European Heart Journal

European Heart Journal Advance Access originally published online on April 18, 2006
European Heart Journal 2006 27(10):1182-1190; doi:10.1093/eurheartj/ehi881

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Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for ‘pleiotropic’ functions of statin therapy

Stephan Fichtlscherer^*, Caroline Schmidt-Lucke, Susanne Bojunga, Lothar Rössig, Christopher Heeschen, Stefanie Dimmeler and Andreas M. Zeiher

Department of Internal Medicine III, Division of Cardiology, Johann W. Goethe-University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt, Germany

Received 20 December 2005; revised 22 March 2006; accepted 23 March 2006; online publish-ahead-of-print 18 April 2006.

^* Corresponding author. Tel: +49 69 6301 7059; fax: +49 69 6301 6374. E-mail address: fichtlscherer{at}em.uni-frankfurt.de

	Abstract

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
Aims Statin therapy is associated with improved endothelial vasodilator function. The clinical availability of ezetimibe, a potent novel cholesterol absorption inhibitor, enables to differentiate lipid-lowering effects from potential non-lipid-lowering (pleiotropic) mechanisms of statins.

Methods and results Forearm blood flow (FBF) responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were measured by venous occlusion plethysmography in four prospectively defined groups of patients with stable coronary artery disease (CAD) before and after 4 weeks of lipid-lowering therapy. Group A (n=15): de novo monotherapy with 10 mg/day ezetimibe; Group B (n=15): 10 mg/day ezetimibe as an add-on to chronic simvastatin therapy with 20 mg/day; Group C (n=15): dose escalation from chronic 10 to 40 mg/day atorvastatin; and Group D (n=15): de novo monotherapy with 40 mg/day atorvastatin. After 4 weeks of therapy, LDL cholesterol levels were significantly reduced in all four groups. Neither ezetimibe monotherapy (Group A) nor ezetimibe combined with 20 mg simvastatin (Group B) was associated with an increase in ACH-mediated FBF responses after 4 weeks. In contrast, dose escalation of atorvastatin from 10 to 40 mg/day (Group C) or de novo therapy with 40 mg atorvastatin/day (Group D) was associated with a significant increase in ACH-mediated FBF responses (P<0.013).

Conclusion Thus, both statins and ezetimibe effectively lower LDL-levels within 4 weeks of therapy. However, only statin therapy is associated with improved endothelial vasodilator function, disclosing the relevance of pleiotropic effects of statins during short-term treatment of patients with CAD.

Key Words: Endothelial function • Coronary artery disease • Statins • Ezetimibe

	Introduction

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Incontrovertible evidence now exists for the clinical benefit from therapy with the potent cholesterol-lowering 3-hydroxy-3-methylglutanyl coenzyme A (HMG-CoA) reductase inhibitors (statins) in both primary and secondary prevention of atherosclerosis.¹ Besides their beneficial lipid-lowering effects, statins were clinically shown to exert anti-inflammatory, anti-oxidative, and antithrombotic functions in patients at risk for atherosclerosis.² However, controversy persists regarding the clinical relevance of these potential non-LDL-cholesterol-lowering ‘pleiotropic’ functions of statins.¹ Given the close direct relationship between the achieved level of LDL cholesterol and event rate in the major primary and secondary prevention statin trials, LDL cholesterol lowering is still regarded as the primary mechanism underlying the clinical benefits of statin therapy.² Moreover, there is a lack of direct clinical evidence that distinguishes the lipid-lowering-dependent functions from the lipid-lowering-independent functions of statins.

The availability of ezetimibe, a potent intestinal cholesterol-absorption inhibitor, offers the potential to begin to address the question whether some of the benefits conferred by statins may accrue independently of their effects on LDL cholesterol lowering. Ezetimibe was recently shown to significantly lower LDL cholesterol blood levels either when used as monotherapy or in addition to statin therapy.³ Therefore, we investigated whether short-term cholesterol lowering with ezetimibe or atorvastatin differentially affects endothelium-dependent vasodilator function of the forearm circulation, a well established beneficial effect associated with statin-mediated cholesterol lowering in patients with coronary artery disease (CAD).⁴

	Methods

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
Patients
A total of 60 patients with stable CAD were analysed. Patients were prospectively allocated to four predefined groups (Figure 1). Patients who had not previously received statin therapy were randomized to either 10 mg ezetimibe/day (Group A) or 40 mg atorvastatin/day (Group D). Patients, who were chronically (>6 months) treated with a fixed dose of statins, were allocated to either additional 10 mg ezetimibe, if they were on chronic 20 mg simvastatin/day (Group B), or, if they were on 10 mg atorvastatin/day (>6 months), the dose of atorvastatin was increased to 40 mg/day (Group C). On the basis of previously published results using ezetimibe in combination with simvastatin,⁵ the design of our study was chosen in order to maximize the likelihood of equipotent serum cholesterol reductions in Groups B and C.

View larger version (16K): [in this window] [in a new window]   Figure 1 Study flowchart.

 
All patients had angiographically documented atherosclerotic coronary artery lesions. Patients with inflammatory disease or malignancy, ejection fraction <50%, clinical evidence of heart failure, or patients with angina >Braunwald class II were excluded. Vasoactive medications including calcium channel blockers, ACE-inhibitors, and long-acting nitrates were withheld at least 24 h prior to the study. All patients were on chronic aspirin (100 mg/day) and chronic beta-blocker therapy.

All patients gave written informed consent. The study protocol was approved by the Ethical Committee of the Johann Wolfgang Goethe-University of Frankfurt/Main.

Study protocol
Venous occlusion plethysmography for the measurement of forearm blood flow (FBF) was performed in the morning in a quiet and temperature-controlled (22°C) laboratory as previously described.⁶ For the assessment of endothelium-dependent vasodilatation, acetylcholine (ACH; Ciba Vision GmbH, Wessling, Germany) was infused intra-arterially in increasing doses from 10 to 50 µg/min. To assess endothelium-independent vasodilatation, sodium nitroprusside (SNP; Schwarz Pharma, Mohnheim, Germany) was infused in increasing doses from 2 to 8 µg/min. FBF measurements were obtained at baseline and after 4 weeks under identical conditions. The lipid-lowering therapy was withheld for 24 h prior to the control measurements after 4 weeks. In addition, in eight patients, 10 mg ezetimibe/day was continued and an additional FBF measurement was obtained after 3 months. Analysis of the plethysmographic recordings was performed by a technician (M.M.-A.), who was unaware of the patient's therapy or the lipid levels.

Laboratory analysis
At the time of the FBF study, blood samples were collected, and serum and plasma were aliquoted and stored at –80°C until analysed for the measurement of high-sensitive C-reactive protein (hs-C-reactive protein) using an ultrasensitive assay (N Latex C-reactive protein mono; Behring) as described.⁶ Serum lipid levels (total cholesterol, HDL cholesterol, and triglycerides) were analysed by commercially available tests (Roche Diagnostics GmbH, Mannheim, Germany). In a subset of patients, serum was analysed for levels of interleukin 6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) as well as myeloperoxidase (MPO). All tests (ELISA) were performed with commercially available kits (R & D systems Wiesbaden, Germany, for IL-6 and sICAM-1, and Immundiagnostik Bensheim, Germany for MPO).

Statistical analysis
Data are expressed as mean value ± SEM. Continuous variables were tested for normal distribution with the Kolmogorov–Smirnov test and compared by one-way ANOVA. Categorical variables were compared by the ² test and the Fisher exact test. In the case of non-normal distribution, Mann–Whitney U test was used. All the tests performed were two-sided. FBF responses to the drug infusions were examined using a general linear model procedure with repeated measures for the different doses of each drug. To compare the different responses in the four groups of patients, absolute changes in FBF responses were calculated using the area under the curve (AUC) for the ACH- and SNP-induced FBF responses for each individual patient. Comparisons between groups were analysed by one-way ANOVA. Post hoc range tests and pairwise multiple comparisons between the groups were performed with the t-test (two-sided) with LSD adjustment. P-values<0.05 were considered statistically significant. All statistical analyses were performed using SPSS for Windows 11.0.

	Results

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
Table 1 illustrates that the four groups of patients did not differ with respect to age, extent of CAD, the presence of classic risk factors for CAD, or concurrent medication. At baseline, serum lipid levels and C-reactive protein levels were similar in all four groups, except for LDL cholesterol, which was slightly, but significantly lower in Group C (Table 2). After 4 weeks of therapy, total cholesterol levels and LDL cholesterol serum levels were significantly reduced compared with baseline in all four groups, whereas HDL serum levels remained unchanged (Table 2). Most importantly, although LDL cholesterol serum levels were significantly higher in the group of patients receiving ezetimibe monotherapy (Group A), LDL cholesterol serum levels were similar in Groups B, C, and D after 4 weeks of therapy (Table 2). The percent changes in serum cholesterol levels were significantly smaller in the patients of Group A compared with Groups B and D (Figure 2). In addition, percent changes in total cholesterol levels were greater in patients of Group D compared with Groups A and C (Figure 2). Similar results were obtained for LDL cholesterol reductions (Figure 2). Thus, both total and LDL cholesterol lowering were not significantly different in patient Groups B and C. Likewise, C-reactive protein serum levels did not differ between the four groups after 4 weeks of therapy. Furthermore, percent changes in C-reactive protein serum levels did not differ significantly between the four groups (Figure 2).

View this table: [in this window] [in a new window]   Table 1 Baseline characteristics of the study population

 

View this table: [in this window] [in a new window]   Table 2 Lipid and C-reactive protein serum levels before and after therapy

 

View larger version (15K): [in this window] [in a new window]   Figure 2 Relative reduction (% from baseline) of total cholesterol, LDL cholesterol, and C-reactive protein serum levels after 4 weeks of therapy in patients treated with 10 mg ezetimibe/day as mono therapy (A), ezetimibe 10 mg/day as an add-on therapy on top of chronic statin therapy (B), dose escalation from chronic 10 to 40 mg atorvastatin/day (C), or de novo 40 mg atorvastatin/day (D). Values represent mean ± SEM.

 
Figure 3 illustrates FBF responses to ACH (Figure 3A) or SNP (Figure 3B) in the four groups of patients before and after 4 weeks of lipid-lowering therapy. Neither ezetimibe monotherapy (Group A) nor ezetimibe in combination with 20 mg simvastatin (Group B) was associated with any measurable increase in ACH-mediated FBF responses after 4 weeks. In contrast, increasing the dosage of atorvastatin from 10 to 40 mg/day (Group C) or first-time therapy with 40 mg atorvastatin/day (Group D) was associated with a significant increase in ACH-mediated FBF responses. Figure 4 illustrates the absolute changes in ACH-mediated FBF responses, expressed as AUC of the dose response, for the four groups of the patients. Both groups of patients receiving atorvastatin (Groups C and D) demonstrated a significantly greater improvement in ACH-mediated FBF responses compared with the groups of patients receiving ezetimibe (Groups A and B).

View larger version (22K): [in this window] [in a new window]   Figure 3 FBF responses to ACH (A) or SNP (B) in patients treated with 10 mg ezetimibe/day as mono therapy (a), ezetimibe 10 mg/day as an add-on therapy on top of chronic statin therapy (b), dose escalation from chronic 10 to 40 mg atorvastatin/day (c), or de novo 40 mg atorvastatin/day (d). Values represent mean ± SEM.

 

View larger version (13K): [in this window] [in a new window]   Figure 4 (A) Absolute changes of ACH-induced FBF responses after 4 weeks of therapy in patients treated with 10 mg ezetimibe/day as mono therapy (A), ezetimibe 10 mg/day as an add-on therapy on top of chronic statin therapy (B), dose escalation from chronic 10 to 40 mg atorvastatin/day (C), or de novo 40 mg atorvastatin/day (D). Values represent mean±SEM. (B) Absolute changes of SNP-induced FBF responses after 4 weeks of therapy in patients treated with either 10 mg ezetimibe/day as mono therapy (A), ezetimibe 10 mg/day as an add-on therapy on top of chronic statin therapy (B), dose escalation from chronic 10 to 40 mg atorvastatin/day (C), or de novo 40 mg atorvastatin/day (D). Values represent mean±SEM.

 
Thus, despite comparable and significant reductions in LDL cholesterol serum levels, 10 mg ezetimibe/day as add-on to chronic 20 mg simvastatin/day (Group B) did not alter endothelial vasodilator function, whereas increasing the dose of atorvastatin from 10 to 40 mg/day was associated with a significant improvement in endothelial vasodilator function of the forearm circulation in patients with CAD. FBF responses to the endothelium-independent mediator SNP did not significantly change in any of the four groups after 4 weeks of treatment (Figure 3B).

In order to investigate whether extending the treatment period would potentially unmask an effect of lipid lowering with ezetimibe on endothelial function, eight patients of Group A were continued on 10 mg ezetimibe/day monotherapy for further 8 weeks and FBF measurements were repeated at 12 weeks. (These eight patients liked to continue the initiated therapy with ezetimibe and agreed for a third FBF measurement after 12 weeks.) In these eight patients, LDL cholesterol serum levels were 117.6±6.7 mg/dL at baseline, 94.8±4.2 mg/dL at 4 weeks, and further significantly (P<0.046) decreased to 89.8±5.1 mg/dL at 12 weeks. However, as illustrated in Figure 5, even extending the treatment period to 12 weeks did not affect FBF responses to ACH.

View larger version (25K): [in this window] [in a new window]   Figure 5 (A) FBF responses to ACH and SNP at baseline, after 4 weeks, and after 3 months in eight patients receiving 10 mg ezetimibe as a mono therapy. Values represent mean±SEM. (B) FBF responses expressed as area under the dose response curve for each individual patient at baseline, after 4 weeks, and after 12 weeks of 10 mg/day ezetimibe monotherapy. Values represent mean±SEM.

 
Finally, in order to address potential underlying mechanisms, we measured serum levels of MPO as a marker of oxidative stress,⁷ as well as IL-6 and sICAM-1 as direct inflammatory mediators of the vascular wall in a subset of our patients. However, as illustrated in Figure 6, none of these serum parameters was differentially affected by the various lipid-lowering regimens tested in our patient groups.

View larger version (13K): [in this window] [in a new window]   Figure 6 Alterations of MPO, interleukin-6 (IL-6), and soluble intercellular adhesion molecule-1 (sICAM-1) after 4 weeks of therapy in patients treated with 10 mg ezetimibe/day as mono therapy (A), ezetimibe 10 mg/day as an add-on therapy on top of chronic statin therapy (B), dose escalation from chronic 10 to 40 mg atorvastatin/day (C), or de novo 40 mg atorvastatin/day (D). Values represent mean ±SEM.

 

	Discussion

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
The results of the present study demonstrate that 4 weeks of efficient LDL cholesterol lowering with ezetimibe is not associated with an improvement in endothelial vasodilator function of the forearm circulation in patients with CAD. Whereas atorvastatin significantly improved systemic endothelial vasodilator function, neither monotherapy with ezetimibe nor ezetimibe on top of chronic simvastatin administration did result in any measurable increase in endothelium-dependent vasodilation, although the combination of ezetimibe with statin therapy resulted in a comparable LDL cholesterol reduction compared with the effects of increasing the dose of atorvastatin therapy from 10 to 40 mg/day. These findings suggest that LDL lowering does not seem to be the primary mechanism underlying the beneficial effects of short-term atorvastatin therapy on endothelial vasodilator function in patients with CAD.

Previous studies demonstrating statin-mediated improvements in endothelial function to occur within days in humans, even after a single dose and before any significant effects on lipids,^8,9 provided initial suggestive evidence for a potential lipid-lowering-independent mechanism to contribute to improved endothelial function. However, aggressive short-term lipid lowering using a single session of LDL apheresis was also previously shown to improve endothelial vasodilator function within a few hours.¹⁰

The present study, to our knowledge, is the first to provide direct clinical evidence to distinguish the effects of LDL cholesterol lowering by inhibiting intestinal uptake from the effects of statins on endothelial vasodilator function in patients with stable CAD. By the design of our study, the patients receiving ezetimibe on top of chronic simvastatin therapy had similar changes in their blood lipid levels as those patients in whom chronic therapy with 10 mg atorvastatin/day was increased to 40 mg atorvastatin/day. Moreover, the achieved levels of LDL cholesterol after the 4-weeks treatment period were similar in both groups of patients. Finally, both treatment strategies resulted in similar alterations of systemic markers of oxidative stress and inflammation. However, only those patients receiving atorvastatin demonstrated an improvement in endothelial vasodilator function. These findings clearly indicate that LDL cholesterol lowering itself is not the primary mechanism of statin-mediated improvements in endothelial vasodilator function in patients with CAD.

Experimental and clinical studies demonstrated that statins upregulate expression and activity of eNOS,^11,12 scavenge reactive oxygen species directly¹³ or indirectly via activation of the potent radical scavenger thioredoxin,¹⁴ and rapidly increase the level of circulating endothelial progenitor cells.¹⁵ All these mechanisms may have contributed to the observed LDL cholesterol-lowering-independent improvement in endothelial vasodilator function associated with 4 weeks of atorvastatin treatment. Indeed, Landmesser et al.¹⁶ very recently demonstrated an increase in circulating endothelial progenitor cells associated with decreased oxidative stress following 4 weeks of simvastatin treatment in patients with advanced stages of predominantly non-ischaemic heart failure, irrespective of the extent of lipid lowering, supporting the concept of pleiotropic effects of statins in a different patient population.

However, the present clinical study obviously cannot distinguish statin-mediated functions that are dependent on the lowering of cellular isoprenoids from functions that are irrelevant to interactions with the HMG-CoA reductase itself.¹

Both our study population and the study design itself merit some critical consideration. The baseline serum cholesterol levels were rather low in all four groups of patients. However, mean LDL cholesterol levels were still above the threshold levels proposed by clinical practice guidelines for secondary prevention in patients with established CAD.¹⁷ Thus, it is exactly this patient population in which dose escalation of statin therapy or the addition of ezetimibe to statin therapy is appropriate to achieve the desired serum cholesterol levels. Indeed, after 4 weeks of intensified statin therapy or combination therapy with ezetimibe, mean serum LDL cholesterol levels were below 70 mg/dL, which was recently shown not only to confer increased benefit in patients after an acute coronary syndrome,¹⁸ but also to significantly slow the progression of disease in patients with stable CAD.¹⁹ Thus, the lipid profile of our study population clearly reflects current clinical practice to maximize the effects of secondary prevention by lowering serum cholesterol levels. We purposely compared the effects of adding 10 mg ezetimibe to ongoing chronic 20 mg simvastatin therapy with atorvastatin dose escalation from 10 to 40 mg/day, as the 10 mg ezetimibe/20 mg simvastatin dose is marketed worldwide as a fixed-dose, single-tablet product and was shown to result in equipotent LDL cholesterol reductions when compared with 40 mg atorvastatin monotherapy.^5,20 Finally, we decided to use the forearm microcirculation in order to quantitatively assess endothelial vasodilator function using venous occlusion plethysmography, as the forearm circulation does not develop overt atherosclerotic lesions. Indeed, Lüscher and co-workers documented that the endothelial cell layer overlying atherosclerotic lesions in conductance vessels exhibits reduced expression of eNOS coinciding with a blunted NO release.²¹ Thus, the functional effects of short-term lipid lowering may not be readily detectable when studying vasomotor responses of atherosclerotically diseased conductance vessels when compared with the microcirculation. Indeed, previous studies investigating the effects of statin therapy on epicardial artery endothelial function have provided conflicting results, with some showing a beneficial effect on epicardial artery vasomotor responses to ACH,^22,23 whereas other studies did not.^24,25 In contrast, previous studies assessing the effects of statin therapy on microvascular responses in both the forearm and the coronary circulation revealed more homogeneous results, demonstrating an improvement in vasodilator function.^4,24,26–28

Moreover, venous occlusion plethysmography of the forearm circulation is highly reproducible in individual patients, allowing for rather small sample sizes of patient populations in order to detect statistically significant intergroup differences. Nevertheless, we are unable to account for all possible confounders because of the small sample size.

The lack of at least a 3-month treatment period with ezetimibe to improve endothelial vasodilator function in patients with CAD despite effective LDL cholesterol and C-reactive protein lowering does not exclude the potential that long-term therapy with ezetimibe will confer clinical benefits. Indeed, both clinical and experimental observations previously indicated that lipid lowering by means other than statins, such as dietary intervention or ileal bypass surgery, requires markedly more time to manifest clinical benefits or plaque-stabilizing effects.^2,29 Nevertheless, the mechanism underlying the beneficial effects of short-term atorvastatin treatment on endothelial vasodilator function clearly extends beyond the lowering of cholesterol blood levels.

Thus, as there are currently no clinical data supporting the use of ezetimibe in combination with statins (or alone) in secondary prevention for CAD, we would suggest some caution in the use of ezetimibe together with simvastatin in order to improve clinical outcome in patients with established CAD.

Limitations
Whereas patients without prior statin therapy (Groups A and D) were randomly assigned to receive either ezetimibe (Group A) or atorvastatin (Group D), patients in Group B (additional therapy with ezetimibe) and Group C (dose escalation of atorvastatin) were consecutively recruited into the study. Thus, the non-randomized patient allocation to Groups B and C might be confounded by other factors.

Moreover, we cannot exclude that the patient number is probably too small to allow for definite conclusions regarding the potential capacity for lowering the inflammatory burden as measured by proinflammatory cytokines or C-reactive protein levels.

	Acknowledgements

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
We gratefully acknowledge Margret Müller-Ardogan for expert technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (SFB 553, Project C5).

Conflict of interest: none declared.

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Top Abstract Introduction Methods Results Discussion Acknowledgements References

 

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