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

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce mortality in left heart failure. In pre-capillary pulmonary hypertension (PH), preclinical data suggest SGLT2i may improve right ventricular (RV) function through metabolic modulation, reduced perivascular inflammation, and inhibition of vascular remodeling through pulmonary arterial smooth muscle cell (PASMC) proliferation pathways. Purpose The purpose of the DAPAH trial was to evaluate whether the metabolic and cardioprotective benefits of SGLT2 inhibition observed in preclinical models and left heart failure translate into clinical efficacy for stable symptomatic patients (WHO function class 2 or 3) with Group 1 PAH or Group 4 CTEPH on background vasodilator therapy. 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 the change in Peak VO2 from baseline to week 12. Secondary endpoints included invasive hemodynamics, NT-proBNP, 6-minute walk distance (6MWD) and REVEAL Lite 2 scores. Treatment effects were analyzed using ANCOVA with adjustment for baseline values and WHO group stratification. All changes are reported as dapagliflozin vs. placebo (positive values indicate dapagliflozin superiority). The study was powered at 80% to detect a clinically relevant difference in peak VO2 of 2 mL/kg/min between groups. Results Baseline characteristics were balanced (n=52; mean age 66.5 years; 63% female; n=40 PAH, n=12 CTEPH). At 12 weeks, there was no significant difference in the primary endpoint of Peak VO2 (Adjusted Mean Difference: -0.67 mL/kg/min; 95% CI [-1.67, 0.33]; p=0.187). Individual trajectories of peak VO2 from baseline to follow up are shown in Figure 1. No significant treatment effects were observed for PVR (Adjusted Difference: 0.38 WU; p=0.25), 6MWD (Difference: 14.5 m; p=0.22), or NT-proBNP trajectory through week 4 and 12 (mixed model, interaction p=0.39). REVEAL Lite 2 scores showed a nominal reduction with dapagliflozin (-0.66; p=0.031). Dapagliflozin was safe and well-tolerated. Conclusion This is the first randomized study of SGLT2i in patients with pre-capillary pulmonary hypertension. In patients with stable PAH and CTEPH, 12 weeks of treatment with dapagliflozin was safe but did not significantly improve exercise capacity, hemodynamics, or functional status compared to placebo. These results suggest that the benefits of SGLT2 inhibition seen in left heart failure may not directly translate to the distinct pathophysiology of pre-capillary PH over a 12-week period.