Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Abstract

Aim: Ezetimibe reduces serum low-density lipoprotein cholesterol (LDL-C) levels by inhibiting intestinal cholesterol absorption; however, the effects of ezetimibe, including its pleiotropic effects, have not been fully clarified. The aims of our study were to examine the efficacy of ezetimibe for hypercholesterolemia and its pleiotropic effects. Methods: Outpatients with hyper LDL-C levels were treated with 10 mg ezetimibe once a day for 12 weeks. Serum lipid profiles, atherosclerotic and inflammatory markers, glucose, insulin, liver function, and cholesterol absorption and synthesis markers were measured before and after treatment. Results: Seventy-five patients treated with ezetimibe monotherapy and 16 patients treated with combined therapy of ezetimibe with different statins completed this study. Following 12 weeks of ezetimibe monotherapy, serum LDL-C, triglyceride, remnant-like particles cholesterol, matrix metalloproteinase-9, insulin, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, the relative mobility of the peak of the LDL fraction, and cholesterol absorption markers were significantly decreased, and high-density lipoprotein cholesterol and lathosterol were significantly increased. In the combined therapy group, LDL-C and cholesterol absorption markers were significantly decreased after treatment. In patients with a high basal ALT level that were treated with monotherapy, ALT and the AST/ALT ratio were significantly decreased and increased, respectively, after treatment. Conclusion: Ezetimibe ameliorated not only atherogenic lipid profiles but also atherosclerotic and inflammatory markers, insulin sensitivity, and liver dysfunction in Japanese hypercholesterolemia patients, suggesting that ezetimibe treatment is a beneficial and effective strategy for the treatment of hypercholesterolemia, especially patients with obesity, metabolic syndrome, and/or fatty liver.

Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet

“…However, ezetimibe reduced hepatic triglycerides in the HE and HIE groups compared with the H and HI groups, respectively, in agreement with previous reports (Zheng et al, 2008;Muraoka et al, 2011;de Bari et al, 2012). Furthermore, recent studies have demonstrated the efficacy of ezetimibe treatment on NAFLD in humans (Park et al, 2011;Tamaki et al, 2012). Previous reports showed that ezetimibe ameliorates hepatic steatosis by reducing Srebp-1c mRNA expression in the livers of mice fed a high-fat diet and by inducing hepatic mRNA expression of microsomal triglyceride transfer protein (MTTP), which secretes very-low-density lipoprotein triglyceride into the blood, in human NASH patients (Muraoka et al, 2011;Yoneda et al, 2011).…”

“…This agent influences the fatty acid supply to the body not only through suppression of cholesterol absorption but also by influencing the synthesis and secretion of chylomicrons (de Bari et al, 2012). It has been reported that the agent reduces postprandial hyperlipidemia (Yunoki et al, 2011), improves insulin resistance, and reduces low-density lipoproteins (Tamaki et al, 2012).…”

Evaluating the safety of Liptruzet (ezetimibe and atorvastatin): what are the potential benefits beyond low-density lipoprotein cholesterol-lowering effect?

“…For instance, the administration of ezetimibe in mice and rats was shown to be associated with improvement in insulin liver signaling, insulin secretion, protection of pancreatic cells and glycemic control in animal models of T2DM. Administration of ezetimibe for 3 months in different human studies was also associated with improvement in insulin sensitivity, liver enzymes and improvement in glycemic control in T2DM individuals [38,39]. It is not yet clear whether this improvement in insulin sensitivity associated with ezetimibe administration will decrease the risk of diabetes associated with atorvastatin administration.…”

Treatment of Dyslipidemia in Allogeneic Hematopoietic Stem Cell Transplant Patients

“…Ezetimibe has also been shown to reduce inflammatory markers in patients with hyperlipidemia, but the mechanism for this anti-inflammatory effect has not been elucidated. 80,81 The reduction in inflammation may simply result from a reduction in lipid values. Ezetimibe is typically well-tolerated, with diarrhea being the most common complaint (occurring in approximately 4% of patients), and this agent can be used safely in combination with statins to gain additional LDL lowering efficacy.…”