Effect of Empagliflozin on Whole Body, Cardiac, and Renal Sympathetic Outflows in Type 2 Diabetes

BACKGROUND: Sodium glucose co-transporter type 2 inhibitors improve cardiovascular outcomes in people with type 2 diabetes, though mechanisms by which this occurs remain unclear. OBJECTIVES: The purpose of this study was to evaluate empagliflozin's effect on whole body, cardiac, and renal sympathetic activity in people with type 2 diabetes and cardiovascular disease or high cardiovascular risk. METHODS: Adults with type 2 diabetes, randomized to 25 mg/day empagliflozin or placebo for 12 weeks, had norepinephrine (NE) spillover kinetics assessed during right heart catheterization. Endpoints were mean spillover rates at the end of treatment, adjusted for baseline (primary outcome whole-body spillover; secondary outcomes cardiac and renal spillovers). RESULTS: . Baseline NE spillover rates did not differ between the 2 groups. Twelve weeks of empagliflozin treatment did not significantly alter whole body, cardiac, or renal NE spillover rates compared to placebo (P > 0.30 for all comparisons). Empagliflozin significantly lowered pulmonary capillary wedge pressure (adjusted between-group difference: -1.8 mm Hg; 95% CI: -3.4 to -0.1), and glycated hemoglobin (-0.3%; 95% CI: -0.6 to -0.02), with trends toward lower diastolic blood pressure (-3.9 mm Hg; 95% CI: -7.7 to -0.1) and body weight (-2.6 kg; 95% CI: -3.8 to -1.4), with no impact on heart rate or N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: In this exploratory study, 12 weeks of empagliflozin treatment lowered cardiac filling pressures, but without the anticipated reflex increase in sympathetic nervous activity.