Key result
Dapagliflozin significantly reduced right ventricular systolic pressure (39.11 vs 49.14 mmHg) and pulmonary vascular remodeling in PAH rats, but adding it to sildenafil provided no additional benefit over sildenafil alone.
Why the study?
The study was conducted to determine whether dapagliflozin improves pulmonary vascular remodelling and to evaluate its efficacy as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension.
Does dapagliflozin alone or in combination with sildenafil improve right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of pulmonary arterial hypertension?
Does dapagliflozin alone or in combination with sildenafil improve right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of pulmonary arterial hypertension?
Absolute Event Rate: 39.11% vs 49.14%
p-value: p=<0.005
Dapagliflozin improves hemodynamics and pulmonary vascular remodeling in a PAH rat model, but does not provide additive benefits when combined with sildenafil.
Dapagliflozin add-on effects in rat PAH are hypothesis-generating; human trials required before any clinical consideration.
BACKGROUND: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH). METHODS: A monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments. RESULTS: Dapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone. CONCLUSIONS: Dapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.
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Tang et al. (2022) studied Pulmonary arterial hypertension (n=40). Dapagliflozin, sildenafil, or combination vs. Vehicle (0.5% hydroxyethylcellulose) was evaluated on Right ventricular systolic pressure (RVSP) (p=<0.005). Dapagliflozin significantly reduced right ventricular systolic pressure (39.11 vs 49.14 mmHg) and pulmonary vascular remodeling in PAH rats, but adding it to sildenafil provided no additional benefit over sildenafil alone.
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