Empagliflozin Ameliorates Experimental Pulmonary Vascular Remodeling, but May Not Benefit Patients With Pulmonary Arterial Hypertension

BACKGROUND: Sodium glucose cotransporter 2 inhibitors may improve mitochondrial biogenesis and attenuate pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). We investigated the impact of empagliflozin in PAH. METHODS: Microvascular endothelial cells (MVECs) were collected from the lungs of control patients and patients with PAH, and the effects of empagliflozin on MVECs were evaluated. Subsequently, treatment effects of empagliflozin (300 mg/kg chow, n=12) or placebo (n=12) were evaluated in experimental PAH rats (SU5416 injection followed by 3weeks of hypoxia). In addition, we conducted a phase IIa proof-of-concept trial, EMPHOWER PoC (Feasibility Study of Empagliflozin as Treatment for Idiopathic Pulmonary Arterial Hypertension), to assess the feasibility of 12weeks of empagliflozin treatment in patients with PAH. RESULTS: In comparison to control MVECs, PAH MVECs showed increased protein expression of sodium glucose cotransporter 2. Empagliflozin enhanced expression of mitochondrial-encoded genes and respiration, while attenuating oxidative stress and proliferation of PAH MVECs. In SU5416 and hypoxia rats, chronic empagliflozin treatment reduced pulmonary vascular resistance and thickening of the intima of small pulmonary arteries. Finally, 8 patients diagnosed with idiopathic and heritable PAH were enrolled in EMPHOWER PoC. No discontinuation of empagliflozin during the study period or treatment-associated serious adverse events were observed. There were no changes in N-terminal pro-B-type natriuretic peptide, World Health Organization functional class, 6-minute walk distance, or emPHasis score; however, right ventricular ejection fraction slightly worsened (from 45%±10% to 38%±12%, P=0.031). CONCLUSIONS: Empagliflozin attenuates proliferation of PAH MVECs. Empagliflozin reduces pulmonary vascular remodeling in experimental PAH. While 12weeks of empagliflozin treatment was feasible in patients with idiopathic or hereditary PAH, we observed signs of right ventricular deterioration.