Longitudinal assessment of SNPs rs72552763 and rs622342 in SLC22A1 over HbA1c control among Mexican-Mestizo diabetic type 2 patients

<b>Background:</b> In Mexico, 75% of diabetes mellitus type 2 (DMT2) patients are not in glycaemic control criteria (HbA1c<7%); this entails a significantly variable drug response. Amongst the factors influencing such variability, are genetics, more specifically, single nucleotide polymorphisms (SNPs). Three genes implied in metformin pharmacokinetics are <i>SLC22A1</i>, <i>SLC22A2</i>, and <i>SLC22A3</i>, which are polymorphic. While there have been cross-sectional studies on their SNPs impact over drug response, a longitudinal study would contribute valuable information on their effect over time. <b>Methods:</b> SNPs of <i>SLC22A1</i> (rs72552763, rs622342, rs12208357, rs2282143, rs594709, rs628031, and rs683369), <i>SLC22A2</i> (rs316019), and <i>SLC22A3</i> (rs2076828), were determined through PCR-TR. The clinical records of 69 patients undergoing metformin monotherapy were retrospectively assessed. Metformin is the first line treatment against DMT2. A level of HbA1c <7% (time 0) was considered as an inescapable inclusion criterion. The study's cases were those patients who reported HbA1c ≥ 7% (time1) after time 0 (t0). Kaplan-Meier curves including a Log-Rank test and a Cox multivariate analysis of proportional risks were performed. <b>Aim:</b> Determining clinical, biochemical, and genetic variables which may affect non-control (HbA1c ≥ 7%) survival time spans amongst DMT2 Mexican-Mestizo patients undergoing metformin monotherapy at <i>Hospital Regional de Alta Especialidad de Ixtapaluca</i> (HRAEI) between October 2013 and December 2023. <b>Results:</b> All 69 patients were monitored over a median period of 642 days (273-1,134). A comparison between time 0 and time 1 (t1) revealed differences in weight (<i>p</i> = 0.036), metformin dose mg/kg/day (<i>p</i> = 0.003), plasmatic glucose mg/dL (<i>p</i> = 0.048), and HbA1c (<i>p</i> < 0.001). The median non-control survival rate was different across the 3 genotypes of rs62552763 in <i>SLC22A1</i> (<i>p</i> = 0.0034) and the dominant genotypic model GAT/GAT vs. GAT/del + del/del (<i>p</i> = 0.009). There were differences between rs622342 genotypes as well (<i>p</i> = 0.041). In GAT/GAT the Cox model found HR = 0.407 (IC95%: 0.202-0.818, <i>p</i> = 0.011) in the univariate analysis and HR = 0.418 (IC95%: 0.204-0.856, <i>p</i> = 0.034) in the multivariate analysis, adjusted by initial metformin dose (mg/kg/day), initial weight (kg), and final metformin dose (mg/kg/day). Genotype A/A of rs622342 in <i>SLC22A1</i>, reported HR = 0.392 (IC95%: 0.169-0.910, <i>p</i> = 0.029) in the multivariate analysis as well. <b>Conclusion:</b> Among DMT2 Mexican-Mestizo patients undergoing metformin monotherapy the minor allele del in rs72552763 and the minor allele C in rs622342 reported a significantly shorter survival median respect to the wild type variant. Patients carrying del in rs72552763 or C in rs622342, both in <i>SLC22A1</i>, will reach non-control in less time with respect to other patients. Therefore these genotypes may constitute a therapeutic response biomarker for this population.