Sodium-glucose cotransporter-2 inhibitor (SGLT2i) plus glucagon-like peptide type 1 receptor combination is more effective than SGLT2i plus dipeptidyl peptidase-4 inhibitor combination in treating obese mice metabolic dysfunction-associated steatotic liver disease (MASLD).

Background: Monotherapy to treat obesity-associated liver insult is limited.

Objectives: In diet-induced obese mice showing metabolic dysfunction-associated steatotic liver disease (MASLD), we aimed to compare the combinations of sodium-glucose cotransporter-2 inhibitor (SGLT2i, empagliflozin, E), dipeptidyl peptidase-4 inhibitor (DPP4i, linagliptin, L), and glucagon-like peptide type 1 receptor agonist (GLP1RA, dulaglutide, D).

Methods: Male 3-month-old C57BL/6J mice were fed for 12 weeks in a control (C, n = 10) or high-fat (HF, n = 30) diet. Then, mice were followed for three additional weeks: C, HF, HF E + L, and HF E + D (n = 10/group).

Results: HF versus C showed higher hepatic triacylglycerol (TAG, +82%), steatosis (+850%), glucose intolerance (+71%), insulin (+98%), and insulin resistance (+68%). Compared to the HF group, HF E + L showed lower glucose intolerance (-60%), insulin (-61%), insulin resistance (-46%), TAG (-61%), and steatosis (-58%), and HF E + D showed lower glucose intolerance (-71%), insulin (-58%), insulin resistance (-62%), TAG (-61%), and steatosis (-82%). The principal component analysis (PCA) placed the HF group and the HF E + D group on opposite sides, while the HF E + L group was placed between C and HF E + D.

Conclusion: PCA separated the groups considering the metabolism-related genes (glucose and lipid), mitochondrial biogenesis, and steatosis. The two pharmacological combinations showed beneficial effects in treating obesity and MASLD. However, the combination of SGLT2i and GLP1RA showed more potent beneficial effects on MASLD than SGLT2i and DPP4i and, therefore, should be the recommended combination.