Effect of the dipeptidyl peptidase-4 inhibitor linagliptin on atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits: iMap-IVUS and pathological analysis

Dipeptidyl peptidase-4 (DPP-4) inhibitors have potential as a treatment for atherosclerosis. However, it is unclear whether DPP-4 inhibitors stabilize atherosclerotic plaque or alter the composition of complex plaque. Sixteen Watanabe heritable hyperlipidemic rabbits aged 10–12 weeks with atherosclerotic plaque in the brachiocephalic artery detected by iMap^™ intravascular ultrasound (IVUS) were divided into a DPP-4 inhibitor group and a control group. Linagliptin was administered to the DPP-4 inhibitor group via nasogastric tube at a dose of 10 mg/kg/day for 16 weeks, and control rabbits received the same volume of 0.5% hydroxyethylcellulose. After evaluation by IVUS at 16 weeks, the brachiocephalic arteries were harvested for pathological examination. IVUS revealed that linagliptin significantly reduced the plaque volume and vessel volume (control group vs. DPP-4 inhibitor group: ∆plaque volume, 1.02 ± 0.96 mm³ vs. − 3.59 ± 0.92 mm³, P = 0.004; ∆vessel volume, − 1.22 ± 2.36 mm³ vs. − 8.66 ± 2.33 mm³, P = 0.04; %change in plaque volume, 6.90 ± 5.62% vs. − 15.06 ± 3.29%, P = 0.005). With regard to plaque composition, linagliptin significantly reduced the volume of fibrotic, lipidic, and necrotic plaque (control group vs. DPP-4 inhibitor group: ∆fibrotic volume, 0.56 ± 1.27 mm³ vs. − 5.57 ± 1.46 mm³, P = 0.04; ∆lipidic volume, 0.24 ± 0.24 mm³ vs. − 0.42 ± 0.16 mm³P = 0.04; ∆necrotic volume, 0.76 ± 0.54 mm³ vs. − 0.84 ± 0.25 mm³, P = 0.02). Pathological examination did not show any significant differences in the %smooth muscle cell area or %fibrotic area, but infiltration of macrophages into plaque was reduced by linagliptin treatment (%macrophage area: 12.03% ± 1.51% vs. 7.21 ± 1.65%, P < 0.05). These findings indicate that linagliptin inhibited plaque growth and stabilized plaque in Watanabe heritable hyperlipidemic rabbits.