Zi Wang,1 Xiaoyu Li,1 Qing Xu,1 Yao Yao,1 Xiaoye Li,1 Hongmei Yan,2 Qianzhou Lv1 

1Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China

Correspondence: Qianzhou Lv, Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Email lv.qianzhou@zs-hospital.sh.cn Hongmei Yan, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Email yan.hongmei@zs-hospital.sh.cn

Background: The influence of genetic variants on the glucose-lowering effects of dapagliflozin remains unclear. This study aims to investigate the impact of polymorphisms in solute carrier family 5 member 2 (SLC5A2), uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9), solute carrier family 2 member 2 (SLC2A2) and member 4 (SLC2A4) on the anti-hyperglycemic effect of dapagliflozin in patients with type-2 diabetes mellitus (T2DM).
Methods: A total of 141 patients with T2DM were included in this prospective cohort study. Twenty-nine single nucleotide polymorphisms (SNPs) were selected and genotyped using the Sequenom MassArray platform or Sanger sequencing. Glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels were compared before and after the treatment with dapagliflozin.
Results: Among the 29 SNPs selected, 27 were successfully analyzed. After three months of dapagliflozin treatment, FBG levels were significantly reduced (8.00 mmol/L (5.45– 10.71) mmol/L vs 6.40 mmol/L (5.45– 9.20) mmol/L, p = 0.003) in patients with T2DM. However, there was no significant change in HbA1c levels (8.10% (6.88– 10.00)% vs 8.10% (6.83– 10.00)%, p = 0.452). Analysis of covariance showed that patients with the minor allele homozygote or heterozygote of rs12471030 (CT/TT), rs12988520 (AC/CC) or rs2602381 (TC/CC) had higher FBG levels compared to those with the major allele homozygote (p = 0.014, p = 0.024, and p = 0.044, respectively). After adjusting for baseline FBG level, age, gender, body mass index, use of insulin and use of metformin, three SNPs—rs12471030, rs12988520 and rs2602381—were associated with the anti-hyperglycemic effect of dapagliflozin. However, using a stringent significance threshold (p < 0.002 with Bonferroni correction), none of these selected SNPs were significantly associated with FBG and HbA1c levels after dapagliflozin treatment.
Conclusion: After adjusting for confounding variables, polymorphisms in SLC5A2, UGT1A9, SLC2A2 and SLC2A4 genes were not associated with the anti-hyperglycemic effect of dapagliflozin in the Chinese population.
Clinical Trial Registration Number: ChiCTR2200059645.

Keywords: dapagliflozin, fasting blood glucose, glycated hemoglobin, polymorphisms, UGT1A9