Skip to main content

Research Repository

Advanced Search

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Dawed, Adem Y.; Mari, Andrea; Brown, Andrew; McDonald, Timothy J.; Li, Lin; Wang, Shuaicheng; Hong, Mun Gwan; Sharma, Sapna; Robertson, Neil R.; Mahajan, Anubha; Wang, Xuan; Walker, Mark; Gough, Stephen; Hart, Leen M.‘t; Zhou, Kaixin; Forgie, Ian; Ruetten, Hartmut; Pavo, Imre; Bhatnagar, Pallav; Jones, Angus G.; Pearson, Ewan R.; 't Hart, L. M.; Abdalla, M.; Adam, J.; Adamski, J.; Adragni, K.; Allin, K. H.; Arumugam, M.; Atabaki Pasdar, N.; Baltauss, T.; Banasik, K. B.; Baum, P.; Bell, J. D.; Bergstrom, M.; Beulens, J. W.; Bianzano, S.; Bizzotto, R.; Bonneford, A.; Brorsson, C. A.B.; Brown, A. A.; Brunak, S. B.; Cabrelli, L.; Caiazzo, R.; Canouil, M.; Dale, M.; Davtian, D.; De Masi, F. M.; de Preville, N.; Dekkers, K. F.; Dermitzakis, E. T.; Deshmukh, H. A.; Dings, C.; Donnelly, L.; Dutta, A.; Ehrhardt, B.; Elders, P. J.M.; Engel Thomas, C. E.T.; Engelbrechtsen, L.; Eriksen, R. G.; Eriksen, R. E.; Fan, Y.; Fernandez, J.; Ferrer, J.; Fitipaldi, H.; Forman, A.; Franks, P. W.; Frau, F.; F...


Adem Y. Dawed

Andrea Mari

Andrew Brown

Timothy J. McDonald

Lin Li

Shuaicheng Wang

Mun Gwan Hong

Sapna Sharma

Neil R. Robertson

Anubha Mahajan

Xuan Wang

Stephen Gough

Leen M.‘t Hart

Kaixin Zhou

Ian Forgie

Hartmut Ruetten

Imre Pavo

Pallav Bhatnagar

Angus G. Jones

Ewan R. Pearson

L. M. 't Hart

M. Abdalla

J. Adam

J. Adamski

K. Adragni

K. H. Allin

M. Arumugam

N. Atabaki Pasdar

T. Baltauss

K. B. Banasik

P. Baum

J. D. Bell

M. Bergstrom

J. W. Beulens

S. Bianzano

R. Bizzotto

A. Bonneford

C. A.B. Brorsson

A. A. Brown

S. B. Brunak

L. Cabrelli

R. Caiazzo

M. Canouil

M. Dale

D. Davtian

F. M. De Masi

N. de Preville

K. F. Dekkers

E. T. Dermitzakis

C. Dings

L. Donnelly

A. Dutta

B. Ehrhardt

P. J.M. Elders

C. E.T. Engel Thomas

L. Engelbrechtsen

R. G. Eriksen

R. E. Eriksen

Y. Fan

J. Fernandez

J. Ferrer

H. Fitipaldi

A. Forman

P. W. Franks

F. Frau

A. Fritsche

P. Froguel

G. Frost

J. Gassenhuber

G. N. Giordano

T. Giorgino

S. Gough

U. Graefe-Mody

H. Grallert

R. Grempler

L. Groeneveld

L. Groop

V. G. Gudmundsdóttir

R. G. Gupta

M. Haid

T. Hansen

T. H. Hansen

A. T. Hattersley

R. S. Haussler

A. J. Heggie

A. M. Hennige

A. V. Hill

R. W. Holl

M. G. Hong

M. Hudson

B. Jablonka

C. Jennison

J. Jiao

J. J. Johansen

A. G. Jones

A. Jonsson


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. Funding: Innovative Medicines Initiative and the Wellcome Trust


Dawed, A. Y., Mari, A., Brown, A., McDonald, T. J., Li, L., Wang, S., …Jonsson, A. (2023). Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials. Lancet Diabetes and Endocrinology, 11(1), 33-41.

Journal Article Type Article
Acceptance Date Jan 1, 2023
Online Publication Date Dec 15, 2022
Publication Date Jan 1, 2023
Deposit Date Apr 6, 2023
Publicly Available Date Apr 13, 2023
Journal The Lancet Diabetes and Endocrinology
Print ISSN 2213-8587
Electronic ISSN 2213-8595
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 11
Issue 1
Pages 33-41
Public URL


You might also like

Downloadable Citations