Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics. Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption. Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Déclaration de conflit d'intérêts

Conflict of interest: F.Z. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer and, Cellprothera, other from CVCT, and Cardiorenal, outside the submitted work. J.P.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. J.B. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave and Vifor, outside the submitted work. G.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Medtronic, Vifor, Servier, Novartis, Bayer, Amgen and Boehringer Ingelheim, outside the submitted work. J.L.J., a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics, consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics, and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia and Takeda. M.S. and M.Z. are employees of Boehringer Ingelheim. M.S. is an employee of Elderbrook Solutions. S.J.P. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. S.A. reports personal fees from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Abbott Vascular, Vifor, personal fees from Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis and Servier, outside the submitted work. N.S. has consulted for Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharmaceuticals, Novo Nordisk, Novartis, Novartis, Sanofi and Pfizer and received grant support from Boehringer Ingelheim. S.D.A. reports grants and personal fees from Vifor Int. and Abbott Vascular, and personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor Int. Personal fees from Boehringer Ingelheim during the conduct of the study. M.P. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Abbvie, Actavis, Altimmune, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra, outside the submitted work.