Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes
dc.contributor.author | Cardoso, P | |
dc.contributor.author | Young, KG | |
dc.contributor.author | Nair, ATN | |
dc.contributor.author | Hopkins, R | |
dc.contributor.author | McGovern, AP | |
dc.contributor.author | Haider, E | |
dc.contributor.author | Karunaratne, P | |
dc.contributor.author | Donnelly, L | |
dc.contributor.author | Mateen, BA | |
dc.contributor.author | Sattar, A | |
dc.contributor.author | Holman, RR | |
dc.contributor.author | Bowden, J | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Pearson, ER | |
dc.contributor.author | Jones, AG | |
dc.contributor.author | Shields, BM | |
dc.contributor.author | McKinley, TJ | |
dc.contributor.author | Dennis, JM | |
dc.date.accessioned | 2024-01-11T15:57:10Z | |
dc.date.issued | 2024-02-22 | |
dc.date.updated | 2024-01-11T15:37:57Z | |
dc.description.abstract | Aims/hypothesis: A precision medicine approach in type 2 diabetes could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the recently developed Bayesian causal forest (BCF) method to develop and validate an individualised treatment selection algorithm for two major type 2 diabetes drug classes, SGLT2-inhibitors (SGLT2i) and GLP1-receptor agonists (GLP1-RA). Methods: We designed a predictive algorithm using BCF to estimate individual-level conditional average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA, based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England (Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2,252 people with type 2 diabetes from Scotland (SCI-Diabetes [Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were replicated in clinical trial data (HARMONY programme: Liraglutide [n=389] and Albiglutide [n=1,682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on glycaemic response on weight change, tolerability, and longer-term risk of new-onset microvascular complications, macrovascular complications, and adverse kidney events. Results: Model development identified marked heterogeneity in glycaemic response, with 4,787 (17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>2.4%) with SGLT2i over GLP1-RA and 5,551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1- RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an independent Scottish dataset identified clear differences in glycaemic outcomes between those predicted to benefit from each therapy. Sex, with females markedly more responsive to GLP1-RA, was identified as a major treatment effect modifier in both the UK observational datasets and in clinical trial data: HARMONY-7 Liraglutide (GLP1-RA): 4.4 (95%CI 2.2;6.3) mmol/mol greater response in females than males. Targeting the two therapies based on predicted glycaemic response was also associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications. Conclusions/interpretation: Precision medicine approaches can facilitate effective individualised treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical features for treatment selection could support low-cost deployment in many countries. | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | BHF-Turing Cardiovascular Data Science Award | en_GB |
dc.identifier.citation | Published online 22 February 2024 | en_GB |
dc.identifier.doi | 10.1007/s00125-024-06099-3 | |
dc.identifier.grantnumber | MR/N00633X/1 | en_GB |
dc.identifier.grantnumber | SP/19/6/34809 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/135001 | |
dc.identifier | ORCID: 0000-0002-9485-3236 (McKinley, Trevelyan) | |
dc.language.iso | en | en_GB |
dc.publisher | Springer | en_GB |
dc.relation.url | https://cprd.com/research-application | en_GB |
dc.relation.url | https://github.com/Exeter-Diabetes/CPRD-Pedro-SGLT2vsGLP1 | en_GB |
dc.rights | © The Author(s) 2024. Open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Bayesian non-parametric modelling | en_GB |
dc.subject | GLP1-receptor agonists | en_GB |
dc.subject | heterogeneous treatment effects | en_GB |
dc.subject | precision medicine | en_GB |
dc.subject | SGLT2-inhibitors | en_GB |
dc.subject | type 2 diabetes | en_GB |
dc.title | Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2024-01-11T15:57:10Z | |
dc.identifier.issn | 1432-0428 | |
dc.description | This is the final version. Available on open access from Springer via the DOI in this record | en_GB |
dc.description | Data availability statement: The UK routine clinical data analysed during the current study are available in the CPRD repository (CPRD; https://cprd.com/research-applications), but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. For re-using these data, an application must be made directly to CPRD. Data from Scotland are anonymized real-world medical records available by request through the Scottish Care Information-Diabetes Collaboration, Tayside & Fife, Scotland unit (https://www.sci0-diabetes.scot.nhs.uk/). Clinical trial data are not publicly available, for access an application must be made directly to GSK and www.ClinicalStudyDataRequest.com. | en_GB |
dc.description | Code availability statement: All R code used for the analysis is provided at https://github.com/Exeter-Diabetes/CPRD-Pedro-SGLT2vsGLP1 | en_GB |
dc.identifier.journal | Diabetologia | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dcterms.dateAccepted | 2024-01-04 | |
dcterms.dateSubmitted | 2023-10-17 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2024-01-04 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2024-01-11T15:38:00Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2024-02-28T15:21:31Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © The Author(s) 2024. Open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/