT). We will conduct separate NMAs for MASLD and MASH populations using a frequentist graph-theoretic random-effects model. Certainty of evidence will be assessed using GRADE. Subgroup and sensitivity analyses will explore effect modification by comorbidities and study quality.