Association of SLC2A2 rs8192675 and SLC22A1 rs72552763 polymorphisms to metformin treatment outcomes in Ethiopian patients with type 2 diabetes mellitus
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Date
2024-04
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Addis Ababa University
Abstract
Metformin is recommended as the first-line oral glucose-lowering agent by most clinical
guidelines for people with type 2 diabetes mellitus (T2DM), although there are extensive
variations in the metformin treatment outcomes, related to the differences in individual
genetic profiles. Thus, in this study the association of SLC2A2 rs8192675 and SLC22A1
rs72552763 polymorphisms with metformin treatment response and SLC22A1 rs72552763
with metformin gastrointestinal intolerance were investigated in Ethiopian patients with
T2DM. Recently diagnosed patients with T2DM were enrolled at St Paul’s Hospital
Millennium Medical College. In the metformin treatment response study, a prospective
observational cohort was conducted on 86 patients receiving metformin treatment for < 1
year. The participants were classified into metformin responders and non-responders based
on a cut-off value of 0.5% reduction in HbA1c levels. Genotyping of rs8192675 and
rs72552763 was performed using TaqMan® Pre-Designed and Drug Metabolism Enzyme
SNP Genotyping Assay, respectively. The association of each one of the polymorphisms
with metformin response was assessed by measuring the change in HbA1c levels, while
the association of rs8192675 polymorphism with metformin response in diabetic
dyslipidemia was assessed by measuring the absolute change in lipid parameters as well as
HbA1c levels. On the other hand, in the metformin gastrointestinal intolerance study, a
retrospective study was conducted in 47 patients on metformin treatment for < 3 years. The
association of rs72552763 polymorphism to metformin-induced gastrointestinal
intolerance was assessed based on switching to a new class of glucose-lowering agents or
failure to up-titrate metformin dose due to gastrointestinal intolerance. Dyslipidemia was
defined in accordance with the adult treatment panel III. Chi-square, logistic regression,
student’s t-test, Mann-Whitney and Kruskal-Wallis statistical tests were used as applicable.
A p-value of less than 0.05 was taken as statistically significant. The minor allele frequency
iv
(MAF) of the C-allele in the T>C substitution SNP of SLC2A2 (rs8192675) was 66.2%
while the MAF of the 3-base pair (GAT) deletion mutation at rs72552763 was 9.4% in our
study population. Metformin response was significantly higher in deletion_GAT (del_G)
genotypes as compared to wild-type GAT_GAT (G_G) genotypes 3.675 95% CI (1.005–
13.436) (p = 0.049). Furthermore, a significantly lower median treatment HbA1 level was
found in del_G genotypes as compared to G_G genotypes 7% vs 8% (p=0.015). However,
the association of rs72552763 with metformin response was not replicated at the allele
level. Furthermore, the minor del_allele was significantly associated with good glycemic
control compared to the G_allele 3.206 95% CI (1.165–8.823) (p = 0.016), though not
replicated at del_G genotypes level. In contrast, the rs8192675 polymorphism showed no
significant association with metformin treatment response, glycemic control and
dyslipidemia. Likewise, no significant association was also observed between rs72552763
and metformin- induced gastrointestinal intolerance. The prevalence of dyslipidemia was
92.1 %. The prevalence of mixed atherogenic dyslipidemia, combined dyslipidemia and
isolated dyslipidemia was 37 (29.1 %), 34 (26.8 %), and 27 (21.3%), respectively. The
findings demonstrated that heterozygous carriers of the Met420del variants of SLC22A1
have an increased response to metformin. However, rs8192675 and rs72552763 genetic
polymorphisms were not associated with metformin treatment response and metformin-
induced gastrointestinal intolerance, respectively. The study also indicated a high
prevalence of dyslipidemia in people with T2DM, with atherogenic mixed dyslipidemia
being the commonest pattern.
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Keywords
Type 2 diabetes mellitus, Metformin Response, SLC2A2, rs8192675, diabetic dyslipidemia, Metformin intolerance, SLC22A1, rs72552763, Ethiopia