The following is a summary of the “Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomized controlled trials,” published in the January 2023 issue of Diabetes and Endocrinology by Dawed, et al.

GLP-1 receptor agonists are used to treat type 2 diabetes because of their beneficial effects on blood glucose levels, body weight, and cardiovascular health. Individual differences in response to and tolerance of GLP-1 receptor agonists account for their wide range of pros and cons. Biological insight into drug action and biomarkers to guide clinical decision-making can be gleaned from human pharmacogenomic studies of this inter-individual variation. Therefore, we determined whether any heritable factors could predict how well a patient would respond to treatment with a GLP-1 receptor agonist.

GLP-1 receptor agonist-treated adults (aged 18 years) with type 2 diabetes and baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and 2 randomized clinical trials were included in this genome-wide analysis (HARMONY phase 3 and AWARD). Around 6 months after initiating GLP-1 receptor agonists, the primary endpoint was a reduction in HbA1c. In addition, they performed a gene-based burden assay and a genome-wide association study after analyzing GLP1R variants. They considered 4,571 adults for our analysis; approximately 2,140 (47%) were female. Of the White European participants, 3,339 (73%) were, while 449 (10%) were Hispanic, 312 (7%) were American Indian or Alaska Native, and 471 (10%) were other. 

Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10-5). Low-frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10-8), largely driven by rs140226575G-A (Thr370Met; 25% [SE 0.06] or 27 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10-6), reduction with GLP-1 receptor agonists treatment. ARRB1 Thr370Met has a similar effect size in Hispanic and American Indian or Alaska Native populations, which is more common (6-11%) than in White European populations. About 4 percent of the population showed a 30% greater reduction in HbA1c when these 2 genes were combined, compared to the 9% who showed a worse response. This genome-wide pharmacogenomic analysis of GLP-1 receptor agonists reveals new biological and clinical insights. When genotype is routinely available when prescribing, people with ARRB1 variants may gain from earlier initiation of GLP-1 receptor agonists.