The effect of statin alone or in combination with ezetimibe on postprandial lipoprotein composition in obese metabolic syndrome patients☆
Introduction
Abdominal obesity is frequently associated with a clustering of cardiovascular risk factors such as fasting and postprandial dyslipidemia, hyperglycemia, elevated blood pressure, low grade inflammation and altered hemostatics [1], [2]. This clustering is often referred to as metabolic syndrome and is associated with an increased risk for cardiovascular morbidity and mortality as well as for type 2 diabetes [3]. The atherogenic lipoprotein profile observed in these patients is characterized by elevated fasting plasma levels of triglyceride-rich lipoproteins (TRLs) in combination with low high-density lipoprotein-cholesterol (HDL-C) levels and increased concentrations of small-dense low-density lipoprotein particles [3]. Insulin resistance, a main characteristic of metabolic syndrome, underlies this dyslipidemia by reducing lipoprotein lipase activity resulting in attenuated hydrolysis of triglycerides into free fatty acids (FFAs) from TRLs and reduced uptake of FFAs into adipocytes during the postprandial phase [4]. In addition, more FFAs are released from enlarged adipocytes into the (portal) circulation since hormone sensitive lipase, in concerted action with adipose triglyceride lipase, is no longer inhibited by insulin [5]. These combined metabolic alterations, in addition to decreased apoB degradation due to insulin resistance, result in an increased substrate for hepatic TRL synthesis (VLDL-1) and a prolonged residence time of hepatic and intestinal derived TRL-remnants during the postprandial phase [6]. Increased levels of TRLs (VLDL, chylomicrons and their remnants) contribute to the development of atherosclerosis since these particles are able to invade the subendothelial space providing substrate for foam cell formation [7]. The presumed importance of postprandial lipid metabolism is further illustrated by the fact that humans are in a non-fasting condition most times of the day. Recently it has been shown that non-fasting plasma triglyceride concentrations are associated with an increased cardiovascular risk in both men and women, independently of other lipids [8], [9]. Ezetimbe lowers LDL-C plasma levels by inhibiting the absorption of dietary and biliary cholesterol by the Niemann-Pick C1like 1 protein [10]. Simvastatin, a HMG-CoA reductase inhibitor, at high dose (80 mg) and the combination of low dose simvastatin combined with ezetimibe 10 mg have proven to be safe and effective in reducing fasting LDL-C, RLP-C and triglyceride levels and to slightly raise HDL-C plasma concentrations [11], [12]. Although statins decrease fasting lipid levels, fat load induced hypertriglyceridemia is unaffected [13], [14]. Whether ezetimibe influences postprandial lipid metabolism is not yet clear.
The aim of the present randomized, double blind, cross over study is therefore to evaluate post fat load lipid concentrations and the lipid composition of lipoprotein fractions after 6 weeks treatment with simvastatin 10 mg combined with ezetimibe 10 mg compared to simvastatin 80 mg alone in obese male patients with metabolic syndrome.
Section snippets
Subjects
Nineteen, non-smoking obese male subjects, aged 18–70 years, were recruited by advertisement which called for subjects with waist circumference > 102 cm. All subjects were screened for the presence of metabolic syndrome according to the Adult Treatment Panel III criteria including three or more of the following metabolic abnormalities [3]:
- 1.
abdominal obesity (waist circumference > 102 cm);
- 2.
high blood pressure (≥130 mmHg systolic or ≥85 mmHg diastolic);
- 3.
hypertriglyceridemia (serum triglycerides ≥ 1.70 mmol/l
Anthropometric measurements
Before and after each treatment period, patient's weight and height were measured without heavy clothing and shoes. Body mass index (BMI) was calculated as weight to height squared. Waist circumference was measured each visit twice halfway between the lower rib and the iliac crest. Total body fat percentage was estimated by using Omron body fat monitor BF306 (Omron Matsusaka Co. Ltd., Japan).
Oral fat load
Fresh cream was used which is a 40% (w/v) fat emulsion with a poly-unsaturated/saturated fat ratio of
Baseline characteristics
In total 37 subjects were screened, of whom 19 patients were eligible and included in the study. The clinical and laboratory characteristics of the study subjects at baseline are show in Table 1. Weight (100.3 ± 11.5 kg), waist circumference (111 ± 7 cm) and body fat percentage (31 ± 3%) remained stable during the study. Fasting triglycerides were 1.66 ± 0.13 mmol/l and HDL-C was 1.14 ± 0.06 mmol/l at baseline. Other components of metabolic syndrome at baseline were blood pressure 138 ± 13 (systolic) and 89 ± 6
Discussion
In the present double blind, crossover trial it is shown that treatment with low dose simvastatin (10 mg) in combination with ezetimibe (10 mg) did not result in lower post fat load lipoprotein plasma concentrations nor in differences in lipoprotein particle content when compared to high dose simvastatin (80 mg) monotherapy in obese male metabolic syndrome patients.
In metabolic syndrome subjects an atherogenic lipid profile, comprising elevated plasma levels of triglycerides, small dense LDL-C
Conflict of interest
All authors declare that they have no conflict of interest.
Acknowledgements
The help of the research nurses of the Vascular Research Unit of the UMC Utrecht, Corina Joosten, Inge Klaassen and Annemieke Sloeserwij is greatly acknowledged.
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Trial registration; Clinicaltrials.gov; Identifier: NCT00189085.