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

BackgroundIn 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 insight 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. MethodsWe 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. FindingsVariation 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=6.0x10-05) and low frequency variants in ARRB1 (pskato=6.72x10-08), largely driven by rs140226575G>A (Thr370Met) (2.7mmol/mol greater HbA1c reduction per Methionine, p=5.2x10-06). A 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. InterpretationThis 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. FundingInnovative Medicines Initiative, Wellcome Trust