PT-003 - A LONGITUDINAL HBA1C MODEL IN PATIENTS WITH TYPE 2 DIABETES ELUCIDATES THE ROLE OF CODING VARIANT IN GLUCOSE TRANSPORTER GENE, SLC2A2, ON GLYCEMIC RESPONSE TO METFORMIN.

E. Yang¹, A. Riselli¹, F. Xu², S. Sridhar², M. Kvale¹, K. Giacomini¹, M. Hedderson², S. Yee¹, R. Savic¹; ¹University of California, San Francisco, ²Kaiser Permanente Northern California.

Background: Metformin remains the primary treatment for type 2 diabetes globally, while its effects vary significantly among patients, potentially leading to variations in clinical outcomes. Here, we conducted the largest population analysis of longitudinal HbA1c trajectories after metformin initiation in patients with type 2 diabetes. A prior genome-wide association study linked a genetic variant in the hepatic glucose transporter gene, SLC2A2, to metformin-induced changes in HbA1c. Building on that, we assessed the influence of the SLC2A2 genetic polymorphism on glycemic response to metformin.

Methods: A longitudinal HbA1c model was developed based on HbA1c data in type 2 diabetic patients under metformin monotherapy, which were from Kaiser Permanente Northern California’s electronic health record. The genotype of the coding variant rs5398 in SLC2A2 was extracted from genotyping arrays or imputed genotype information. The effect of SLC2A2 variant allele on metformin response was evaluated in the developed HbA1c model. The analysis was performed using NONMEM v.7.5.1.

Results: The analysis included 59,883 HbA1c measurements from 7,106 patients (Caucasian 71%, Black 10%, Asian 7%). The SLC2A2 rs5398 A allele frequency was 31.0%. HbA1c data including up to 6 years of measurements was best characterized by a turnover model with four mixture groups for metformin response (greater or less) and disease progression (high or low). Based on the assigned mixture groups, patients carrying the SLC2A2 rs5398 A allele were more likely to have greater metformin response and high disease progression compared to patients possessing the SLC2A2 rs5398 G allele. Patients with the SLC2A2 rs5398 A allele had a significantly greater metformin response, with a 13.9% increase in the GA group and a 22.7% increase in the AA group (P < 0.001), compared to patients homozygous for the G allele.

Conclusion: This study furnishes quantitative evidence establishing the SLC2A2 rs5398 A allele, a synonymous variant and the top liver expression quantitative trait loci, as a significant genetic determinant of enhanced metformin response in patients with type 2 diabetes. Our model can be further utilized to identify the sources of unexplained variability in metformin response and long-term disease progression, ultimately contributing to personalized therapy.