Assessing the effects of naltrexone‐bupropion on hepatic steatosis and fibrosis in patients with T2DM and overweight or obesity: Insights from a placebo‐controlled trial

Abstract Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) is prevalent among individuals with overweight or obesity and type 2 diabetes (T2DM), increasing the risk for liver‐related and cardiovascular complications. Lifestyle changes to reduce body weight are the primary intervention to decrease the risk of MASLD and liver fibrosis. This study aimed to evaluate the impact of a pharmacological intervention with naltrexone/bupropion (NB) on hepatic steatosis and fibrosis risk in patients with T2DM using non‐invasive tests. Materials and Methods In this post hoc analysis of a 56‐week, randomized, double‐blind, placebo‐controlled trial 505 adults with T2DM and overweight or obesity were randomized to either NB or placebo (2:1), both combined with structured lifestyle counselling. Hepatic outcomes were measured using the Hepatic Steatosis Index (HSI), Metabolic Dysfunction‐Associated Fibrosis‐5 (MAF‐5) and Fibrosis‐4 (FIB‐4) indices. Changes in liver‐related indices were analysed by treatment arm and weight loss strata (<5%, ≥5%, ≥10%), and multivariable regression was used to identify predictors of hepatic improvement. Results At Week 56, the NB group achieved significantly greater body weight loss (−6.3 ± 7.2 kg vs. −2.5 ± 5.2 kg, p < 0.001). Lifestyle intervention with NB treatment compared with placebo significantly reduced HSI (−2.9 vs. −1.2, p < 0.001) and MAF‐5 (−0.80 vs. −0.31, p = 0.003), while FIB‐4 scores remained unchanged in both groups. The best improvements in HSI and MAF‐5 were observed in those achieving ≥5% or ≥ 10% weight loss compared with those with <5% (all p < 0.001). Weight change correlated strongly with HSI reduction ( r = 0.796, p < 0.001) and moderately with MAF‐5 ( r = 0.488, p < 0.001), but not with FIB‐4 ( r = 0.034, p = 0.590). Multiple regression analysis identified weight change as the strongest predictor of improvements in hepatic markers (HSI, MAF‐5, ALT and AST), with no significant contributions from other factors. Conclusion Weight loss was the key driver of hepatic improvements in patients with T2DM and overweight or obesity. Treatment with NB resulted in significantly greater weight reduction and significantly greater improvements in HSI and MAF‐5 compared with placebo, suggesting an added benefit for liver health.