Repurposing SGLT2 inhibitors in pulmonary arterial hypertension: A multi-center longitudinal pilot study demonstrating favorable effects on risk profile and ventricular coupling

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) confer broad cardiovascular benefits, but their role in pulmonary arterial hypertension (PAH) remains unclear.ObjectiveTo investigate the potential therapeutic role of SGLT2 inhibitors in PAH by evaluating their longitudinal association, including improvement in risk profile, functional status, and ventricular coupling.DesignMulticenter retrospective longitudinal pilot study.MethodsAdults with Group 1 PAH confirmed by right heart catheterization were followed and categorized by exposure to SGLT2 inhibitors. Time-to-clinical improvement was assessed using Cox proportional hazard models adjusted for age, gender, PAH etiology, pulmonary vascular resistance, and baseline risk profile. Two predefined endpoints were evaluated: (1) improvement by ≥ 1 category in a four-level risk stratification, and (2) achievement of a low-risk profile. Longitudinal changes in functional, biomarkers, and echocardiographic measures were analyzed using linear mixed-effects models adjusting for relevant covariates.ResultsAmong 83 patients with PAH, 43 received SGLT2 inhibitors. SGLT2 inhibitor use was independently associated with a higher rate of improvement by ≥ 1 risk category (hazard ratio [HR] 2.21, 95%CI 1.06-4.63; p = 0.034) and a higher likelihood of achieving a low risk profile (HR 2.62, 95% CI 1.02-6.76; p = 0.045). Longitudinal improvement was observed across the cohort in six-minute walk distance, Borg dyspnea score, B-type natriuretic peptide (BNP) levels, and composite risk score (all p <0.001), with SGLT2 inhibitor use associated with greater improvement in persistently lower log-BNP levels during follow-up (p = 0.007). Echocardiographic demonstrated reductions in pulmonary artery systolic pressure and improvement in RV-pulmonary artery coupling over time.ConclusionIn this real-world cohort, SGLT2 inhibitor use was associated with a higher likelihood of clinical improvement and achieving a low-risk profile in PAH, alongside favorable longitudinal changes in biomarkers and hemodynamics. Prospective randomized trials are warranted.