Combined dapagliflozin is no more effective in reducing PAHs in a preclinical study

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The study used rats with monocrotaline-induced PAH (MCT) to examine whether the addition of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, would provide additional benefit when used with sildenafil .

According to results published in BMC Pulmonary Medicine.

Led by researchers at Hunan Provincial People’s Hospital, the study used rats with monocrotaline-induced PAH (MCT) to examine whether the addition of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor , would provide additional benefit when used with sildenafil. Dapagliflozin has been shown to have benefits across the spectrum of heart failure, in addition to its ability to provide glycemic control by allowing excess glucose to pass into the urine.

Rats with PAH were divided into 4 groups and treated for 3 weeks, with daily doses of 1 of the following drugs: (1) dapagliflozin 1 mg/kg/day, (2) sildenafil 25 mg/kg/day, (3) combination of dapagliflozin and sildenafil doses, or (4) placebo. Additionally, the study followed a group of non-PAH-induced rats. Investigators took hemodynamic measurements and tests to detect changes in PAH after the treatments.

According to the results, dapagliflozin significantly reduced MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Although sildenafil and dapagliflozin both reduced PSR separately, 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 HRV: both drugs offered benefits as monotherapy, but adding dapagliflozin to sildenafil did not substantially increase benefit (combination 0.32 ± 0.05 vs sildenafil alone 0.36 ± 0.04, P = 0.13).

Rats with MCT-induced PAH that 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 P = 0.172).

In other measures, researchers found that “dapagliflozin attenuated inflammasome activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) in lung tissue and levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma.” However, adding the SGLT2 inhibitor to sildenafil did not show more benefit on RVSP and pulmonary vascular remodeling in MCT rats than sildenafil alone, they wrote.

In this rat model with 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 monotherapy with sildenafil in rats with PAH.”

Reference

Tang Y, Tan S, Li M, et al. Dapagliflozin, sildenafil and their association in monocrotaline-induced pulmonary arterial hypertension. BMC Lung Med. 2022;22(1):142. doi:10.1186/s12890-022-01939-7

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