Rats with monocrotaline (MCT)-induced PAH were evaluated in the study to investigate whether the addition of dapagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, would provide additional benefit when used with sildenafil.
A preclinical study combining a blockbuster drug for diabetes and heart failure with sildenafil, a vasodilator, failed to provide a greater benefit for pulmonary arterial hypertension (PAH), according to results published in BMC Lung Medicine.
Led by researchers at Hunan Provincial People’s Hospital, the study in rats with monocrotaline (MCT)-induced PAH examined whether the addition of dapagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, when used with sildenafil provided an additional would bring benefit. Dapagliflozin has been shown to have benefits across the spectrum of heart failure, in addition to its ability to control blood sugar levels by excreting excess glucose through the urine.
The rats with PAH were divided into 4 groups and treated for 3 weeks with daily doses of 1 of the following: (1) dapagliflozin, 1 mg/kg/day, (2) sildenafil, 25 mg/kg/day, (3) combination of dapagliflozin and sildenafil doses, or (4) a placebo. In addition, the study followed a group of rats that were not induced with PAH. Investigators performed hemodynamic measurements and assays to detect changes in PAH after treatments.
According to the results, dapagliflozin significantly reduced the MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Although both sildenafil and dapagliflozin separately reduced RVSP, their combination did not significantly improve this measure (combination, 33.35 ± 3.76 vs. sildenafil alone, 35.52 ± 5.02 mmHg, P = 0.29). The same was true for RVH: both drugs offered benefits as monotherapy, but the addition of dapagliflozin to sildenafil did not significantly increase the benefit (combination 0.32 ± 0.05 vs. sildenafil alone 0.36 ± 0.04, P = 0.13).
Rats with MCT-induced PAH who received the placebo showed a significant increase in medial wall thickness compared to those in the control group without PAH (46.00 ± 2.69% vs. 18.18 ± 1.47%; P < 0.0001). Dapagliflozin helped control much of this increase (29.52 ± 3.20%), as did sildenafil (27.91 ± 1.72%). The combination of the two offered limited additional benefit to sildenafil monotherapy (26.98 ± 1.16% vs. 27.91 ± 1.72; P = 0.172).
In other measurements, the researchers found that “dapagliflozin increased inflammasome activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) in lung tissue and plasma levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18). However, the addition of the SGLT2 inhibitor to sildenafil did not show a greater benefit for RVSP and pulmonary vascular remodeling in MCT rats than sildenafil alone, they wrote.
In this rat model of MCT-induced PAH, “dapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodeling,” the researchers concluded. “However, combination therapy with dapagliflozin and sildenafil was no more effective than sildenafil monotherapy in PAH rats.”
Tang Y, Tan S, Li M, et al. Dapagliflozin, sildenafil and their combination in monocrotaline-induced pulmonary arterial hypertension. BMC Lung Med. 2022;22(1):142. doi:10.1186/s12890-022-01939-7.