SGLT2 inhibitors modulate inflammation by altering macrophage metabolism and decreasing monocyte platelet aggregates 3256

Abstract Description Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are diabetes drugs that reduce cardiometabolic diseases in patients with and without diabetes through unclear mechanisms. SGLT2is also reduce inflammation in animals and in vitro. We hypothesized that SGLT2is reduce inflammation in humans as a mechanism of cardiometabolic benefit. In a pilot, we treated eight women with obesity and pre-diabetes with the SGLT2i empagliflozin (25 mg/day) and collected subcutaneous adipose and blood at baseline, 2 and 12 weeks of treatment. We performed single-cell RNA sequencing and computational metabolic modeling on immune cells. Baseline characteristics include age 61±6.1yrs, weight 93±16.9kg, and BMI 35.6±4kg/m². Empagliflozin upregulated genes involved in mitochondrial metabolism and glutathione synthesis, important in the oxidative stress response, in lipid-associated macrophages (LAMs; p < 0.001). We also found that empagliflozin reduced monocyte-platelet aggregates (MPAs) in blood (-2.9±2.1% [-5.0, -0.8], p = 0.018 at 2 weeks; -4.1±2.1 [-6.2, -1.9], p = 0.002] at 12 weeks). MPAs are key mediators of vascular inflammation in cardiovascular disease. In summary, we found that empagliflozin increases expression of genes associated with mitochondrial metabolism and oxidative stress in adipose LAMs and decreases circulating MPAs. These changes may contribute to the cardiometabolic benefits seen with these drugs. Future studies will validate above findings in an ongoing randomized trial. Topic Categories Immune Mechanisms of Human Disease (HUM)