(VP054) GLP-1RA THERAPY IS ASSOCIATED WITH HIGHER VASCULAR REGENERATIVE CELL CONTENT AND LOWER INFLAMMATORY BURDEN IN PEOPLE LIVING WITH TYPE 2 DIABETES

Background: Cardiovascular outcome trials with glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated safety in people living with type 2 diabetes (T2D) with or at risk for cardiovascular disease. Many of the same trials have also revealed that GLP-1RAs significantly reduce cardiovascular events. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and GLP-1RAs are recommended, in many jurisdictions, for people living with T2D who have established cardiovascular disease. In a randomized trial of people living with T2D with coronary artery disease, we found that use of the SGLT2i empagliflozin for 6 months increased the frequency of circulating vascular regenerative (VR) cells that mediate vessel repair.

METHODS AND RESULTS: To determine if GLP-1RA therapy has a similar impact on VR cell subsets, we retrospectively analyzed data from an ongoing research program with adults >40 years of age living with T2D. Peripheral blood mononuclear cells were isolated and profiled with an established flow cytometry assay founded on the activity of the anti-oxidative enzyme aldehyde dehydrogenase (ALDH), which is highly expressed in progenitor cells (ALDHhi) compared to mature cells (ALDHlow). At baseline, 17 participants were on a GLP-1RA (9 of whom were also on an SGLT2i), 35 were on an SGLT2i but not a GLP-1RA, and 37 were not on any drugs from drug class. Mean age, weight, body mass index, glycated hemoglobin A1C, and duration of T2D were balanced across the groups. The frequency of ALDHhiSSClow cells (primitive hematopoietic and endothelial progenitor cells that coordinate angiogenesis) was higher in participants who were on a GLP-1RA (0.064%) or on an SGLT2i (0.049%) relative to those were on neither (0.036%; P< 0.05 for both). Although the frequencies of ALDHhiSSCmid monocyte subsets in all three groups were comparable, the frequency of pro-inflammatory ALDHhiSSChi granulocyte precursor cells in participants on a GLP-1RA (2.9%) was lower than that in individuals on an SGLT2i (4.3%; P=0.05) and that in those on neither (5.9%; P< 0.01). Expression of the vessel repair marker CD49d within the ALDHhiSSChi granulocyte subset was highest in individuals on a GLP-1RA (43%) relative to that in those on an SGLT2i (38%; p>0.05) and that in those on neither (31%; P< 0.05).

Conclusion: GLP-1RA therapy in people living with T2D was associated with greater VR progenitor cell content alongside lower inflammatory precursor burden. Augmented vessel repair supported by ALDHhiSSClow progenitor cells with previously documented pro-angiogenic secretory capacity may contribute to the cardiovascular benefits observed with GLP-1RA therapy in the setting of T2D.