TY - JOUR
T1 - The influence of metformin treatment on the circulating proteome
AU - IMI-DIRECT
AU - IMI-RHAPSODY
AU - Connolly, Ben
AU - McCreight, Laura
AU - Slieker, Roderick C.
AU - Bedair, Khaled F.
AU - Donnelly, Louise
AU - de Klerk, Juliette A.
AU - Beulens, Joline W.J.
AU - Elders, Petra J.M.
AU - Bergström, Göran
AU - Hong, Mun Gwan
AU - Koivula, Robert W.
AU - Franks, Paul W.
AU - Schwenk, Jochen M.
AU - Gummesson, Anders
AU - Pearson, Ewan R.
AU - ‘t Hart, Leen M.
AU - Abdalla, Moustafa
AU - Adam, Jonathan
AU - Adamski, Jerzy
AU - Adragni, Kofi
AU - Allesøe, Rosa Lundbye L.
AU - Allin, Kristine H.
AU - Artati, Anna A.
AU - Arumugam, Manimozhiyan
AU - Atabaki Pasdar, Naeimeh
AU - Baltauss, Tania
AU - Banasik, Karina
AU - Barnett, Anna
AU - Baum, Patrick
AU - Bell, Jimmy D.
AU - Bianzano, Susanna
AU - Bizzotto, Roberto
AU - Bonnefond, Amelie
AU - Brorsson, Caroline Anna A.
AU - Brown, Andrew A.
AU - Brunak, Søren
AU - Cabrelli, Louise
AU - Caiazzo, Robert
AU - Cederberg, Henna
AU - Chabanova, Elizaveta
AU - Clos-Garcia, Marc
AU - Dale, Matilda
AU - Davtian, David
AU - Dawed, Adem Y.
AU - De Masi, Federico
AU - de Preville, Nathalie
AU - Dekkers, Koen F.
AU - Deshmukh, Harshal A.
AU - Dings, Christiane
AU - Thomas, Elizabeth Louise L.
N1 - Publisher Copyright:
© 2025 The Author(s)
PY - 2025/8
Y1 - 2025/8
N2 - Background: Metformin is one of the most used drugs worldwide. Given the increasing use of proteomics in trials, bioresources, and clinics, it is crucial to understand the influence of metformin on the levels of the circulating proteome. Methods: We analysed a combined longitudinal proteomics dataset from the IMPOCT, RAMP and S3WP-T2D clinical trials in 98 participants before and after metformin exposure. This discovery analysis contained 372 proteins measured by proximity extension assays (Olink). We followed up experiment–wise statistically significant findings in two cross-sectional cohorts of people with type 2 diabetes comparing metformin treated and untreated individuals: IMI-DIRECT (784 participants, 372 proteins, Olink) and IMI-RHAPSODY (1175 participants, 1195 proteins, SomaLogic). Findings: Overall, 23 protein analytes were robustly associated with exposure to metformin in the discovery and replication. This includes 11 protein-metformin associations that replicated in both replication sets and platforms (REG4, GDF15, REG1A, t-PA, TFF3, CDH5, CNTN1, OMD, NOTCH3, THBS4 and CD93), with the remaining 12 protein-metformin associations replicated using the Olink platform (EPCAM, SPINK1, SAA-4, COMP, ITGB2, ADGRG2, FAM3C, MERTK, COL1A1, HAOX1, VCAN, TIMD4) but not measured on the SomaLogic platform. Gene-set enrichment analysis revealed that the metformin exposure was associated with intestinal associated proteins. Interpretation: These data highlight the need to account for exposure to metformin, and potentially other drugs, in proteomic studies and where protein biomarkers are used for clinical care. Funding: Innovative Medicines Initiative Joint Undertaking 2, under grant agreement no. 115881 (RHAPSODY) and the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution as well as the Swiss State Secretariat for Education Research' and Innovation (SERI), under contract no. 16.0097 (RHAPSODY).
AB - Background: Metformin is one of the most used drugs worldwide. Given the increasing use of proteomics in trials, bioresources, and clinics, it is crucial to understand the influence of metformin on the levels of the circulating proteome. Methods: We analysed a combined longitudinal proteomics dataset from the IMPOCT, RAMP and S3WP-T2D clinical trials in 98 participants before and after metformin exposure. This discovery analysis contained 372 proteins measured by proximity extension assays (Olink). We followed up experiment–wise statistically significant findings in two cross-sectional cohorts of people with type 2 diabetes comparing metformin treated and untreated individuals: IMI-DIRECT (784 participants, 372 proteins, Olink) and IMI-RHAPSODY (1175 participants, 1195 proteins, SomaLogic). Findings: Overall, 23 protein analytes were robustly associated with exposure to metformin in the discovery and replication. This includes 11 protein-metformin associations that replicated in both replication sets and platforms (REG4, GDF15, REG1A, t-PA, TFF3, CDH5, CNTN1, OMD, NOTCH3, THBS4 and CD93), with the remaining 12 protein-metformin associations replicated using the Olink platform (EPCAM, SPINK1, SAA-4, COMP, ITGB2, ADGRG2, FAM3C, MERTK, COL1A1, HAOX1, VCAN, TIMD4) but not measured on the SomaLogic platform. Gene-set enrichment analysis revealed that the metformin exposure was associated with intestinal associated proteins. Interpretation: These data highlight the need to account for exposure to metformin, and potentially other drugs, in proteomic studies and where protein biomarkers are used for clinical care. Funding: Innovative Medicines Initiative Joint Undertaking 2, under grant agreement no. 115881 (RHAPSODY) and the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution as well as the Swiss State Secretariat for Education Research' and Innovation (SERI), under contract no. 16.0097 (RHAPSODY).
KW - Biomarker
KW - Metformin
KW - Proteomics
KW - Type 2 diabetes
UR - https://www.scopus.com/pages/publications/105010956959
U2 - 10.1016/j.ebiom.2025.105859
DO - 10.1016/j.ebiom.2025.105859
M3 - Article
C2 - 40684475
AN - SCOPUS:105010956959
SN - 2352-3964
VL - 118
JO - EBioMedicine
JF - EBioMedicine
M1 - 105859
ER -
