Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits

Metabolism. 2016 Jun;65(6):893-903. doi: 10.1016/j.metabol.2016.03.010. Epub 2016 Mar 18.


Introduction: Several studies have demonstrated suppression of aortic atherosclerosis by dipeptidyl peptidase-4 (DPP-4) inhibitors in hypercholesterolemic mice. However, it remains unknown whether DPP-4 inhibitors also exert anti-atherogenic effects in coronary arteries. We examined the effect of anagliptin, a DPP-4 inhibitor, on atherosclerosis development in the aorta and coronary arteries in a high-cholesterol diet-fed rabbits.

Methods: Japanese white rabbits were fed either normal chow (n=8) or a diet containing 0.5% cholesterol (n=34) for 14weeks. Cholesterol-fed rabbits were given 0.3% anagliptin or not in drinking water (each n=16 and 18) for 12weeks.

Results: Dietary cholesterol intake markedly increased serum total cholesterol (TC) levels (1464±150mg/dL, mean±SE), and the most striking increase was observed among the major lipoproteins in very low-density lipoprotein (VLDL) as determined by high-performance liquid chromatography. No significant changes were observed in body weight, water intake, hemoglobin A1c, or glucose response to intravenous glucose loading following anagliptin administration. Anagliptin decreased TC and VLDL-cholesterol as well as cholesterol absorption markers sitosterol and campesterol slightly, although not significantly. Serum DPP-4 activity was suppressed by 82%, and active glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels were increased 2- to 3-fold by anagliptin treatment. Severe hypercholesterolemia resulted in the development of atherosclerosis in the aorta, and the ratio of atherosclerotic lesions to the total aortic surface area was 22±2%. Anagliptin suppressed the lesion ratio to 9±2% (p<0.001). Atherosclerotic lesions were clearly observed in the coronary arteries, where the mean intima-media area was enlarged, and intimal formation was developed. Anagliptin treatment attenuated the intima-media area and the intimal area by 43%. Alpha-smooth muscle actin-positive and macrophage-positive areas in the coronary arteries were suppressed by 66 and 75%, respectively, after anagliptin treatment. The aortic lesion ratio and the coronary intima area were correlated with each other (r=0.506, p<0.01), and each lesion correlated with TC in the whole cholesterol-fed rabbits. Gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in the carotid arteries was markedly reduced by approximately 90%, and vascular DPP-4 activity was reduced by 66% after anagliptin treatment.

Conclusions: We demonstrated for the first time that a DPP-4 inhibitor can substantially suppress plaque formation in coronary arteries with a marked reduction in macrophage accumulation likely via its anti-inflammatory properties.

Keywords: Atherosclerosis; Cholesterol; Dipeptidyl peptidase-4; Macrophage; Rabbits.

MeSH terms

  • Animals
  • Aorta / drug effects*
  • Aorta / metabolism
  • Aorta / pathology
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Cholesterol / blood
  • Coronary Vessels / drug effects*
  • Coronary Vessels / metabolism
  • Coronary Vessels / pathology
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Hypercholesterolemia / drug therapy
  • Hypercholesterolemia / metabolism
  • Hypercholesterolemia / pathology
  • Lipoproteins, VLDL / blood
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Male
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rabbits


  • Dipeptidyl-Peptidase IV Inhibitors
  • Lipoproteins, VLDL
  • Pyrimidines
  • Cholesterol
  • anagliptin