Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials
Authors' conclusion
This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.
Study context
- Population
- Adults (aged ≥18 years) with T2D treated with GLP-1 RA with baseline HbA1c ≥7% (53 mmol/mol); 73% White European, 10% Hispanic, 7% American Indian or Alaskan Native; ≈47% women
- Participants
- 4,571 adults
- Primary endpoint
- HbA1c reduction after starting GLP-1 RA
- Follow-up
- 6 months
Methodological details4 prospective observational cohorts (DIRECT, PRIBA, PROMASTER, GoDARTS), 2 RCTs (HARMONY phase 3, AWARD), GLP1R candidate variants, genome-wide association study and gene-based burden tests
- 4 prospective observational cohorts (DIRECT, PRIBA, PROMASTER, GoDARTS)
- 2 RCTs (HARMONY phase 3, AWARD)
- GLP1R candidate variants, genome-wide association study and gene-based burden tests
Primary result
As reported in the abstract
HbA1c reduction with GLP-1 RA, by genetic variant
- GLP1R rs6923761G→A (Gly168Ser): lower HbA1c reduction per serine, 95% CI 0.04-0.12, p=6.0 × 10-5
- 0.08% or 0.9 mmol/mol
- Low frequency variants in ARRB1: optimal sequence kernel association test
- p=6.7 × 10-8
- ARRB1 rs140226575G→A (Thr370Met): greater HbA1c reduction per methionine, SE 0.06 (% scale) / SE 0.7 (mmol/mol), p=5.2 × 10-6
- 0.25% or 2.7 mmol/mol
Further findings
ARRB1 Thr370Met in Hispanic and American Indian or Alaska Native populations
- Similar effect size; higher variant frequency than in White European populations
- 6-11%
Combined GLP1R and ARRB1 genotype
- Greater HbA1c reduction in 4% of the population vs the 9% with the worse response
- 30%
Original publication
Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials. Lancet Diabetes Endocrinol. Published January 2023. doi:10.
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