The influence of metformin treatment on the circulating proteome

TY - JOUR

T1 - The influence of metformin treatment on the circulating proteome

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 - Davtian, David

AU - Dawed, Adem Y.

AU - Deshmukh, Harshal A.

AU - Forgie, Ian M.

AU - Kennedy, Gwen

AU - Loftus, Heather

AU - McCarthy, Mark I.

AU - Palmer, Colin N.

AU - Thomas, Elizabeth Louise L.

AU - Viñuela, Ana

AU - White, Margaret W.

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 -