Hypoglycemia and Glycemic Control With Glyburide in Women With Gestational Diabetes and Genetic Variants of Cytochrome P450 2C9 and/or OATP1B3

Abstract

Glyburide is mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme and enters the liver via the transporter OATP1B3. The variants OATP1B3*4 (699 G>A; rs7311358) and CYP2C9*2 and *3 are known to have a significant influence on the hepatic uptake and metabolism of glyburide, with lower clearance than in the wild type. In an ancillary study of the INDAO trial, we selected 117 pregnant women with gestational diabetes treated by glyburide and assessed the role of the combined CYP2C9 and OATP1B3 genetic polymorphisms in hypoglycemia and glycemic control. Three groups were constituted: (1) the wild‐type genotype group (wild‐type allele genotype for both CYP2C9*1 and OATP1B3*1 (699G)), (2) the intermediate group (carriers of CYP2C9*2 allele or OATP1B3*4 (699G>A) heterozygous), and (3) the variant group (carriers of CYP2C9*3 allele and/or OATP1B3*4 (699G>A) homozygous variant). We found that the risk of hypoglycemia was significantly higher in the variant genotype at the second week of treatment: 20.0% (4/20) vs. 8.1% (3/37) in the intermediate group and 4.1% (2/49) in the wild‐type genotype group (P = 0.03). The last daily dose of glyburide during pregnancy was lower for patients in the variant genotype group: 4.7 mg (SD 3.5) vs. 8.7 mg (SD 5.7) in the wild‐type group and 5.7 mg (SD 3.7) in the intermediate group (P < 0.01). In conclusion, the no‐function variants CYP2C9*3 and OATP1B3*4 are associated with a higher risk of hypoglycemia and a lower dose of glyburide in women with gestational diabetes treated with glyburide, which is consistent with the pharmacokinetic roles of both CYP2C9 and OATP1B3.

Precision Gestational Diabetes Treatment: Systematic review and Meta-analyses

“…Importantly, there was a lack of data on other potential precision treatment biomarkers, with only two eligible low quality studies reporting maternal genetic and metabolomic findings 67,68 . In the non-pregnancy literature, efficacy of dietary interventions has been reported to differ for patients with distinct metabolic profiles, for example high fasting glucose vs high fasting insulin, or insulin resistance vs low insulin secretion [73][74][75] .…”

“…A further 2 eligible studies reported maternal genetic predictors of need for supplementary insulin after glyburide (n=117 participants) 67 and maternal lipidome responses to metformin and insulin (n=217 participants) 68 .…”

“…There was a paucity of data in examining other precision markers with only weak evidence that the maternal lipidome 68 or genetics 67 hold potential as precision markers of need for pharmacological treatment (Supplementary Table 1).…”

Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 1: Modulation of TRPM4

“…Studying the function in vivo is definitely more complicated, as whole animal models need to be used. These models complicate both the pharmacological and genetic approaches, as the compound must be added in a way that provides an effective concentration [12]. Furthermore, KD and/or overexpression might need to be performed in an organ-/tissue-specific manner [13,14].…”

Assessment of glibenclamide pharmacokinetics in poloxamer 407-induced hyperlipidemic rats

“…1 ) is an oral 2nd generation sulfonylurea, with a potent and sustained hypoglycemic impact, often prescribed to manage type 2 diabetes mellitus ( Ju et al, 2020 , Zou et al, 2020 ). Gb is also widely considered to treat gestational diabetes mellitus ( Affres et al, 2020 , Bouchghoul et al, 2020 , Shuster et al, 2020 ), Gb has been observed to accumulate in pancreatic beta cells after chronic use ( Hellman et al, 1984 ). These variables can lead to the extended action of the drug and cause hypoglycemia in certain circumstances.…”