Abstract
Context and ObjectiveInvestigating the effects of lipid-lowering drugs on HDL subclasses has shown ambiguous results. This study assessed the effects of ezetimibe, simvastatin, and their combination on HDL subclass distribution.Design and ParticipantsA single-center randomized parallel 3-group open-label study was performed in 72 healthy men free of cardiovascular disease with a baseline LDL-cholesterol of 111±30 mg/dl (2.9±0.8 mmol/l) and a baseline HDL-cholesterol of 64±15 mg/dl (1.7±0.4 mmol/l). They were treated with ezetimibe (10 mg/day, n = 24), simvastatin (40 mg/day, n = 24) or their combination (n = 24) for 14 days. Blood was drawn before and after the treatment period. HDL subclasses were determined using polyacrylamide gel-tube electrophoresis. Multivariate regression models were used to determine the influence of treatment and covariates on changes in HDL subclass composition.ResultsBaseline HDL subclasses consisted of 33±10% large, 48±6% intermediate and 19±8% small HDL. After adjusting for baseline HDL subclass distribution, body mass index, LDL-C and the ratio triglycerides/HDL-C, there was a significant increase in large HDL by about 3.9 percentage points (P<0.05) and a decrease in intermediate HDL by about 3.5 percentage points (P<0.01) in both simvastatin-containing treatment arms in comparison to ezetimibe. The parameters obtained after additional adjustment for the decrease in LDL-C indicated that about one third to one half of these effects could be explained by the extent of LDL-C-lowering.ConclusionsIn healthy men, treatment with simvastatin leads to favorable effects on HDL subclass composition, which was not be observed with ezetimibe. Part of these differential effects may be due to the stronger LDL-C-lowering effects of simvastatin.Trial RegistrationClinicalTrials.gov NCT00317993
Highlights
There is great clinical interest in raising levels of high-density lipoprotein cholesterol (HDL-C), given its epidemiologically wellestablished inverse association with atherosclerosis and cardiovascular disease (CVD) risk [1]
After adjusting for baseline HDL subclass distribution, body mass index, low-density lipoprotein cholesterol (LDL-C) and the ratio triglycerides/HDL-C, there was a significant increase in large HDL by about 3.9 percentage points (P,0.05) and a decrease in intermediate HDL by about 3.5 percentage points (P,0.01) in both simvastatin-containing treatment arms in comparison to ezetimibe
The parameters obtained after additional adjustment for the decrease in LDL-C indicated that about one third to one half of these effects could be explained by the extent of LDL-C-lowering
Summary
There is great clinical interest in raising levels of high-density lipoprotein cholesterol (HDL-C), given its epidemiologically wellestablished inverse association with atherosclerosis and cardiovascular disease (CVD) risk [1]. Recent failures of drugs that raised HDL-C without reducing CVD events [6,7] or atherosclerosis [8] have fueled interest away from a cholesterol-centric view towards alternative indexes of HDL quantity (i.e., HDL-P or apolipoprotein A-I) or possibly HDL ‘‘quality’’, such as particle size, subclass distribution [9], or various measures of HDL functionality [2,10,11]. It was shown for example that HDL particle concentrations were associated with intima-media thickness and incident coronary events independently of atherogenic lipoproteins and HDL-C [12]. In the setting of potent statin therapy, HDL particle number may be a better marker of residual risk than HDL-C or apoA-I [13]
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