• Min Qin, Lingxi Chao, and Shiqun Liu.
• Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
• Medicine (Baltimore). 2025 Jan 10; 104 (2): e41061e41061.

BackgroundThis study evaluates the efficacy and safety of sitagliptin versus gliclazide, combined with metformin, in treatment-naive patients with type 2 diabetes mellitus (T2DM) and glucotoxicity.MethodsIn this single-center, randomized, controlled noninferiority trial, 129 treatment-naive patients with T2DM with glucotoxicity (fasting plasma glucose [FPG] ≥ 200 mg/dL and glycated hemoglobin ≥ 9.0%) were randomized to receive sitagliptin plus metformin (n = 66) or gliclazide plus metformin (n = 63) for 12 weeks. Sitagliptin and gliclazide were given for the first 4 weeks, followed by metformin monotherapy for 8 weeks. Efficacy end points included changes in glycemic control, body weight, and β-cell function at baseline, 4 weeks, and 12 weeks.ResultsAfter 12 weeks, mean glycated hemoglobin reductions were 4.03% in the sitagliptin group and 4.13% in the gliclazide group, with a mean difference of -0.097 (95% confidence interval, -0.648 to 0.453), confirming noninferiority. Both groups showed significant FPG reductions at 4 weeks (P < .05). The sitagliptin group achieved faster glycemic targets, greater FPG and body weight reductions, and higher rates of FPG < 6.1 mmol/L (26.2% vs 5.7%; P = .012). No significant differences were observed in β-cell function or hypoglycemia incidence (P > .05). Genetic analysis showed specific single-nucleotide polymorphisms affected drug efficacy: dipeptidyl peptidase-4 rs2909451 TT and rs4664443 GG genotypes showed lower efficacy with sitagliptin, while GLP1R rs3765467 AG and KCNJ11 rs2285676 CC genotypes responded better to sitagliptin.ConclusionSitagliptin combined with metformin is noninferior to gliclazide combined with metformin in treatment-naive patients with T2DM with glucotoxicity. Genetic polymorphisms significantly affect drug efficacy, highlighting the importance of personalized medicine. The sitagliptin group achieved glycemic targets more quickly and had greater weight reductions without increased adverse effects.Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.

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