Abstract

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists 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-1 receptor agonist treatment. 

Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. 

Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. 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) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: 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.

Original languageEnglish
Pages (from-to)33-41
Number of pages9
JournalThe Lancet Diabetes and Endocrinology
Volume11
Issue number1
Early online date15 Dec 2022
DOIs
Publication statusPublished - 1 Jan 2023

Bibliographical note

Funding Information:
The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115317 (DIRECT), resources of which are composed of financial contribution from the EU's Seventh Framework Programme (FP7/2007-2013), and European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution. ERP was funded by a Wellcome Investigator award (102820/Z/13/Z). This publication is based on research using data from GSK that has been made available through secured access. GSK has not contributed to or approved, and is not in any way responsible for, the contents of this publication. We thank both GSK and ClinicalStudyDataRequest.com for providing us data and access. We would also like to thank the MetGen and MetGen Plus consortia for provision of summary level data for metformin and sulphonylurea response.

Data sharing
Summary level data that underlie the results reported in this article will be available upon request to the corresponding authors.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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