Weight Loss as a Determinant of Histological Improvement in Metabolic Dysfunction-Associated Steatotic Liver Disease in People With Obesity. A Systematic Review and Network Meta-Analysis of Randomised Clinical Trials

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to obesity and insulin resistance, and sustained weight loss is associated with histological improvement. Whether different obesity-management modalities exert weight-independent hepatic effects remains uncertain. Methods: We conducted a systematic review and network meta-analysis (NMA) of randomised controlled trials evaluating lifestyle intervention, obesity management medications, endoscopic sleeve gastroplasty and metabolic and bariatric surgery in adults with BMI ≥ 27 kg/m2 and biopsy-confirmed MASH. The primary endpoint was MASH resolution without worsening of fibrosis. Study-level meta-regressions explored associations between total body weight loss (TBWL%) and histologic outcomes. Results: Six RCTs (n = 1379) met inclusion criteria. Tirzepatide, semaglutide, sleeve gastrectomy and Roux-en-Y gastric bypass were superior to placebo or standard care for achieving MASH resolution. Because the network was weakly connected and largely placebo-anchored, indirect estimates were imprecise. Across study arms, greater TBWL% was associated with higher rates of MASH resolution and fibrosis improvement; however, these associations were strongly influenced by a small number of high-weight-loss surgical arms. Conclusions: Weight loss was consistently associated with histologic improvement across available RCTs. However, the limited evidence base, sparse network structure and ecological nature of the meta-regression preclude causal inference. These findings should be considered exploratory and hypothesis-generating, underscoring the need for adequately powered head-to-head trials.