In people who are overweight or obese and have fatty liver disease, taking semaglutide for six months cut liver enzymes (ALT and AST) by about a third, helped them lose roughly 5% of their body weight, and lowered blood sugar (HbA1c) by a similar amount. These changes were much bigger than what was seen in a large group of similar people who didn’t use any anti‑obesity drugs.

In the phase 3 ESSENCE clinical trial, semaglutide demonstrated improved histological outcomes for patients with metabolic dysfunction-associated steatohepatitis (MASH) with moderate or advanced fibrosis. There is limited real-world evidence regarding the effect of semaglutide on liver enzymes and cardiometabolic markers in routine clinical practice. This retrospective cohort analysis used linked administrative claims and laboratory data from December 2020 to November 2024 and included patients with MASH and either overweight or obesity. We compared patients initiating semaglutide and those not using anti-obesity medications (comparator) in terms of changes in liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and other laboratory markers, including body weight, Hemoglobin A1c (HbA1c), and lipids. Absolute and percent change from baseline was reported for each outcome at 6&#x2009;months. Dependent within-group comparisons were computed using paired t-tests. To compare the change in ALT and AST between the comparison groups, difference in differences (DiD) estimates were calculated using generalized linear models adjusting for baseline characteristics. We identified 4,124 individuals initiating semaglutide and 168,284 individuals not using anti-obesity medications. Those receiving semaglutide were younger, more often female, and had fewer cardiometabolic comorbidities. Patients on semaglutide with available liver enzyme data experienced a 36% reduction in ALT (mean decrease: 19.4&#x2009;U/L; <i>p</i>&#x2009;&lt;&#x2009;0.01; <i>N</i>&#x2009;=&#x2009;27) and a 29% reduction in AST (mean decrease: 10.9&#x2009;U/L; <i>p</i>&#x2009;=&#x2009;0.01; <i>N</i>&#x2009;=&#x2009;29). The comparator group experienced a 7% reduction in ALT (mean decrease: 2.8&#x2009;U/L; <i>p</i>&#x2009;&lt;&#x2009;0.01; <i>N</i>&#x2009;=&#x2009;2,680) and a 5% reduction in AST (mean decrease: 1.7&#x2009;U/L; <i>p</i>&#x2009;&lt;&#x2009;0.01; <i>N</i>&#x2009;=&#x2009;2,699). Comparing the changes in ALT and AST between the two comparison groups, the semaglutide group showed a greater reduction in ALT (DiD: -15.9; 95% CI: -27.5 to -4.2; <i>p</i>&#x2009;=&#x2009;0.01) and trend towards greater reduction in AST (DiD: -8.7; 95% CI: -18.5 to 1.2; <i>p</i>&#x2009;=&#x2009;0.08). The semaglutide groups demonstrated a 5.3% reduction in body weight and a 5.4% decrease in Hemoglobin A1c (both <i>p</i>&#x2009;&lt;&#x2009;0.01), while the comparator groups showed a 0.3% weight loss (<i>p</i>&#x2009;&lt;&#x2009;0.01) and no change in Hemoglobin A1c. In patients with MASH and either overweight or obesity, semaglutide was associated with a clinically and statistically significant reduction in ALT after 6&#x2009;months of continuous use. Reductions in AST, weight, and HbA1c were also observed.