Combined treatment with DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice

Abstract

Incretin therapy has emerged as one of the most popular medications for type 2 diabetes. We have previously reported that the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin attenuates neointima formation after vascular injury in non-diabetic mice. In the present study, we examined whether combined treatment with linagliptin and the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin attenuates neointima formation in diabetic mice after vascular injury. Diabetic db/db mice were treated with 3 mg/kg/day linagliptin and/or 30 mg/kg/day empagliflozin from 5 to 10 weeks of age. Body weight was significantly decreased by empagliflozin and the combined treatment. Blood glucose levels and glucose tolerance test results were significantly improved by empagliflozin and the combined treatment, but not by linagliptin. An insulin tolerance test suggested that linagliptin and empagliflozin did not improve insulin sensitivity. In a model of guidewire-induced femoral artery injury in diabetic mice, neointima formation was significantly decreased in mice subjected to combined treatment. In an in vitro assay using rat aortic smooth muscle cells (RASMC), 100, 500, or 1000 nM empagliflozin significantly decreased the RASMC number in a dose-dependent manner. A further significant reduction in RASMC proliferation was observed after combined treatment with 10 nM linagliptin and 100 nM empagliflozin. These data suggest that combined treatment with the DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice in vivo and smooth muscle cell proliferation in vitro .

Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice

“…Empagliflozin was diluted in the drinking water (0,073 mg/ml) and given at a dose of 35 mg/kg body weight per day; at a similar dose range reported by others 11,12 . Empaglifozin was given in the drinking water to replicate the route of intake in humans and to avoid the stress associated with parenteral administration.…”

Pemafibrate, a PPAR alpha agonist, attenuates neointima formation after vascular injury in mice fed normal chow and a high-fat diet

“…Cell proliferation assays were performed as described previously [6,7] with minor modifications. Briefly, RASMCs were seeded in 12-well tissue culture plates and maintained in complete media with or without 1-1000 nM pemafibrate or 100-500 μM bezafibrate (#022-16091, Fujifilm Wako Chemicals, Osaka, Japan).…”

Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling

“…Fourth, as far as we know, there are two reports to show that SGLT2 inhibitors suppressed the neointimal hyperplasia after arterial injury in rodent models [44, 45]. One study showed that ipragliflozin, an oral inhibitor of SGLT2 attenuated cuff-induced femoral artery remodeling in western diet-fed mice partly via increase in adipocyte size of abdominal PVAT with reduced secretion of pro-inflammatory factors [44].…”

“…Effects of SGLT2 inhibitors on adipocytes may differ among the location of PVAT; howerver, we did not know the exact reason for the discrepant effects of SGLT2 inhibitors on adipocyte size and pro-inflammatory factors among abdominal, thoracic, and femoral PVAT. Furthermore, since the other study suggested the direct growth inhibitory effect of empagliflozin on smooth muscle cells [45], it would be interesting to clarify the effects of luceogliflozin on PDGF-B-induced smooth muscle cell proliferation and migration in vitro.…”