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

DIRECT consortium

doi:10.1016/S2213-8587(22)00340-0

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

DIRECT consortium

Research output: Contribution to journal › Article › peer-review

40 Citations (SciVal)

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 HbA_1c 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 HbA_1c 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 HbA_1c 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 HbA_1c 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 HbA_1c 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 HbA_1c 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 language	English
Pages (from-to)	33-41
Number of pages	9
Journal	The Lancet Diabetes and Endocrinology
Volume	11
Issue number	1
Early online date	15 Dec 2022
DOIs	https://doi.org/10.1016/S2213-8587(22)00340-0
Publication status	Published - 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.

Funding

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. 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.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Endocrinology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/S2213-8587(22)00340-0Licence: CC BY

Cite this

@article{968d71c47ccb460b893dabeed0bf32bd,

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

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.",

author = "{DIRECT consortium} and Dawed, {Adem Y.} and Andrea Mari and Andrew Brown and McDonald, {Timothy J.} and Lin Li and Shuaicheng Wang and Hong, {Mun Gwan} and Sapna Sharma and Robertson, {Neil R.} and Anubha Mahajan and Xuan Wang and Mark Walker and Stephen Gough and Hart, {Leen M.{\textquoteleft}t} and Kaixin Zhou and Ian Forgie and Hartmut Ruetten and Imre Pavo and Pallav Bhatnagar and Jones, {Angus G.} and Pearson, {Ewan R.} and {'t Hart}, {L. M.} and M. Abdalla and J. Adam and J. Adamski and K. Adragni and Allin, {K. H.} and M. Arumugam and {Atabaki Pasdar}, N. and T. Baltauss and Banasik, {K. B.} and P. Baum and Bell, {J. D.} and M. Bergstrom and Beulens, {J. W.} and Brown, {A. A.} and B. Ehrhardt and J. Fernandez and G. Frost and Stephen Gough and Hill, {A. V.} and Hong, {M. G.} and Christopher Jennison and Johansen, {J. J.} and Jones, {A. G.} and N. Shah and S. Sharma and Thomas, {M. K.} and White, {M. W.}",

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{\textquoteright} 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.",

year = "2023",

month = jan,

day = "1",

doi = "10.1016/S2213-8587(22)00340-0",

language = "English",

volume = "11",

pages = "33--41",

journal = "The Lancet Diabetes and Endocrinology",

issn = "2213-8587",

publisher = "Elsevier",

number = "1",

}

TY - JOUR

T1 - Pharmacogenomics of GLP-1 receptor agonists

T2 - a genome-wide analysis of observational data and large randomised controlled trials

AU - DIRECT consortium

AU - Dawed, Adem Y.

AU - Mari, Andrea

AU - Brown, Andrew

AU - McDonald, Timothy J.

AU - Li, Lin

AU - Wang, Shuaicheng

AU - Hong, Mun Gwan

AU - Sharma, Sapna

AU - Robertson, Neil R.

AU - Mahajan, Anubha

AU - Wang, Xuan

AU - Walker, Mark

AU - Gough, Stephen

AU - Hart, Leen M.‘t

AU - Zhou, Kaixin

AU - Forgie, Ian

AU - Ruetten, Hartmut

AU - Pavo, Imre

AU - Bhatnagar, Pallav

AU - Jones, Angus G.

AU - Pearson, Ewan R.

AU - 't Hart, L. M.

AU - Abdalla, M.

AU - Adam, J.

AU - Adamski, J.

AU - Adragni, K.

AU - Allin, K. H.

AU - Arumugam, M.

AU - Atabaki Pasdar, N.

AU - Baltauss, T.

AU - Banasik, K. B.

AU - Baum, P.

AU - Bell, J. D.

AU - Bergstrom, M.

AU - Beulens, J. W.

AU - Brown, A. A.

AU - Ehrhardt, B.

AU - Fernandez, J.

AU - Frost, G.

AU - Gough, Stephen

AU - Hill, A. V.

AU - Hong, M. G.

AU - Jennison, Christopher

AU - Johansen, J. J.

AU - Jones, A. G.

AU - Shah, N.

AU - Sharma, S.

AU - Thomas, M. K.

AU - White, M. W.

N1 - 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.

PY - 2023/1/1

Y1 - 2023/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85143970662&partnerID=8YFLogxK

U2 - 10.1016/S2213-8587(22)00340-0

DO - 10.1016/S2213-8587(22)00340-0

M3 - Article

C2 - 36528349

AN - SCOPUS:85143970662

SN - 2213-8587

VL - 11

SP - 33

EP - 41

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

IS - 1

ER -

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this