Affiliation:
1. Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden
2. Department of Biochemistry Faculty of Medicine Khartoum University Khartoum Sudan
3. Function Area Clinical Chemistry Karolinska University Laboratory Function Karolinska University Hospital Stockholm Sweden
4. Department of Surgery Karolinska Institutet at Danderyd Hospital Stockholm Sweden
5. Wihuri Research Institute Helsinki Finland
6. Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme Karolinska University Hospital Stockholm Sweden
7. Metabolism Unit Department of Medicine Karolinska Institutet at Karolinska University Hospital Huddinge Stockholm Sweden
Abstract
Background
In randomized trials (SHARP [Study of Heart and Renal Protection],
IMPROVE
‐IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2
DM
), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied.
Methods and Results
Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with
qPCR
. Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans (
PG
) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB‐lipoprotein
PG
binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found.
Conclusions
Combined treatment caused atheroprotective changes on ApoB‐lipoproteins, remnant particles, bile components, and in ApoB‐lipoprotein affinity for arterial
PG
. These effects might explain the decrease of cardiovascular events seen in the
SHARP
and
IMPROVE
‐
IT
trials.
Clinical Trial Registration
URL
:
www.clinicaltrialsregister.eu
. Unique identifier: 2006‐004839‐30).
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
22 articles.
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