Journal of Cardiovascular Pharmacology:
The Effects of Low-Dose Simvastatin and Ezetimibe Compared to High-Dose Simvastatin Alone on Post-Fat Load Endothelial Function in Patients With Metabolic Syndrome: A Randomized Double-Blind Crossover Trial
Olijhoek, Jobien K MD, PhD*; Hajer, Gideon R MD, PhD*; Graaf, Yolanda van der MD, PhD†; Dallinga-Thie, Geesje M PhD‡; Visseren, Frank L J MD, PhD*
From the *Department of Vascular Medicine, University Medical Centre Utrecht; †Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht; and ‡Department of Vascular Medicine, Laboratory of Experimental Vascular Medicine, Academic Medical Centre (AMC),, Amsterdam, the Netherlands.
Received for publication February 4, 2008; accepted May 15, 2008.
Clinicaltrials.gov identifier: NCT00189085.
The authors do not have financial relations (personal or institutional) that might be a potential conflict of interest.
Reprints: Frank L. J. Visseren, MD, PhD, Internal Medicine, Section of Vascular Medicine, UMC Utrecht, F02.126, Heidelberglaan 100; 3584 CX Utrecht, the Netherlands (e-mail: email@example.com).
Background and Aims: Insulin resistance is associated with postprandial hyperlipidemia and endothelial dysfunction. Patients with metabolic syndrome, characterized by insulin resistance, are at increased cardiovascular risk. The aim of the present study was to investigate whether a similar low-density lipoprotein cholesterol (LDL-c) reduction with combination therapy of low-dose simvastatin and ezetimibe or with high-dose simvastatin alone has similar effects on (post-fat load) endothelial function.
Methods: Randomized, double blind, crossover trial in 19 male obese patients with metabolic syndrome with high-dose simvastatin 80 mg versus combination therapy of low-dose simvastatin 10 mg with ezetimibe 10 mg. Fasting and post-fat load lipids and endothelial function (brachial artery flow-mediated dilation) were determined.
Results: Fasting LDL-c concentrations (2.1 ± 0.5 mmol/L) and fasting endothelial function (6.9 ± 0.8 vs. 7.6 ± 1.2%) were the same after both treatments. Although post-fat load plasma triglycerides concentrations were higher (3.2 ± 0.4 vs. 2.6 ± 0.2 mmol·h/L) with combination therapy compared to monotherapy, ApoB particles were comparable (0.9 ± 3.3 vs. −0.2 ± 2.3 g·h/L). Combination therapy did not decrease post-fat load endothelial function (7.6 ± 1.2 vs. 7.7 ± 1.6%), contrary to high-dose simvastatin monotherapy (6.9 ± 0.8 vs. 4.3 ± 0.6%).
Conclusions: Combination therapy with low-dose simvastatin and ezetimibe preserved post-fat load endothelial function, contrary to treatment with high-dose simvastatin monotherapy in male metabolic syndrome patients. There were no differences in fasting lipid profiles and endothelial function.
Lowering plasma concentrations of low-density lipoprotein cholesterol (LDL-c) is a cornerstone in cardiovascular risk reduction in patients at elevated risk for vascular events.1 Intensive LDL-c lowering can be achieved by high-dose statin treatment or with combination therapy of lower doses of statin and ezetimibe.2 It is unclear whether a similar LDL-c reduction with combination therapy of low-dose simvastatin and ezetimibe or with high-dose simvastatin alone has similar effects on fasting and post-fat load endothelial function. Statin therapy may improve fasting and post-fat load endothelial function but it is not known whether this is an indirect effect of lipid lowering or a direct vascular effect of statins influencing the stability of endothelial nitric oxide synthase (eNOS), often referred to as pleiotropic effects.3,4 Inhibition of cholesterol absorption may influence postprandial lipid metabolism and may therefore have effects on postprandial endothelial function. Ezetimibe inhibits cholesterol absorption but effects on post-fat load hyperlipidemia and endothelial function are unknown. Postprandial hyperlipidemia could be regarded as a cardiovascular risk factor, as indicate145-150d by the induction of postprandial endothelial dysfunction.5-7 Chylomicron remnants and very low density lipoprotein (VLDL) particles may impair endothelial dependent vasodilatation.8
Insulin resistance, often observed in the metabolic syndrome, is associated with elevated triglyceride-rich lipoproteins in the VLDL-1 fraction and their remnants in the postprandial state.9,10 Insulin resistance causes endothelial dysfunction and decreased nitric oxide bioavailability by several mechanisms including inflammation (as reflected by elevated C-reactive protein [CRP] plasma levels), disruption of insulin receptor signalling cascades, increased production of cytokines (among them interleukin [IL]-6 and tumor necrosis factor [TNF]-α) and activation of the renin angiotensin system.11,12 Adiponectin, an adipocyte-derived protein, stimulates the production of nitric oxide in vascular endothelial cells in vitro, and hypoadiponectinemia observed in insulin resistance is associated with endothelial dysfunction.13,14
Goals of the present study were to compare the effects of the combination therapy of low-dose simvastatin and ezetimibe with high-dose simvastatin monotherapy, aiming at a similar fasting LDL-c reduction, on fasting and post-fat load lipid profiles and endothelial function in obese male patients with metabolic syndrome.
Nineteen nonsmoking obese male subjects, aged 18-70 years, were recruited by an advertisement that called for subjects with waist circumference >102 cm. All subjects were screened for the presence of the metabolic syndrome according to the Adult Treatment Panel III criteria.15 Glucose level ≥7.8 mmol/L after a standardized (75 g) oral glucose tolerance test was also regarded as fulfilling the glucose criterion. Patients with thyroid, hepatic, or renal diseases were excluded. Other exclusion criteria were the history of macrovascular disease (investigated by a standardized health questionnaire), use of vasoactive medication (eg, beta-blockers, calcium antagonists, angiotensin-converter enzyme inhibitors, angiotensin type 1 receptor blockers, statins, aspirin, nonsteroidal inflammatory drugs), blood pressure (≥180 mm Hg systolic and/or ≥110 mm Hg diastolic), body mass index >35, HbA1c >6.5%, and plasma triglycerides >8.0 mmol/L. Blood pressure was measured 3 times with 5-minute intervals. The 3 measurements were averaged. The local ethics committee approved the study and all participants gave their written informed consent.
In this prospective, randomized, crossover, double blind trial, patients received once-daily simvastatin 80 mg or the combination of simvastatin 10 mg and ezetimibe 10 mg.16 Vascular function, as determined with flow-mediated dilation measurements, was performed after 6 weeks of treatment. Between the two treatment periods, patients had a washout period of 4 weeks. Crossover of therapy occurred after washout followed by reassessment of vascular function after 6 weeks. Flow-mediated dilation (FMD) was measured before and 4 hours after an oral fat load during both treatment periods. At the beginning and at the end of each 6-week treatment period, patients underwent physical examination (including height, body weight, waist circumference, body fat, and blood pressure measurements) and blood sampling to determine laboratory parameters.
Assessment of Vascular Function With FMD
A noninvasive technique of assessing endothelial function by ultrasonography of the brachial artery was used. Measurements were made of the vasodilatory responses of the brachial artery to postischemic hyperemia, causing endothelium-dependent dilation. As described previously, all measurements were made with a Wall Track System (WTS) (Pie Medical, Maastricht, the Netherlands) which consists of a standard 7.5-MHz linear array transducer connected to a data acquisition system and a personal computer.17 The first three measurements were averaged to provide a baseline arterial diameter. By inflation of the blood pressure cuff for 5 minutes above a pressure of 250 mm Hg, ischemia was applied in the forearm distal to the location of the echo probe. Upon release of the cuff, the brachial artery will dilate through endothelial NO release (endothelium-dependent vasodilatation). Ultrasonographic measurements were performed 4 times after cuff release at 15 seconds intervals and then 5 times after 30-second intervals. Maximal postischemic dilation was assessed by the widest lumen diameter. Then nitroglycerine (0.4 mg) was administrated sublingually to determine endothelium-independent vasodilatation. WTS measurements were stored and analyzed offline by a blinded observer using WTS software analysis. FMD and nitroglycerine-induced vasodilatation were expressed as percentage change relative to the baseline diameter.
Oral Fat Load
For the fat load, fresh cream was used, which was 40% (weight/volume) fat emulsion with a polyunsaturated/saturated fat ratio of 0.10, containing 0.001% (w/v) cholesterol and 3% (w/v) carbohydrates and representing a total energy content of 3700 kCal/L. Cream was ingested at a dose of 50 g fat and 3.75 g glucose per meter squared of body surface (with a maximum of 250 mL) within 5 minutes. Participants remained supine during the day and were only allowed to drink water. Venous blood samples were obtained before and at 2, 3, and 4 hours after ingestion and were immediately put on ice. Plasma was isolated by centrifugation for 15 min at 3000 revolutions per minute at 4°C. Plasma samples were stored at −80°C for further analyses.
Buffy coats were sampled for isolation of DNA for apoE genotyping. Insulin was measured with an immunometric assay (Diagnostic Products Corporation, Los Angeles, CA). Plasma cholesterol, HDL-c, and LDL-c were measured using commercially available assays (Wako, Osaka, Japan) on a Cobas Mira autoanalyzer (Roche, Basel, Switzerland). VLDL cholesterol was then calculated (VLDL-c = total cholesterol - LDL-c - HDL-c). Plasma triglycerides were analyzed using an automated assay (Randox laboratories, Crumlin United Kingdom). Plasma apoB was analyzed using a nephelometric commercial assay using the Cobas Mira auto analyzer. Plasma remnant-like particle cholesterol (RLP-c) was analyzed using a commercial available assay as described previously.18 Measurements of plasma adiponectin, IL-6, and hs-CRP levels were performed with a commercially available enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, MN).
Waist circumference was measured halfway between the lower rib and the iliac crest. Total body fat percentage was estimated by using Omron body fat monitor BF306 (Omron Matsusaka, Japan).
Fasting and post-fat load FMD measurements were analyzed by an experienced observer blinded to all patients' characteristics and treatment. The post-fat load variations of lipids were integrated as area under the curve (AUC) and were calculated by the trapezoidal rule using GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, CA). Incremental integrated AUC (AUIC) was calculated after correction for baseline values. Differences in FMD and in AU(I)Cs for post-fat load lipids between simvastatin 80 mg and combination therapy of simvastatin 10 mg with ezetimibe 10 mg were analyzed by paired t-test; statistical significance was taken at the 5% level. Carry-over and period effects were calculated with independent-sample t-test.19 Calculations were performed using SPSS for Windows version 12.1. (SPSS Inc., Chicago, IL).
No carryover effects or period effects between the two treatments periods were observed for fasting and post-fat load lipid profiles. Demographic, clinical, and laboratory characteristics of the 19 patients at baseline and after the 2 treatment periods are provided in Table 1. Mean age was 54 ± 7 years. Weight, waist circumference and body fat remained stable during the study. Creatinine kinase (CK) was slightly elevated after treatment (116 ± 53 U/L vs. 143 ± 67 U/L and 152 ± 134 U/L). Only one patient had CK plasma levels (646 U/L) above three times the upper limit of normal (170 U/L) after treatment with combination therapy. No differences were observed in the lipid composition of VLDL, LDL, and HDL particles between simvastatin alone and simvastatin/ezetimibe combination after 6 weeks treatment.
Fasting and Post-Fat Load Lipid Profiles, Insulin, and IL-6 Plasma Concentrations
Total cholesterol decreased from 5.6 ± 0.9 mmol/L to 3.7 ± 0.9 mmol/L during treatment with simvastatin 80 mg and to 3.8 ± 0.9 mmol/L during treatment with combination therapy. Plasma LDL-c concentration was similarly reduced by both treatment regimens (from 3.7 ± 0.7 mmol/L to 2.1 ± 0.5 mmol/L). In Table 2, AUCs and AUICs for LDL-c, VLDL-c, RLP-c, triglycerides, and apoB are shown. No differences were observed for the AUICs for post-fat load LDL-c (−0.20 ± 0.11 vs. −0.14 ± 0.08 mmol·h/L), RLP-c (14 ± 2 vs. 13 ± 2 mmol·h/L) and VLDL-c (0.4 ± 0.1 vs. 0.6 ± 0.1 mmol·h/L) between both treatment regimens. AUICs for triglycerides were slightly higher after treatment with combination therapy compared to high-dose simvastatin alone (3.2 ± 0.4 vs. 2.6 ± 0.2 mmol·h/L), but AUICs for apoB were comparable (0.9 ± 3.3 vs. −0.2 ± 2.3 g·h/L).
In Table 3, it is shown that before as well as 3 and 4 hours after an oral fat load, plasma concentrations of IL-6 were slightly higher during treatment with high-dose simvastatin monotherapy compared to combination therapy (4-hour post-fat load 3.41 ± 0.67 vs. 2.87 ± 0.44 pg/mL). In addition, insulin plasma concentrations were marginally higher after oral fat load during high dose simvastatin monotherapy compared to combination therapy.
Fasting and Post-Fat Load Endothelial Function
Fasting FMD was comparable during both treatment periods (6.9% ± 0.8 vs. 7.6% ± 1.2) (Table 4). However, during simvastatin monotherapy, FMD significantly decreased 4 hours after oral fat load ingestion (6.9% ± 0.8 vs. 4.3% ± 0.6, P = 0.001), whereas no difference in FMD was observed after fat load during combination therapy (7.6% ± 1.2 vs. 7.7% ± 1.6, P = 0.8). Nitroglycerine-induced endothelium-independent vasodilatation of the brachial artery was comparable between the two treatment periods for both fasting and after oral fat load.
In the present randomized, double-blind crossover trial in male patients with metabolic syndrome, combination therapy of low-dose simvastatin and ezetimibe preserved post-fat load endothelial function contrary to high-dose simvastatin monotherapy, whereas the same reduction in fasting plasma LDL-c was obtained after 6 weeks of treatment. Post-fat load plasma triglyceride concentrations were higher during combination therapy compared to monotherapy but apoB concentrations were similar. The post-fat load RLP-c concentration was the same after both treatments.
Ezetimibe decreases LDL-c levels by inhibition of uptake of dietary and biliary cholesterol by binding to the Niemann-Pick C1-like 1 protein at the brush border membrane of enterocytes, a receptor involved in intestinal cholesterol uptake, thereby preventing dietary cholesterol uptake.20,21 We initially hypothesized that postprandial lipid metabolism would benefit from treatment with a cholesterol uptake inhibitor like ezetimibe in combination with simvastatin compared to high-dose simvastatin. However, in the present study we did not observe differences in RLP-c during either treatment regimens. In a recent report, no significant effects of ezetimibe on the postprandial kinetics of intestinally derived apoB 48-containing triglyceride-rich lipoprotein particles were observed. It was shown that ezetimibe treatment led to a reduction of plasma LDL-c by increasing the catabolism of hepatic derived apoB-100 containing lipoproteins without reducing chylomicron particle numbers.22
Increased postprandial lipoprotein remnant levels are associated with an inflammatory response and with development of atherosclerosis.18,23 In the present study, the inflammatory response to a fat load might have been different during both treatments resulting in differential effects on post fat load endothelial function. Low-grade inflammation (reflected by elevated concentrations of CRP) is associated with endothelial dysfunction and it was previously shown that at each statin dose level, coadministration of ezetimibe induced significantly more hs-CRP reduction compared to monotherapy.12,24 In the present study, plasma levels of IL-6 were marginally higher during treatment with high-dose simvastatin monotherapy compared to treatment with low-dose simvastatin combined with ezetimibe, as well as at the time of assessment of endothelial function 4 hours after fat load; however, this difference was not statistically significant. Because hepatic CRP release is under the influence of plasma levels of IL-6, increased levels of hs-CRP during treatment with simvastatin 80 mg monotherapy can also be expected.25
After oral fat load, plasma insulin concentrations were higher during treatment with high-dose simvastatin monotherapy compared with combination therapy, and was most pronounced at the time of FMD measurement. Although insulin enhances eNOS transcription, hyperinsulinemia is associated with endothelial dysfunction by stimulating the release of the potent vasoconstrictor endothelin.12 It has been shown that compared to placebo, the use of statins improved postprandial insulin sensitivity in patients with the metabolic syndrome.26 However, the combination of statins with ezetimibe was not investigated. Although no differences were observed in post-fat load RLP-c during both treatment regimens, it could be speculated that differences in post-fat load lipoprotein composition due to the different treatment regimens lead to differences in postprandial endothelial function.27
In patients with chronic heart failure, 4 weeks of treatment with simvastatin 10 mg improved endothelial function compared to treatment with ezetimibe 10 mg monotherapy, despite a similar decrease in plasma LDL-c concentration.28 In a recent partially randomized trial in patients with stable coronary artery disease, it was shown that both statins and ezetimibe effectively lowered LDL-c plasma concentrations, but only statin therapy was associated with improvement in endothelial function.29 In both studies, it was suggested that pleiotropic, LDL-c-independent effects of statins were involved (ie, increased vascular nitric oxide bioavailability, reduced oxidant stress, improved endothelial progenitor cell function). Positive effects of LDL-c lowering on endothelial function have already been described in various studies, as well as endothelial dysfunction after an oral fat load.5-7,30 In the present study, we did not observe a difference in fasting endothelial function between treatment with simvastatin 80 mg and simvastatin 10 mg combined with ezetimibe 10 mg. Regarding improvement of endothelial function, we could not confirm the existence of pleiotropic effects of high-dose statins in our study cohort during 6 weeks treatment. In addition, combination therapy of low-dose simvastatin with ezetimibe preserved endothelial function after an oral fat load, contrary to high-dose simvastatin monotherapy. Strength of our study was that all patients received both treatments in a crossover design, diminishing variation in endothelial function as often seen in studies with parallel groups.
The existence of pleiotropic effects of statins cannot completely be ruled out by these findings because it is possible that beyond 10 mg simvastatin the maximal pleiotropic effects are already reached. The effects of different lipid-lowering regimens on endothelial function in patients with the metabolic syndrome have been investigated in an open-label nonrandomized comparison.31 In that study, in a small number of metabolic syndrome patients, combination therapy of atorvastatin 10 mg and ezetimibe 10 mg resulted in more reduction in serum total cholesterol and triglycerides concentrations and better endothelial function compared to atorvastatin 40 mg alone. In contrast to our study, plasma LDL-c reductions were not similar, potentially leading to differences in endothelial function. Besides this, post-fat load lipid profiles and endothelial function were not assessed.
We acknowledge some limitations of our study. Only male patients with the metabolic syndrome were studied. Therefore, caution should be taken to generalize these results to female patients. Carryover and crossover effects were not observed and are therefore unlikely to have influenced our results but could not be completely ruled out. Considering the elimination half-life of statins and ezetimibe and a washout period of 4 weeks plus 6 weeks treatment, carryover effects are unlikely to have occurred. To assess post-fat load endothelial function and lipid profiles, a standardized but nonphysiological high-fat meal was used.
In male patients with the metabolic syndrome, 6 weeks of treatment with low-dose simvastatin combined with ezetimibe preserved postprandial endothelial function contrary to high-dose simvastatin monotherapy, whereas no differences were observed in fasting FMD. Post-fat load RLP-c concentration was similar between both treatment regimens. However, the clinical implications of these effects remain to be established.
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