Wolin Hou1, Dandan Zhang, Wei Lu, Taishan Zheng, Lili Wan, Qing Li, Yuqian Bao, Fang Liu, Weiping Jia. 1. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai Key Laboratory of Diabetes, Shanghai, 200233, People's Republic of China.
Abstract
BACKGROUND AND OBJECTIVES: This study aimed to investigate how the organic cation transporter 2 nucleotide polymorphism at site 808 (G → T) affects metformin pharmacokinetics and its long-term anti-diabetic effect. METHODS: A total of 220 newly diagnosed type 2 diabetes patients takingoral metformin were recruited, genotyped and then divided into three groups by SLC22A2 genotypes (G/G, G/T, T/T). Nine patients in the GG genotype group, five patients in the GT genotype group and four patients in the TT genotype group were randomly selected for the metformin pharmacokinetic study. A randomized cohort study with 1-year follow-up was performed to clarify the metformin pharmacodynamics. RESULTS: After 1 year, the decrease in glycosylated hemoglobin (HbA1c) levels in subjects with the heterozygous variant genotype (GT) was significantly greater than in those with the wild-type homozygote (-2.2 % in GT vs. -1.1 % in GG, P < 0.05) after adjustment for baseline HbA1c levels, exercise and diet in each group. There were also differences in the pharmacokinetic parameters (95 % confidence interval) of metformin between these two groups [area under the concentration-time curve (AUC)0-∞ 19.7 (15.7-23.8) vs. 14.3 (11.7-16.9) μg h/L; renal clearance (CLr) 16.8 (8.5-25.0) vs. 34.1 (24.9-43.2) L/h; tubular secretion clearance (CLt) 8.1 (2.2-18.1) vs. 22.7 (15.5-29.8) L/h; all P < 0.05]. Multivariate analysis further revealed that the presence of T alleles and gender were independent influencing factors of urine excretion of metformin (P < 0.05). CONCLUSION: As well as gender, the glucose-lowering efficiency of metformin can be enhanced by SLC22A2 808G > T variants through the delay of its transportation and CLr in Chinese type 2 diabetes populations.
RCT Entities:
BACKGROUND AND OBJECTIVES: This study aimed to investigate how the organic cation transporter 2 nucleotide polymorphism at site 808 (G → T) affects metformin pharmacokinetics and its long-term anti-diabetic effect. METHODS: A total of 220 newly diagnosed type 2 diabetespatients taking oral metformin were recruited, genotyped and then divided into three groups by SLC22A2 genotypes (G/G, G/T, T/T). Nine patients in the GG genotype group, five patients in the GT genotype group and four patients in the TT genotype group were randomly selected for the metformin pharmacokinetic study. A randomized cohort study with 1-year follow-up was performed to clarify the metformin pharmacodynamics. RESULTS: After 1 year, the decrease in glycosylated hemoglobin (HbA1c) levels in subjects with the heterozygous variant genotype (GT) was significantly greater than in those with the wild-type homozygote (-2.2 % in GT vs. -1.1 % in GG, P < 0.05) after adjustment for baseline HbA1c levels, exercise and diet in each group. There were also differences in the pharmacokinetic parameters (95 % confidence interval) of metformin between these two groups [area under the concentration-time curve (AUC)0-∞ 19.7 (15.7-23.8) vs. 14.3 (11.7-16.9) μg h/L; renal clearance (CLr) 16.8 (8.5-25.0) vs. 34.1 (24.9-43.2) L/h; tubular secretion clearance (CLt) 8.1 (2.2-18.1) vs. 22.7 (15.5-29.8) L/h; all P < 0.05]. Multivariate analysis further revealed that the presence of T alleles and gender were independent influencing factors of urine excretion of metformin (P < 0.05). CONCLUSION: As well as gender, the glucose-lowering efficiency of metformin can be enhanced by SLC22A2 808G > T variants through the delay of its transportation and CLr in Chinese type 2 diabetes populations.
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