GLP-1RA therapy increases circulating vascular regenerative cell content in people living with type 2 diabetes.

Ehab Bakbak, Aishwarya Krishnaraj, David A Hess, Adrian Quan, Hwee Teoh, Subodh Verma, Brady Park, Fallon Dennis

Journal: American journal of physiology. Heart and circulatory physiology 2024;327(2):H370-H376

PMID: 38874618

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline-recommended therapies for the management of type 2 diabetes (T2D), atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. We previously observed in people living with T2D and coronary artery disease that circulating vascular regenerative (VR) progenitor cell content increased following 6-mo use of the SGLT2 inhibitor empagliflozin. In this post hoc subanalysis of the ORIGINS-RCE CardioLink-13 study (ClinicalTrials.gov Identifier NCT05253521), we analyzed the circulating VR progenitor cell content of 92 individuals living with T2D, among whom 20 were on a GLP-1RA, 42 were on an SGLT2 inhibitor but not a GLP-1RA, and 30 were on neither of these vascular protective therapies. In the GLP-1RA group, the mean absolute count of circulating VR progenitor cells defined by high aldehyde dehydrogenase (ALDH) activity (ALDHSSC) and VR progenitor cells further characterized by surface expression of the proangiogenic marker CD133 (ALDHSSCCD133) was higher than the group receiving neither a GLP-1RA nor an SGLT2 inhibitor ( = 0.02) and comparable with that in the SGLT2 inhibitor group ( = 0.25). The absolute count of proinflammatory, granulocyte-restricted precursor cells (ALDHSSC) was significantly lower in the GLP-1RA group compared with the group on neither therapy ( = 0.031). Augmented vessel repair initiated by VR cells with previously documented proangiogenic activity, alongside a reduction in systemic, granulocyte precursor-driven inflammation, may represent novel mechanisms responsible for the cardiovascular-metabolic benefits of GLP-1RA therapy. Prospective, randomized clinical trials are now warranted to establish the value of recovering circulating VR progenitor cell content with blood vessel regenerative functions. In this post hoc subanalysis of 92 individuals living with T2D and at high cardiovascular risk, the authors summarize the differences in circulating vascular regenerative (VR) progenitor cell content between those on GLP-1RA therapy, on SGLT2 inhibitor without GLP-1RA therapy, and on neither therapy. Those on GLP-1RA therapy demonstrated greater circulating VR progenitor cell content and reduced proinflammatory granulocyte precursor content. These results offer novel mechanistic insights into the cardiometabolic benefits associated with GLP-1RA therapy.

Address: Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.; Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.; Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.; Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.; Division of Endocrinology and Metabolism, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.; Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.; Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.; Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.; Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.; Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.; Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.; Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.; Molecular Medicine Research Laboratories, Robarts Research Institute, London, Ontario, Canada.; Division of Cardiac Surgery, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.; Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

DOI: 10.1152/ajpheart.00257.2024

Link outs

Free resources

Full Text Sources:

https://journals.physiology.org/doi/10.1152/ajphea...

Medical:

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-PROM1-2

MeSH Terms: Humans, Diabetes Mellitus, Type 2, Male, Female, Middle Aged, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor, Aged, Regeneration, Stem Cells, Incretins, AC133 Antigen, Hypoglycemic Agents, Treatment Outcome, Benzhydryl Compounds, Glucosides, Glucagon-Like Peptide-1 Receptor Agonists