Effects of lipid-lowering drugs on high-density lipoprotein subclasses in healthy men-a randomized trial

Abstract

Context and objective: Investigating 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 participants: A 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.

Results: Baseline 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.

Conclusions: In 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 registration: ClinicalTrials.gov NCT00317993.

Conflict of interest statement

Competing Interests: The authors have the following interests: The parent trial was supported in part by an investigator-initiated grant from MSD Sharp & Dohme. Dr. Berthold serves as an Academic Editor on the Editorial Board of PLOS ONE. Dr. Rizzo has given lectures, received honoraria or research support, and participated in conferences sponsored by AstraZeneca, Bracco, Bromatech, Chiesi Farmaceutici, Kowa, Novartis, Novo Nordisk, Rikrea and Servier. Dr. Krone has received grant/research support from MSD Sharp & Dohme and speaker's honoraria from AstraZeneca, MSD Sharp & Dohme, Essex Pharma, Pfizer and Sanofi. Dr. Gouni-Berthold has received research grants from Bayer Health Care and honoraria and travel expenses from Genzyme, MSD Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Ipsen, Bristol Myers Squibb, Amgen, Sanofi and Otsuka. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. CONSORT flow diagram: Flow of participants through the trial.

Figure 2. HDL subclass distribution before (solid line) and after 2 weeks of treatment (dotted lines).

The data are means (95% confidence intervals) of the percentage of total HDL cholesterol. (A) ezetimibe, (B) simvastatin, (C) ezetimibe plus simvastatin.

Figure 3. Mean (95% confidence intervals) proportions of HDL subclasses before and 2 weeks after treatment.

(A) large HDL, (B) intermediate HDL, (C) small HDL.