Effects of Ezetimibe Add-on to Statin Therapy on Adipokine Production in Patients With Metabolic Syndrome and Stable Vascular Disease

Abstract

The aim of this study was to determine whether the addition of ezetimibe to ongoing statin therapy in patients with atherosclerosis and metabolic syndrome would favorably affect levels of inflammatory markers and adipokines. Individuals with the metabolic syndrome exhibit higher levels of inflammatory biomarkers and adipokines, which have been implicated in the pathobiology of cardiovascular risk. The impact of the addition of ezetimibe to statin therapy on these proinflammatory mediators is unclear. Fifty patients with metabolic syndrome and concomitant vascular disease receiving stable statin monotherapy, with low-density lipoprotein cholesterol (LDL-C) levels >77.4 mg/dL (>2.0 mM), were treated with ezetimibe 10 mg per day for 12 weeks. The primary study end point was the % change in adiponectin levels from baseline to 12 weeks. Secondary study end points included % changes in the levels of other circulating inflammatory markers, adipokines, and plasma lipids. The addition of ezetimibe to statin therapy resulted in a significant reduction in total cholesterol and LDL-C and the ratio of total cholesterol to high-density lipoprotein cholesterol. However, ezetimibe add-on treatment had no effect on the primary outcome of plasma adiponectin or on any of the secondary outcomes, including leptin, hsCRP, tumor necrosis factor-α, or interleukin-6 concentrations. These observations remained unchanged after adjusting for body mass index and for background statin used. The addition of ezetimibe to stable statin therapy in patients with vascular disease and metabolic syndrome, who were not at guideline recommended LDL-C levels, did not alter adipokine levels after 12 weeks. Short-term add-on with ezetimibe may not be associated with additional inflammatory benefits beyond improvements in cholesterol homeostasis.

The Effect of Ezetimibe and Simvastatin on Monocyte Cytokine Release in Patients With Isolated Hypercholesterolemia

“…The exclusion criteria were as follows: (1) isolated mixed dyslipidemia or hypertriglyceridemia; (2) secondary hypercholesterolemia in the course of nephrotic syndrome, liver and biliary tract diseases, thyroid diseases, autoimmune disorders, chronic pancreatitis, or alcoholism; (3) diabetes mellitus; (4) body mass index .40 kg/m 2 ; (5) any acute and chronic inflammatory processes; (6) symptomatic congestive heart failure; (7) unstable coronary artery disease, myocardial infarction, or stroke within 6 months preceding the study; (8) moderate or severe arterial hypertension (European Society of Cardiology/European Society of Hypertension grade 2 or 3); (9) impaired renal or hepatic function; (10) malignancy within 5 years preceding the study; (11) treatment with any hypolipemic agents within 3 months before the study; (12) concomitant treatment with drugs that may affect inflammatory processes in the vascular wall; (13) concomitant treatment with other drugs known to either affect plasma glucose or lipid levels or to interact with statins or ezetimibe; and (14) poor patient compliance.…”

“…7 When administered to statin-treated patients with atherosclerosis and the metabolic syndrome, it had no effect on plasma adiponectin, leptin, high sensitivity C-reactive protein (hsCRP), TNF-a, or interleukin-6 concentrations. 8 In hypercholesterolemic patients, the combination of ezetimibe and fluvastatin decreased CRP levels in patients with high baseline CRP, more than one cardiovascular risk factor, or with hypertension, and reduced plasma levels of interleukin-1b. 9 Recently, monocyte-derived macrophages have been found to express NPC1L1 and other ezetimibe-binding proteins: aminopeptidase N, annexin-2, and caveolin-1, 10,11 which indicates that these cells may be an important target for ezetimibe action.…”

Effects of short‐term add‐on ezetimibe to statin treatment on expression of adipokines and inflammatory markers in diabetic and dyslipidemic patients

“…In this study, short‐term add‐on ezetimibe treatment reduced adiponectin serum levels in both HC and DM groups. Previous studies reported that combined ezetimibe (10 mg) and simvastatin (20 mg/8 or 12 wk) therapy did not alter adiponectinemia in nondiabetic HC patients, prediabetic HC subjects, and patients with MetS and vascular disease . In the same way, a recent meta‐analysis of 23 controlled trials did not suggest any significant effect on plasma concentrations of adiponectin, and other adipokines, such as leptin, PAI‐1, and IL‐6, was achieved by adding ezetimibe to statin therapy …”

“…Previous studies reported that combined ezetimibe (10 mg) and simvastatin (20 mg/8 or 12 wk) therapy did not alter adiponectinemia in nondiabetic HC patients, prediabetic HC subjects, and patients with MetS and vascular disease. 20,21,29 In the same way, a recent meta-analysis of 23 controlled trials did not suggest any significant effect on plasma concentrations of adiponectin, and other adipokines, such as leptin, PAI-1, and IL-6, was achieved by adding ezetimibe to statin therapy. 30 Yet, treatment with ezetimibe (10 mg) and simvastatin (10 mg/12 wk, or 40 mg/4 wk) increased plasma levels of adiponectin in HC patients.…”

Hypolipidaemic and anti-inflammatory effects of fixed dose combination of atorvastatin plus ezetimibe in Indian patients with dyslipidaemia

“…(35) In contrast, Ballantyne et al, who compared atorvastatin and ezetimibe combination treatment to atorvastatin alone, reported an overall larger reduction in hsCRP levels with the combination. Interestingly, the authors found that this effect was observed by adding ezetimibe 10 mg to a higher dose of atorvastatin (80 mg), but not with a lower dose of atorvastatin (10 mg) despite consistent LDL-C level lowering across the whole dosing range of atorvastatin.…”