Summary
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 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.
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=6.0×10−05) and low frequency variants in ARRB1 (pskato=6.72×10−08), largely driven by rs140226575G>A (Thr370Met) (2.7mmol/mol greater HbA1c reduction per Methionine, p=5.2×10−06). 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.
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
Competing Interest Statement
ERP has received honoraria for speaking from Lilly and Sanofi. The authors have declared that no competing interests exist.
Funding Statement
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 European Unions 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)
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
IMI-DIRECT (DIabetes REsearCh on patient straTification): Approval for the study protocol was obtained from each of the regional research ethics review boards separately (Lund, Sweden: 20130312105459927, Copenhagen, Denmark: H-1-2012-166 and H-1-2012-100, Amsterdam, Netherlands: NL40099.029.12, Newcastle, Dundee and Exeter, UK: 12/NE/0132) and all participants provided written informed consent at enrolment. The research conformed to the ethical principles for medical research involving human participants outlined in the declaration of Helsinki. PRIBA (Predicting Response to Incretin Based Agents in Type 2 Diabetes): All the participants signed informed consent and the Southwest National Research Ethics committee approved the study. GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland): The study was approved by the Tayside Regional Ethics Committee and informed consent was obtained from all subjects. PROMASTER (PROspective Cohort MRC ABPI STratification and Extreme Response Mechanism in Diabetes): All the participants signed informed consent and the Southwest National Research Ethics committee approved the study. Harmony phase 3 trials: Approval is provided by an independent committee that manages access to clinical trials (https://www.clinicalstudydatarequest.com/). All study participants have provided informed consent. AWARD (Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes) trials:The protocol for this study was approved by an independent committee who manage access to clinical trials (https://www.clinicalstudydatarequest.com/). All study participants have provided informed consent. Harmony outcome trial: The protocol for this study was approved by an independent committee who manage access to clinical trials (https://www.clinicalstudydatarequest.com/). All study participants have provided informed consent.
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Data Availability
All data produced in the present study are available upon reasonable request to the authors