Impact of PRKAA2 and LKB1 genetic variants on metabolic alterations in response to metformin–sulfonylurea therapy

Background Metformin-sulfonylurea combination is a widely prescribed as second-line therapy for type 2 diabetes mellitus (T2DM), yet patient responses vary due to individual genetic variation. These variations, particularly in AMP-activated protein kinase (AMPK) and its upstream regulator liver kinase B1 (LKB1), may contribute to differences in treatment response. This study investigated the association of PRKAA2(rs2746338) and LKB1(rs741765) polymorphisms with metformin-sulfonylurea response in T2DM patients.Methods We enrolled 193 T2DM patients on metformin-sulfonylurea therapy after obtaining written consent. Glycemic and lipid parameters were assessed at baseline and after 3 months. Genotyping was performed by PCR-RFLP and ARMS-PCR for PRKAA2(rs2746338) and LKB1(rs741765), respectively. Statistical analysis was conducted using SPSS v27.Results Genotype and allele distributions were not significantly different between responders and non-responders. Carriers of PRKAA2(rs2746338) AA and AG and LKB1(rs741765) CT genotypes showed greater FBG reduction (p = 0.028, p < 0.001, and p < 0.001 respectively). Additionally, PRKAA2(rs2746338) AG and LKB1(rs741765) CT genotypes showed significant improvements in PPG, HbA1c, triglycerides, and LDL (all p < 0.05).Conclusion We conclude that PRKAA2(rs2746338) and LKB1(rs741765) variants were linked to favorable glycemic and lipid changes, suggesting reduced cardiovascular risk in T2DM. These variants may serve as pharmacogenetic markers for personalized therapy, warranting validation in larger studies.