1479-P: Targeted Exome Sequencing for Long-Term Efficacy and Weight Loss of Dulaglutide in Type 2 Diabetes

Abstract

Introduction: There are individual differences in glucose lowering effect and weight reduction of dulaglutide, long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is expected that genetic variations in the mechanism of action of drugs are involved in treatment response to drugs. This study aims to investigate genetic variants associated with long-term efficacy and weight reduction of dulaglutide using targeted next-generation sequencing. Methods: We recruited 77 patients those who were treated with dulaglutide at least one year after switching from DPP-4 inhibitors (±basal insulin) due to uncontrolled type 2 diabetes (HbA1c ≥8.0%) at Korean VHS medical center between September 2018 and October 2019, and followed up until March 2021. The responder was defined by ≥1.0% HbA1c reduction at 24 weeks and achievement of HbA1c ≤7.5% at 52 weeks. We designed targeted exome panel based on the mechanism of drug action, and candidate genetic variants included known GLP-1 response related genes (n=10), gastric emptying related genes (n=18), pancreatic insulin secretion related genes (n=25). At the same time, we also performed whole exome sequencing. Results: During follow-up period of median 2.5±1.3 years, HbA1c was 9.7±1.3% at baseline and reduced to 8.2±1.5% at 6 months, and maintained thereafter up to 4 years. Glycemic response was associated with GNB3, SPARC, and COL4A1 genes. Weight loss (n=13) was more frequently observed in patients with minor G alleles of COL4A1 gene (OR 2.516, 95% CI 1.013, 6.249, p=0.047). Glycemic effectiveness of dulaglutide therapy is associated with genetic variants (OR 2.106, 95% CI 1.358, 3.265, p=0.001) as well as baseline HbA1c (OR 1.682, 95% CI 1.067, 2.650, p=0.025). Conclusion: The glucose lowering effect of dulaglutide, which exempts some patients from insulin therapy, has been associated with GNB3, SPARC, and COL4A1 variants. Polymorphisms in COL4A1 gene was associated with weight loss, although further studies are needed for validation. Disclosure Y.Kim: None. J.Seo: None. Funding VHS Medical Center (VHSMC20026)