Dapagliflozin in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: The DAPAH randomized controlled trial.

BACKGROUND: SGLT2 inhibitors (SGLT2i) reduce mortality in left heart failure. In pulmonary arterial hypertension (PAH), preclinical data suggest SGLT2i improve right ventricular function through metabolic modulation and inhibition of vascular remodeling via smooth muscle cell pathways. The DAPAH trial evaluated whether the potential benefits of SGLT2 inhibition translate into clinical efficacy for symptomatic patients on background vasodilator therapy with either PAH or chronic thromboembolic pulmonary hypertension. METHODS: In this single-center, double-blind trial, 52 patients were randomized (1:1) to dapagliflozin 10 mg daily or placebo for 12 weeks. The primary endpoint was change in Peak VO2. Secondary endpoints included invasive hemodynamics, NT-proBNP, 6-minute walk distance (6MWD) and REVEAL Lite 2 scores. RESULTS: Baseline characteristics were balanced (n=52; mean age 66.5 years; 63% female; n=40 PAH, n=12 CTEPH). Fifty-one patients had complete data on Peak VO2. At 12 weeks, there was no significant difference in Peak VO2 (Adjusted Mean Difference: -0.67 mL/kg/min; 95% CI [-1.67, 0.33]; p=0.187). No significant treatment effects were observed for pulmonary vascular resistance (p=0.255), 6MWD (p=0.22), or NT-proBNP trajectory (interaction p=0.681). REVEAL Lite 2 scores showed a small reduction with dapagliflozin (-0.66; 95% CI [-1.25, -0.06]; p=0.031). Metabolic target engagement was evident from a significant reduction in serum urate (P-interaction < 0.001). Dapagliflozin was safe and well-tolerated. CONCLUSION: This randomized study of SGLT2i in pre-capillary PH showed that 12 weeks of dapagliflozin did not significantly improve exercise capacity, hemodynamics, or functional status compared to placebo. CLINICALTRIALS: gov (NCT05179356).