Pharmacogenetic Predictors of Metformin Response in Metabolic Syndrome and Type 2 Diabetes: Evidence from a Cohort Study in Kazakhstan

<b>Background:</b> Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are highly prevalent in Kazakhstan, with metformin as the first-line therapy. However, individual variability in treatment response and adverse effects necessitates pharmacogenetic evaluation. This study is aimed at assessing the clinical and biochemical efficacy of metformin in Kazakh patients with MetS, T2DM, or both and at identifying pharmacogenetic markers associated with treatment response and tolerability. <b>Methods:</b> A prospective cohort of 206 Kazakh patients (MetS: <i>n</i> = 44, MetS + T2DM: <i>n</i> = 123, T2DM: <i>n</i> = 39) was enrolled. Clinical, anthropometric, and biochemical parameters were measured at baseline and 3 months after metformin therapy. Ten SNPs previously implicated in metformin pharmacogenetics were genotyped. Associations with treatment efficacy (HbA1c reduction and glycemic goal achievement) and dyspeptic side effects were analyzed using ANOVA, logistic regression, and chi-square tests. <b>Results:</b> Metformin significantly improved weight, blood pressure, glucose, and lipid profiles across all groups. The SNPs rs2289669 (SLC47A1) and rs3792269 (CAPN10) were significantly associated with greater HbA1c reduction, glycemic goal achievement, and risk of dyspepsia. The rs11212617 variant showed a modest association with treatment efficacy. <b>Conclusions:</b> Metformin is effective across diverse metabolic phenotypes in the Kazakh population, with genetic variation contributing to interindividual differences in efficacy and tolerability. Pharmacogenetic profiling may improve personalized diabetes care.