The Framework of Precision Pharmacotherapy in Metabolic Dysfunction-Associated Steatohepatitis: A Network...

The challenge of precision treatment for metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized, for which comparative evidence remains limited. We performed a network meta-analysis of randomized controlled trials (RCTs) to examine the relative efficacy of pharmacotherapies in MASH. RCTs investigating pharmacologic treatments were systematically searched. The primary outcomes were fibrosis improvement of ≥ 1 stage without worsening of MASH and MASH resolution without worsening of fibrosis. Random-effects models were used to calculate the odds ratios (ORs) with 95% confidence interval. About 69 RCTs, including 16,180 patients with MASH, were included. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, thyroid hormone receptor-β (THR-β) agonists, incretins, and fibroblast growth factor-21 (FGF21) analogs were associated with improvements in both primary outcomes compared with placebo. Subgroup analyses suggested that treatment responses may vary across clinically relevant populations, such as those defined by cirrhosis status and type 2 diabetes (T2D). FGF21 analogs were associated with higher odds of MASH resolution in cirrhotic MASH patients compared with placebo (OR = 4.25, 95% CI = 1.97-9.17), whereas incretins showed favorable associations with MASH resolution in MASH patients without cirrhosis (OR 5.92, 95% CI = 3.46-10.15). Compared with placebo, SGLT2 inhibitors were associated with higher odds of fibrosis improvement in MASH patients with T2D (OR = 9.48, 95% CI = 2.43-37.00) as well as in MASH population without T2D (OR = 4.67, 95% CI = 1.30-16.79). Although the depth of subgroup evidence is currently limited, these findings provide a comparative framework to inform future stratified trial design and therapeutic development in MASH.