Restoration of blood vessel regeneration in the era of combination SGLT2i and GLP-1RA therapy for diabetes and obesity

Abstract Ischaemic cardiovascular diseases, including peripheral and coronary artery disease, myocardial infarction, and stroke, remain major comorbidities for individuals with type 2 diabetes (T2D) and obesity. During cardiometabolic chronic disease (CMCD), hyperglycaemia and excess adiposity elevate oxidative stress and promote endothelial damage, alongside an imbalance in circulating pro-vascular progenitor cells that mediate vascular repair. Individuals with CMCD demonstrate pro-vascular ‘regenerative cell exhaustion’ (RCE) characterized by excess pro-inflammatory granulocyte precursor mobilization into the circulation, monocyte polarization towards pro-inflammatory vs. anti-inflammatory phenotype, and decreased pro-vascular progenitor cell content, impairing the capacity for vessel repair. Remarkably, targeted treatment with the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin in subjects with T2D and coronary artery disease, and gastric bypass surgery in subjects with severe obesity, has been shown to partially reverse these RCE phenotypes. SGLT2is and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the management of individuals with T2D and comorbid obesity. In addition to glucose-lowering action, both drug classes have been shown to induce weight loss and reduce mortality and adverse cardiovascular outcomes in landmark clinical trials. Furthermore, both drug families also act to reduce systemic oxidative stress through altered activity of overlapping oxidase and antioxidant pathways, providing a putative mechanism to augment circulating pro-vascular progenitor cell content. As SGLT2i and GLP-1RA combination therapies are emerging as a novel therapeutic opportunity for individuals with poorly controlled hyperglycaemia, potential additive effects in the reduction of oxidative stress may also enhance vascular repair and further reduce the ischaemic cardiovascular comorbidities associated with T2D and obesity.