Pharmacogenomics of GLP-1 Receptor Agonists: A genome-wide analysis of observational data and large randomized controlled trials

Background: In the treatment of type 2 diabetes (T2D), GLP-1 Receptor Agonists (GLP-1RA) lower glucose levels and body weight, and have cardiovascular benefits. GLP-1RA efficacy and side effects vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insights into drug action and provide biomarkers to inform clinical decision-making. We, therefore, aimed to identify genetic variants associated with glycaemic response to GLP-1RA treatment. Methods: We studied HbA1c reduction at 6 months after starting GLP-1RA in 4,571 subjects with T2D from four prospective observational cohorts and two randomized clinical trials. We evaluated variants in GLP-1R, then undertook a genome-wide association study (GWAS) and gene-based burden test. Findings: Variation in HbA1c reduction with GLP-1RA treatment was associated with rs6923761G>A (Gly168Ser) in the GLP-1R (0.9 mmol/mol lower reduction in HbA1c per Serine, p=6.0e-05) and low-frequency variants in ARRB1 (pskato=6.72e-08), largely driven by rs140226575G>A (Thr370Met) (2.7mmol/mol greater HbA1c reduction per Methionine, p=5.2e-06). Similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian populations who have a higher frequency of this variant (6-11%) than in white populations. A genetic risk score derived from these two genes identified around 5% of the population who had a ~30% greater reduction in HbA1c than the ~43% of the population with the worse response. Interpretation: This first genome-wide pharmacogenomic study of GLP-1RA has provided novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants may benefit from earlier initiation of GLP-1RA. Funding: Innovative Medicines Initiative, Wellcome Trust