16] CONVENTIONAL RISK FACTORS AND PROGNOSTIC LOCALIZATION OF CORONARY ARTERY DISEASE (original) (raw)
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Atherosclerosis, 2011
Introduction: Type 2 diabetes is associated with atherogenic abnormalities of postprandial triglyceriderich lipoproteins. This study evaluated whether ezetimibe, by inhibiting intestinal cholesterol absorption, influences chylomicrons and VLDL particles at fasting and after a standard meal. Methods: By a double blind cross-over design 15 subjects with type 2 diabetes and hypercholesterolaemia followed in random order a 6-week treatment with ezetimibe 10 mg + simvastatin 20 mg (EZE + S) or placebo + simvastatin 20 mg (P + S) and, after a 6-week wash-out period, crossed over to the other treatment (NCT00699023). At the end of each period lipids, apoB-48, and apoB-100 concentrations in plasma and lipoprotein fractions (separated by discontinuous density gradient ultracentrifugation) were determined before and over 6 h following a high-fat test meal. Results: Compared with P + S, EZE + S induced, (a) beside a greater decrease in LDL cholesterol, (b) a significant decrease in chylomicron lipid content both at fasting and postprandially (4.4 ± 2.7 vs. 8.3 ± 8.7 mg/dl × 6 h total AUC for cholesterol, p < 0.05; 18 ± 12 vs. 29 ± 24 mg/dl triglyceride concentrations at 6 h, p < 0.05), (c) a significant decrease in chylomicron postprandial apoB-48 (0.03 ± 0.03 vs. 0.09 ± 0.08 mg/l at 4 h, p < 0.05), and (d) significant fasting and postprandial decreases in the cholesterol content of VLDL, IDL, and LDL, as shown by the significant reduction of the cholesterol/triglyceride ratio in these lipoproteins. Conclusions: A 6-week treatment with ezetimibe and simvastatin, compared to simvastatin alone, positively influences lipoprotein profile both at fasting and postprandially in type 2 diabetic patients by favouring the production of cholesterol-poor chylomicrons and VLDL particles that have less atherogenic potential.
Ezetimibe Increases Endogenous Cholesterol Excretion in Humans
Arteriosclerosis, thrombosis, and vascular biology, 2017
Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers low-density lipoprotein cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly mixing endogenous cholesterol pool into the stool. In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with low-density lipoprotein cholesterol 100 to 200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/d or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 in a lipid emulsion and dietary cholesterol with cholesterol-d5 and sitostanol-d4 solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe r...
Ezetimibe: Rationale and role in the management of hypercholesterolemia
Clinical Cardiology, 2006
Elevated low-density lipoprotein (LDL) cholesterol plays an important role in the development of atherosclerosis. In part, plasma LDL levels are dependent on cholesterol absorption in the intestine and the rate of intrinsic cholesterol synthesis. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors has often proven to be successful in reducing plasma LDL levels. However, a significant number of patients do not reach their target LDL levels despite statin therapy. As is reviewed, drugs that inhibit cholesterol absorption are a useful adjunct to lipid-lowering therapy by statins. This review discusses the mechanisms involved in intestinal absorption of cholesterol and its transport as potential targets of newer agents that affect cholesterol absorption. The use of bile acid sequestrants and esters of plant stanols, as well as other intestinally active agents for reducing plasma LDL levels, has been limited by side effects and difficulties in patient compliance. In contrast, the new selective cholesterol transporter inhibitor ezetimibe has been demonstrated to reduce plasma LDL alone or in combination with statins without significant adverse effects. In spite of the robust lipid-lowering data with ezetimibe, questions about clinical outcomes, safety, and efficacy in various combinations remain.
Life Sciences, 2013
High-risk subjects with elevated C-reactive protein (CRP) are at high risk for cardiovascular events and 25 frequently require potent statins or combined lipid-lowering therapy to achieve lipid targets and decrease in-26 flammation. Our study aimed at evaluating the effects of three lipid-modifying therapies on LDL-cholesterol, 27 CRP levels and markers of cholesterol absorption and synthesis. 28 Main methods: A prospective intervention study was performed in high cardiovascular risk individuals receiv-29 ing atorvastatin 10 mg daily for four weeks. Those with CRP ≥ 2.0 mg/L were randomized to another 30 four-week treatment period with atorvastatin 40 mg, ezetimibe 10 mg or the combination of atorvastatin 31 40 mg / ezetimibe 10 mg. Lipids, markers of cholesterol absorption (campesterol and β-sitosterol), and syn-32 thesis (desmosterol), as well as CRP were quantified at baseline and end of study. 33 Key findings: One hundred and twenty two individuals were included. Atorvastatin alone or combined with 34 ezetimibe reduced both LDL-cholesterol and CRP (P b 0.002 vs. baseline; Wilcoxon); ezetimibe did not mod-35 ify CRP. Ezetimibe-based therapies reduced absorption markers and their ratios to cholesterol (P b 0.0001 vs. 36 baseline, for all; Wilcoxon), whereas atorvastatin alone increased campesterol/cholesterol and β-sitosterol/ 37 cholesterol ratios (P b 0.05 vs. baseline; Wilcoxon). In addition, ezetimibe also increased desmosterol and 38 desmosterol/cholesterol ratio (P b 0.0001 vs. baseline; Wilcoxon). 39 Significance: These results contribute to understanding the link between cellular cholesterol homeostasis, in-40 flammation and lipid-modifying therapies. Our findings highlight the broader benefit of combined therapy 41 with a potent statin and ezetimibe decreasing inflammation, and preventing increase in cholesterol biosyn-42 thesis, an effect not observed with ezetimibe alone. 43
The American Journal of Cardiology, 2010
Ezetimibe is effective in providing additional low-density lipoprotein (LDL) cholesterol lowering when coadministered with statins, but its effect beyond LDL cholesterol lowering is unknown. Oxidized LDL (ox-LDL) is a better predictor of adverse cardiovascular events than standard lipid parameters. The objective of this study was to investigate the effect of ezetimibe on ox-LDL. A total of 100 patients with coronary artery disease or coronary artery disease equivalent were randomized to atorvastatin 40 mg/day and ezetimibe 10 mg/day or to atorvastatin 40 mg/day and placebo. LDL cholesterol, LDL cholesterol subfractions, and ox-LDL were measured at baseline and after 8 weeks of therapy. The ezetimibe group had a larger reduction in total LDL cholesterol compared to placebo. This was due mainly to a larger reduction in large buoyant LDL (24% vs 10%, p ؍ 0.008). Ox-LDL level did not change in the placebo group (50 ؎ 13 vs 51 ؎ 13 U/L), while it decreased in the ezetimibe group, from 51 ؎ 13 to 46 ؎ 10 U/L (p ؍ 0.01 vs baseline and p ؍ 0.02 vs final level in placebo). The change in ox-LDL correlated significantly with those in total LDL and in large buoyant LDL (r ؍ 0.6 and r ؍ 0.5, respectively, p <0.01 for both), but not with that of small dense LDL, high-density lipoprotein, or very low density lipoprotein. In conclusion, this study demonstrates that ezetimibe decreases ox-LDL cholesterol through reductions in total LDL cholesterol and in large buoyant LDL cholesterol.
Clinical Therapeutics, 2007
Background: Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/ simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol. Objective: The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subffactions and LDL particle size in patients with primary hypercholesterolemia. Methods: This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, _>145-_<250 mg/dL; triglycerides, _<350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 rag), simvastatin monotherapy (10, 20, 40, or 80 rag), ezetimibe monotherapy (10 rag), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses. Results: Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern. Conclusion: E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subffactions in these patients with primary hypercholesterolemia.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2001
Ezetimibe (SCH58235) is a potent, selective, cholesterol absorption inhibitor. The objective of this study was to determine whether ezetimibe reduces plasma cholesterol and inhibits atherogenesis in apolipoprotein E knockout (apoEϪ/Ϫ) mice. Cholesterol absorption was inhibited by Ͼ90% at doses of ezetimibe Ͼ3 mg/kg in apoEϪ/Ϫ mice. Atherosclerosis and lipoprotein changes were determined in apoEϪ/Ϫ mice fed a high-fat (0.15% cholesterol) "western" diet, a low-fat (0.15% cholesterol) diet, or a semisynthetic cholesterol-free diet with or without ezetimibe (5 mg/kg per day) for 6 months. Ezetimibe reduced plasma cholesterol levels from 964 to 374 mg/dL, from 726 to 231 mg/dL, and from 516 to 178 mg/dL in the western, low-fat, and cholesterol-free diet groups, respectively. The reductions occurred in the very low density and low density lipoprotein fractions, whereas high density lipoprotein cholesterol levels were increased by ezetimibe treatment. Ezetimibe reduced aortic atherosclerotic lesion surface area from 20.2% to 4.1% in the western diet group and from 24.1% to 7.0% in the low-fat cholesterol diet group. Ezetimibe reduced carotid artery atherosclerotic lesion cross-sectional area by 97% in the western and low-fat cholesterol groups and by 91% in the cholesterol-free group. Ezetimibe inhibits cholesterol absorption, reduces plasma cholesterol, increases high density lipoprotein levels, and inhibits the progression of atherosclerosis under western, low-fat, and cholesterol-free dietary conditions in apoEϪ/Ϫ mice. Although apoEϪ/Ϫ mice are more hypercholesterolemic than are humans and low density lipoprotein reductions with ezetimibe are not as pronounced clinically, ezetimibe may inhibit atherogenesis in individuals consuming restricted-fat or western diets. (Arterioscler Thromb Vasc