Background <p>DPP-4 inhibitors are extensively used as oral anti-diabetic medicines. Individual reactions to DPP-4 inhibitors varied significantly, partly due to underlying genetic variation. Given that the glucagon-like peptide-1 receptor (GLP-1R) is involved in the mechanism of action of DPP-4 inhibitors, it has been proposed that a genetic variation of the GLP-1R gene, rs6923761, may influence reactions to DPP-4 inhibitors.</p> Objective <p>The study aims to see how the rs6923761 SNP in the GLP-1R gene affects glycemic outcomes in Iraqi type 2 diabetes patients using sitagliptin.</p> Methods <p>In a cross-sectional observational study, 80 type 2 diabetic patients taking 100 mg of sitagliptin orally for at least 6 months were invited to participate. Diabetes and socio-demographic information were collected. Participants’ fasting glucose, insulin, HOMA-IR, HbA1c, and serum creatinine levels were measured. DNA extraction, standard PCR amplification, and Sanger sequencing of PCR products were performed.</p> Results <p>This study found a significant difference in the distribution of the rs6923761 SNP between good and poor responders (<i>p</i>= 0.011), with the A-carrier genotype being more prevalent in patients with poor response. In addition, type 2 diabetics with the minor A allele had worse glycemic parameters and a less favorable response to sitagliptin than those with the wild genotype (GG).</p> Conclusion <p>The heterozygous GA and homozygous AA of rs6923761 significantly decreased the likelihood of being a responder to the DPP-4 inhibitor sitagliptin.</p> Graphical Abstract <p></p>