7199 Characterization of patients with type 2 diabetes who relied on sulfonylureas for glycemic control

Abstract

Abstract Disclosure: J. Jang: None. Y. Yang: None. H. Jang: None. S. Moon: None. S. Min: None. S. Lee: None. K. Park: None. H. Jung: None. Gliptins have substituted sulfonylureas (SU) in patients people with type 2 diabetes (T2D). However, in some patients, stopping SU was impossible due to abrupt glycemic deterioration. We have described this subset of patients as ‘SU-dependent patients’ by a retrospective study: they had maintained HbA1c ≤ 7% for ≥ 6 mo with a low-dose SU, while discontinuation of the SU unexpectedly increased HbA1c, and resumption of the SU recovered by resuming SU. This study aimed to prove the “SU-dependent patients” by a prospective design, and to analyze the clinical and genetic characteristics potentially associated with the response to SU. The study recruited 58 patients whose HbA1c levels were < 7.5% on oral anti-diabetics (OAD) including a low-dose SU (glimepiride-equivalent 2 mg/day). After obtaining informed consent, SU was replaced with another OAD, the participants were monitored for 20 wk. If the HbA1c levels deteriorated by ≥ 1.5% point, they were considered SU-dependent and resumed the previous SU (NCT04123587). In the SU-dependent patients, whole exome sequencing (WES) was performed to identify rare variants with a substantial effect size. Single nucleotide variants (SNV) were filtered using a target gene-based analysis focused on functional variants regarding insulin secretion and Asian-specific feature. Among the 58 enrolled participants, 3 withdrew their consent and resumed the SU, 5 met the criteria of SU-dependency and resumed the SU. Fifty persons did not meet the criteria for 20 wk, however, 7 of them resumed the SU thereafter. Lastly, 15 participants (26%) resumed SU within 1 year after the discontinuation, and their HbA1c returned to the baseline levels, which was comparable to that of those who did not resume SU. The 15 persons who required SU did not significantly differ from the others in the clinical features, including age, sex, BMI (24.0 vs 25.7 kg/m2, p=0.082) and the baseline HbA1c (6.9 vs 6.6%, p=0.057). According to the WES conducted on 22 SU-dependent patients (5 from the prospective study and 17 from the retrospective one), 103 SNV were filtered from 75 genes. The average allele frequency was 0.85 x 10-3 in global population, and 7.2 x 10-3 in East Asians. Notably, SNV from 9 genes were repeatedly found in both the separate studies. Several genes harbored stop-gained mutations which may induce downregulation of the gene expression, and one of them in GIPR has been validated by functional experiments (ENDO 2023, #SAT-062). Our study revealed that a portion of Korean patients with T2D are exceptionally susceptible to SU, and identified candidate variants associated with the response using WES. It may contribute to personalized therapy by screening those patients who would spend several years before taking SU, which have a low priority in general. Funding: KHIDI-AZ Diabetes Research Program, SNUH fund (0420190600), and NRF (2022R1A2C2004570) Presentation: 6/2/2024