Comparative effectiveness of subcutaneous GLP-1 receptor agonists versus SGLT2 inhibitors on metabolic and hepatic outcomes in T2DM with MASLD: a propensity score-matched study

AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently coexists with type 2 diabetes mellitus (T2DM), complicating its management. In this population, we aimed to compare the effectiveness of subcutaneous GLP-1 receptor agonists (scGLP-1RA) to SGLT2 inhibitors (SGLT2i) on metabolic and hepatic parameters, while investigating the influence of GLP1R and PNPLA3 genetic variants on treatment response. METHODS: This retrospective study included patients with T2DM starting scGLP-1RA or SGLT2i, balanced through Propensity Score Matching (PSM) to account for baseline clinical differences. Clinical and biochemical data were compared at baseline and after one year of treatment. Genotyping was performed for PNPLA3 (rs738409) and GLP1R (rs761387, rs6923761) polymorphisms. Multivariable linear regression was used to identify independent predictors of HbA1c, BMI, and transaminase reduction. RESULTS: Both drug classes significantly improved glycemic control and BMI. However, scGLP-1RA demonstrated superior efficacy in HbA1c and BMI reduction compared to SGLT2i (β = -0.349, p = 0.001; β = -0.711, p = 0.045). In MASLD subgroups (baseline ALT > 35 U/L or hepatic steatosis), only scGLP-1RA led to a significant reduction in ALT levels (p = 0.02). Multivariable analysis identified the GLP1R rs761387 G allele as an independent predictor of a blunted glycemic response (β = -0.277, p = 0.018). CONCLUSIONS: In a real-world setting, scGLP-1RA showed higher potency than SGLT2i on metabolic and hepatic parameters. These findings support the preferential use of scGLP-1RA in patients with T2DM and MASLD and are consistent with current international recommendations. The association between GLP1R rs761387 variant and HbA1c reduction sheds light on the impact of this variant on treatment response. Further studies are needed to validate this genetic predictor in broader populations.