(VP045) EMPAGLIFLOZIN IMPROVES VASCULAR REGENERATIVE CELL CONTENT IN PEOPLE WITHOUT DIABETES

Background: Originally conceived as an antihyperglycemic agent and then approved for lowering the risk of cardiovascular death in adults living with type 2 diabetes (T2D) and known cardiovascular disease, the sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin is now approved for reducing heart failure hospitalizations and is under review for decreasing the risk of kidney disease progression and cardiovascular death in adults with chronic kidney disease. We previously reported that empagliflozin increases the pool of blood vessel regenerative early myeloid and monocytic progenitor cells in people living with T2D and coronary artery disease. In the current work, we examined the effect of empagliflozin on the vascular regenerative cell exhaustion profile of people without diabetes.

METHODS AND RESULTS: Peripheral blood from a subset of 61 participants from the randomized, controlled EMPA-HEART 2 CardioLink-7 trial, that enrolled people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, was collected at baseline and 6 months after empagliflozin or placebo assignment. Mononuclear cells were characterized with a novel, multi-parametric flow cytometry assay using high aldehyde dehydrogenase activity (ALDHhi) and lineage-restricted cell surface markers to identify progenitor cell subsets with previously documented vascular regenerative (VR) attributes. Blood samples from 33 and 28 individuals assigned to empagliflozin and placebo, respectively, were analyzed. At baseline, the overall frequencies of circulating primitive myeloid (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) progenitor cells were similar between the two groups. However, empagliflozin therapy led to (1) an increase in ALDHhiSSClowCD34+CD133+ cells (P < 0.05), a subset with potent pro-angiogenic function; (2) an increase in ALDHhiSSCmid monocytes with pro-arteriogenic M2-like (CD163+) polarization (P < 0.05), and (3) a decrease in ALDHhiSSCmid monocytes with pro-inflammatory M1-like (CD163-CD86+) polarization (P < 0.05).

Conclusion: Empagliflozin therapy for 6 months promoted the recovery of multiple circulating VR cell populations in people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling. These findings suggest that empagliflozin may confer cardiovascular benefit, in part, by augmenting vessel repair and regeneration mechanisms. The current findings are hypothesis-generating, and functional assays are ongoing to comprehensively evaluate the impact of empagliflozin on pro-angiogenic and pro-arteriogenic progenitor cell functions in this study population. Future studies with larger cohorts and longer durations of SGLT2 inhibitor exposure are warranted to determine if the cardiorenal protective effects of empagliflozin are associated with increases in VR cell content that can subsequently improve vessel repair.