Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling.

Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDH ^hi ) versus mature effector (ALDH ^low ) cell attributes. Samples from individuals assigned to empagliflozin ( n = 25) and placebo ( n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDH ^hi SSC ^low ), monocyte (ALDH ^hi SSC ^mid ), and granulocyte (ALDH ^hi SSC ^hi ) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDH ^hi SSC ^low CD133 ⁺ CD34 ⁺ proangiogenic cells ( P = 0.048), elevated ALDH ^hi SSC ^mid CD163 ⁺ regenerative monocyte precursors ( P = 0.012), and decreased ALDH ^hi SSC ^mid CD86 ⁺ CD163 ^- proinflammatory monocyte ( P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status. NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDH ^hi -CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDH ^hi -CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.