SGLT2 inhibitors reduce liver enzymes ALT and AST more significantly than GLP-1RAs in patients with NAFLD and T2D

Non-alcoholic fatty liver disease (NAFLD), now often termed Metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing global health concern, frequently co-occurring with Type 2 Diabetes (T2D). This comorbidity significantly increases the risk of liver fibrosis, cirrhosis, and cardiovascular events. Current standard-of-care for NAFLD often involves lifestyle modifications, but pharmacological interventions that directly improve liver health are crucial. Both sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown benefits in T2D and some positive effects on NAFLD, but their comparative efficacy on liver enzymes, key markers of liver injury, needed direct evaluation.

This multicenter posterior cohort study analyzed 705 subjects with Type 2 Diabetes (T2D) and Non-alcoholic fatty liver disease (NAFLD) enrolled between January 2020 and December 2024. Participants were categorized by their initial treatment: SGLT2 inhibitors (n=381) or GLP-1 receptor agonists (n=324). To ensure comparability, propensity score matching (PSM) was applied, yielding 243 well-matched pairs with balanced baseline characteristics. The primary endpoints were the differences in alanine aminotransferase (ΔALT) and aspartate aminotransferase (ΔAST) from baseline to 6 months. Changes in metabolic parameters were also assessed, and multivariate linear regression identified independent predictors of liver enzyme changes.

After propensity score matching, 243 well-matched pairs were analyzed. Treatment with SGLT2 inhibitors was associated with significantly greater reductions in liver enzymes compared to GLP-1 receptor agonists. Specifically, ΔALT was -10.55 ± 12.66 U/L for SGLT2is versus -7.28 ± 15.34 U/L for GLP-1RAs (p=0.011). Similarly, ΔAST showed reductions of -7.68 ± 10.07 U/L with SGLT2is compared to -5.18 ± 11.04 U/L with GLP-1RAs (p=0.010). No significant differences were observed between groups for changes in GGT, body weight, glycemic control, or lipid profiles. Multivariable regression analysis further confirmed that SGLT2 inhibitor treatment was independently associated with reductions in both ALT (β = -3.34, p=0.009) and AST (β = -2.32, p=0.016). Weight change was independently associated with AST reduction (β = 0.22, p=0.016) but not ALT reduction.

SGLT2 inhibitors demonstrated a 44.9% greater reduction in ALT and a 48.3% greater reduction in AST compared to GLP-1RAs over 6 months.