Impact of Sodium-Glucose Co-Transporter-2 Inhibitors on Exercise-Induced Pulmonary Hypertension

Abstract

Patients with borderline pulmonary hypertension (PH) often experience shortness of breath or exacerbation of PH during exercise, known as exercise-induced PH. However, the pathogenesis of exercise-induced post-capillary PH (post-EIPH) and its treatment strategies remain unclear. Recent guidelines and consensus documents have highlighted the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in heart failure and chronic kidney disease (CKD). This study aimed to investigate the effects of SGLT2 inhibitors in patients with post-EIPH and CKD. This single-center prospective cohort study enroled 10 patients with CKD (age, 68 years; female, 60%) who exhibited post-EIPH between 1 July 2022 and 31 December 2023. Post-EIPH was defined as a pulmonary capillary wedge pressure (PCWP)/cardiac output (CO) slope > 2 and peak PCWP during exercise ≥ 25 mmHg measured by catheterization. The patients received SGLT2 inhibitor treatment for 6 months. At rest, patients with post-EIPH had borderline-PH (21.5 ± 1.8 mmHg), with preserved left and right ventricular function. SGLT2 inhibitors treatment significantly reduced the PCWP/CO slope during exercise (3.9 ± 1.2 vs. 2.4 ± 1.2 mmHg/L/min, p = 0.013) and improved the 6-min walking distance (489.9 ± 80.2 vs. 568.3 ± 91.9 m, p = 0.014). Magnetic resonance imaging revealed a lower left ventricular global longitudinal strain in patients with post-EIPH, which was increased by SGLT2 inhibitor treatment (-13.8 ± 2.0 vs. -17.3 ± 2.0%, p = 0.003). SGLT2 treatment inhibitors mitigated post-EIPH hemodynamic abnormalities and exercise intolerance, suggesting their potential as its therapeutic option.

Keywords: MRI; SGLT2 inhibitor; exercise induced pulmonary hypertension; right heart catheterization during exercise.

Figure 1

Haemodynamic at rest and during exercise before and after treatment with SGLT2 inhibitor. Paired t‐test were used for hemodynamic changes before and after treatment with SGLT2 inhibitor. CO, cardiac output; HR, heart rate; mAoP, mean aortic pressure; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RA, right atrium; SGLT2, sodium‐glucose cotransporter‐2.

Figure 2

Changes in mPAP/CO and PCWP slopes before and after treatment with SGLT2 inhibitor. Paired t‐test were used for hemodynamic changes before and after treatment with SGLT2 inhibitor. CO, cardiac output; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; SGLT2, sodium‐glucose cotransporter‐2.

Central Illustration 1

Effect of SGLT2 inhibition on exercise‐induced post‐capillary pulmonary hypertension. In this study, patients with exercise‐induced post‐capillary PH (post‐EIPH) exhibited higher BMI, increased PAWP at rest, and lower LVGLS. Those risk factors would lead to poor reserve of left ventricular function, which exacerbate pulmonary hypertension during exercise. This study demonstrated that SGLT2 inhibitor treatment alleviated haemodynamic abnormalities and exercise intolerance associated with post‐EIPH. BMI, body mass index; CO, cardiac output; eGFR, estimated glomerular filtration rate; LV, left ventricular; LVGLS, left ventricular global longitudinal strain; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; SGLT2, sodium‐glucose cotransporter‐2.