GLP1R and OCT1 variants modulate semaglutide and metformin response in type 2 diabetes

Background Large consortia link variants in SLC22A1 , SLC47A1 , and GLP1R to antidiabetic response, yet few data confirm these effects in small real-world cohorts. We tested whether three common polymorphisms translate into measurable 3-month metabolic changes. Methods Twenty-seven Bulgarian adults with type 2 diabetes [BMI ≥ 25 kg/m²; mean glycated hemoglobin (HbA1c): 8.3 ± 0.9%] received metformin XR 2000 mg ( n = 17) or oral semaglutide 14 mg ( n = 10). Sanger sequencing identified SLC22A1 rs628031, SLC47A1 rs2252281, and GLP1R rs6923761. Primary endpoints were 3-month changes (Δ) in weight and HbA1c; analysis of variance and ordinary least squares regression assessed genotype and treatment effects, as well as covariate-adjusted linear models of 3-month change (Δ). Results Semaglutide produced greater weight loss than metformin [–6.5 ± 3.6 vs. –1.6 ± 2.5 kg; 95% confidence interval (CI) –7.6 to –2.2; P = 0.001] and larger BMI reduction (–2.0 ± 1.2 vs. –0.3 ± 0.9 kg/m²; P = 0.001). At an exploratory 10% FDR, only OCT1 rs34130495 dosage was associated with high-density lipoprotein (HDL) change in metformin-treated participants ( β = +0.340 mmol/L per minor allele; P = 0.0026; q = 0.063; N = 16). GLP1R rs6923761 showed nominal trends for weight and BMI change in semaglutide users that did not survive FDR ( P ≈ 0.06–0.07; q ≈ 0.29; N = 10). Conclusion Semaglutide outperformed metformin for short-term weight loss. An HDL signal for OCT1 rs34130495 at an exploratory 10% FDR warrants replication. These hypothesis-generating data support the feasibility of genotype-guided studies in local clinical settings.