Endothelial function in high-risk patients with ezetimibe therapy

doi:10.21203/rs.3.rs-4881243/v1

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Endothelial function in high-risk patients with ezetimibe therapy

https://doi.org/10.21203/rs.3.rs-4881243/v1

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Background

Impaired endothelial function predicts cardiovascular (CV) events, especially in patients with established CV disease. The aim of this post hoc analysis was to compare the endothelial function between high-risk patients on optimized statin therapy with and without additional ezetimibe treatment.

Methods

A total of 91 patients with CV and statin treatment (Atorvastatin or Rosuvastatin) were included and underwent examination of endothelial function by the UNEX EF device. Endothelial function parameters were compared between patients with (E + group) and without ezetimibe therapy (E- group) (NCT03626831).

Results

Compared to patients in the E- group (n = 70), patients in the E + group (n = 21) were younger (67.0 ± 7.4 versus 61.2 ± 7.2 years; p = 0.002), had lower low density lipoprotein cholesterol (91.2 ± 13.3 versus 102.0 ± 18.1 mg/dl (p = 0.013) and lower office systolic blood pressure (123.9 ± 11.4 versus 130.2 ± 14.5 mmHg (p = 0.042). High sensitive C-reactive protein (hsCRP) was lower in the E + group than in the E- group (0.5 ± 0.4 versus 1.1 ± 0.9 mg/L; p = 0.037). We found a greater flow-mediated vasodilation (6.1 ± 2.0 versus 3.7 ± 3.2%; p = 0.004) and lower brachial intima-media thickness (0.28 ± 0.1 versus 0.32 ± 0.0 mm; p = 0.011) in the E + group compared to the E- group. When confounders were entered in a covariance analysis, differences of FMD (p = 0.034) and hsCRP (p = 0.049) between the groups remained significant.

Conclusion

Our data indicate that endothelial function is better in high-risk patients with preexisting CV disease treated with ezetimibe along with statin than in patients with statin monotherapy.

Trial registration Number:

NCT03626831

Date of registration: 2018-08-08

endothelial function

ezetimibe

statins

cardiovascular disease

flow-mediated vasodilatation

Cardiovascular (CV) diseases are the leading cause of mortality and closely related to dyslipidemia, characterized by elevated low density lipoprotein cholesterol (LDL-C). [1] Atherosclerosis is usually the consequence of the accumulation of LDL-C in the arterial walls. [2, 3] Thus, reduction of LDL-C is an important target to reduce atherosclerotic CV disease. The 2019 European Society of Cardiology and the European Atherosclerosis Society (EAS) guidelines recommend a reduction of LDL-C < 55 mg/dL for very high risk-patients and a reduction of LDL-C < 70 mg/dL for high risk patients. [3] Similarly, the American Heart Association recommend lowering of blood cholesterol as much as possible. [2]

Ezetimibe, a cholesterol absorption inhibitor targeting the Niemann-Pick C1-like 1 (NPC1L1) protein, is a LDL-C lowering agent that can be used in combination to statins to achieve the LDL-C targets that are recommended by the guidelines according to the patients’ CV risks. [4, 2, 3] By targeting the intestinal cholesterol absorption, ezetimibe effectively lowers LDL-C levels further reducing CV risk in high-risk patients.[5] The prospective IMPROVE-IT study with 18,144 patients demonstrated that ezetimibe added to a simvastatin therapy lowers the incidence of CV events even in high-risk patients. [6] Although the efficacy of ezetimibe/statin therapy in reducing CV events was evaluated in several studies, [7] data on the impact of this combination on endothelial function in high-risk patients remains scarce. Intact endothelial function is an important parameter of vascular health and is usually impaired in high-risk patients with atherosclerotic CV disease. [8–10]. Endothelial function can be assessed non-invasively by the measurement of flow-mediated vasodilatation (FMD) as a tool to assess vasodilator responsiveness. [11] Our hypothesis was that ezetimibe therapy improves endothelial function thereby contributing to the improvement in CV outcome observed in prospective trials with ezetimibe. We therefore compared endothelial function between high-risk patients on optimized statin therapy with and without additional ezetimibe treatment.

Study design

This single-center, cross-sectional study analysed 91 patients with diagnosed CV disease, who had to be treated with either atorvastatin or rosuvastatin. All patients participated in the “Randomized, double-blind, placebo controlled, parallel-group, prospective clinical study to analyze the effect of evolocumab on vascular function” trial (NCT03626831) conducted between April 2019 and June 2021 in our clinical research center at the University Hospital Erlangen-Nuremberg (www.crc-erlangen.de). First trial registration was on 13/08/2018.

The study was approved by the local Ethical Review Committee (ethics committee of the University of Erlangen-Nuremberg) and the study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all patients prior to study inclusion.

Study cohort

A total of 91 patients with CV disease aged 40–80 years were included in our analysis and 21 patients were treated with ezetimibe in addition to the therapy with either atorvastatin or rosuvastatin. The eligibility criteria for the study included a history of clinically evident atherosclerotic CV disease as evidenced by any of the following: diagnosis of coronary artery disease evidenced by acute coronary syndrome, myocardial infarction, coronary stent implantation, coronary stenosis ≥ 50% by coronary angiography, the diagnosis of non-hemorrhagic stroke or transient ischemic attack or symptomatic peripheral arterial disease. The patients had to have a fasting LDL-C ≥ 70 mg/dL or non-high density lipoprotein cholesterol (HDL-C) ≥ 100 mg/dL despite stable optimized lipid lowering therapy for at least 4 weeks. Main exclusion criteria were statin intolerance or known or suspected homozygous familial hypercholesterolemia. Furthermore, patients with NYHA class III or IV, patients with a left ventricular ejection fraction of < 30%, atrial fibrillation, history of hemorrhagic stroke at any time or an estimated glomerular filtration rate of < 30 ml/min/1.73m² were excluded.

Assessments

Medical history, physical examination, vascular assessments and office blood pressure (BP) were assessed. All patients underwent examination of endothelial function by a semi-automatic high-resolution ultrasound system (UNEX EF 18G; Unex Co., Nagoya, Japan), which was described previously. [12, 13] Briefly, an occlusion cuff was wrapped around the forearm and the pre-cuff-inflation diameter (baseline diameter), the pre-cuff-deflation diameter (minimum diameter) and the post-cuff-dilatation diameter (maximum diameter) were obtained. The endothelial function parameters such as FMD, low flow-mediated vasoconstriction (L-FMC; vasoconstrictor responsiveness) and vasoactive range (VAR; total vasomotor responsiveness). Moreover, brachial intima-media thickness (bIMT) were calculated as described previously [13] and compared between patients with (E + group) and without ezetimibe therapy (E- group).

Blood samples were drawn to measure LDL-C, HDL-C, total cholesterol, triglycerides, serum creatinine, estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and glycated hemoglobin (HbA1c). Office BP was measured with validated devices following the recommendations of the European Society of Hypertension/European Society of Cardiology. [14, 15]

Statistical analysis

Statistical analysis was performed using SPSS Statistics 28.0 (IBM, Armonk, New York, USA) and data were expressed as mean ± standard deviation (SD) in text and tables. A two-sided p-value of < 0.05 was considered statistically significant. The unpaired Student’s t-test was used to determine the statistical significance of the differences between the E + and E- groups. To rule out the influence of potential confounders, we adjusted our approach to all parameters that differed between the two treatment groups with a p-value < 0.10 (i.e. age, baseline office systolic BP and HbA1c) by applying covariance analysis (model 1). In addition we included LDL-C in our covariance analysis to determine potential pleiotropic effects of ezetimibe despite the lower LDL-C in the E + group (model 2). Bivariate correlation analyses were assessed by performing Pearson correlation coefficient.

Baseline characteristics

The baseline characteristics of the E + and E- groups are shown in Table 1. Patients in the E + group were younger than patients in the E- group (p = 0.002), had lower office systolic BP (p = 0.042) and tended to have lower HbA1c (p = 0.086), without significant differences in office BP, body mass index (BMI) gender distribution and triglycerides between the two groups. More patients in the E + group had coronary artery disease (p = 0.042) and symptomatic peripheral artery diseases (p = 0.044) than patients in the E- group. The two treatment groups did not differ in the prevalence of transient ischemic attack or non-hemorrhagic stroke (p > 0.05).

Table 1

Baseline characteristics
	E + group (n = 21)	E- group (n = 70)	P-value
Demographic data
Age (years)	61.2 ± 7.2	67.0 ± 7.4	0.002
Gender (m/f)	19/2	62/8	0.807
BMI (kg/m²)	27.6 ± 3.5	28.6 ± 4.4	0.349
Medical history
Coronary artery disease, n (%)	21 (100)	58 (82.9)	0.042
Non-hemorrhagic stroke, n (%)	0 (0)	11 (15.7)	0.053
Transient ischemic attack, n (%)	1 (4.8)	2 (2.9)	0.668
Symptomatic peripheral artery disease, n (%)	3 (14.3)	2 (2.9)	0.044
Lipid lowering medication
Rosuvastatin, n (%)	3 (14.3)	14 (20)	0.556
Atorvastatin, n (%)	18 (85.7)	56 (80)	0.556
Laboratory values
Total cholesterol (mg/dL)	150.5 ± 20.3	166.6 ± 23.6	0.006
LDL-C (mg/dL)	91.2 ± 13.3	102.0 ± 18.1	0.013
HDL-C (mg/dL)	46.7 ± 9.4	50.6 ± 12.4	0.183
Triglycerides (mg/dL)	115.3 ± 49.2	114.0 ± 53.5	0.920
Hs-CRP (mg/L)	0.5 ± 0.4	1.1 ± 0.9	0.037
Fasting plasma glucose (mg/dL)	100.5 ± 11.0	105.1 ± 19.1	0.293
HbA1c (%)	5.7 ± 0.3	6.0 ± 0.7	0.086
Hemoglobine (g/dL)	14.5 ± 1.0	14.3 ± 0.8	0.314
Hematocrit (%)	42.4 ± 2.9	42.4 ± 2.7	0.980
Creatinine (mg/dL)	0.9 ± 0.2	1.0 ± 0.2	0.435
eGFR, CKDEpi (ml/min/1.73m²)	83.4 ± 16.7	79.0 ± 14.1	0.227
Office BP
Systolic BP (mmHg)	123.9 ± 11.4	130.2 ± 14.5	0.042
Diastolic BP (mmHg)	77.2 ± 8.3	76.4 ± 8.7	0.700
Heart rate (bpm)	65.2 ± 13.8	64.3 ± 9.4	0.737
BMI – body mass index, LDL-C – low density lipid cholesterol, HDL-C – high density lipoprotein cholesterol, hs-CRP – high sensitive C reactive protein, HbA1c – glycated hemoglobin, eGFR - estimated glomerular filtration rate, CKD-Epi - Chronic Kidney Disease Epidemiology Collaboration, BP - blood pressure, bpm – beats per minute.
Data are presented as mean ± SD. Bold values represent p ≤ 0.05.

Lipid status

In the E + group 3 patients had combination therapy with 10 mg ezetimibe and 20 mg Rosuvastatin once daily and 18 patients had combination therapy with 10 mg ezetimibe and 20 mg Atorvastatin (n = 4), 40 mg Atorvastatin (n = 11), or 80 mg Atorvastatin (n = 3) once daily (Table 1). Fourteen patients in the E- group were treated with 10 mg Rosuvastatin (n = 6), 20 mg Rosuvastatin (n = 7) or 40 mg Rosuvastatin (n = 1) and the remaining 56 patients were treated with 10 mg Atorvastatin (n = 9), 20 mg Atorvastatin (n = 17), 40 mg Atorvastatin (n = 23), 60 mg Atorvastatin (n = 2) or 80 mg Atorvastatin (n = 5) once daily. LDL-C and total cholesterol were lower in the E + group compared to the E- group (p = 0.012 and p = 0.013, Table 1).

Endothelial function

FMD was greater in the E + group compared to patients in the E- group (6.1 ± 2.0 versus 3.7 ± 3.2%; p = 0.004, Fig. 1 and Table 2). We did not observe any difference in L-FMC or VAR between the two groups (all p > 0.1, Table 2). bIMT was lower in patients in the E + group compared to the other group (0.28 ± 0.1 versus 0.32 ± 0.0 mm; p = 0.011, Table 2). High-sensitive C-reactive protein (hsCRP) was lower in the E + group than in the E- group (0.5 ± 0.4 versus 1.1 ± 0.9 mg/L; p = 0.037, Table 1 and Fig. 2). In the total study cohort (E + and E- group together) we observed a correlation of total cholesterol with FMD (r=-0.255, p = 0.020, Fig. 3A) and a trend for LDL-C with FMD (r=-0.208, p = 0.059, Fig. 3B).

Table 2

Vascular parameters
	E + group (n = 21)	E- group (n = 70)	P-value	P-value*	P-value**
FMD (%)	6.1 ± 2.0	3.7 ± 3.2	0.004	0.034	0.057
L-FMC (%)	1.6 ± 2.5	0.7 ± 3.2	0.286	0.411	0.419
VAR (%)	4.4 ± 3.2	2.9 ± 4.0	0.156	0.308	0.380
bIMT (mm)	0.28 ± 0.1	0.32 ± 0.0	0.011	0.228	0.191
*Model 1: adjusted for age, office systolic BP and HbA1c
** Model 2: adjusted for age, office systolic BP, HbA1c and LDL-C
FMD – flow mediated dilatation, bIMT – brachial intima-media thickness, L-FMC – low flow mediated vasoconstriction, VAR – vasoactive range,
Data are presented as mean ± SD. Bold values represent p ≤ 0.05.

Coviariance analysis

When confounders (Model 1: age, systolic office BP and HbA1c) were entered in a covariance analysis, differences in FMD (p = 0.034, Table 2) and hsCRP (p = 0.041), but not in bIMT (p = 0.228, Table 2) remained significant between the two groups.

When we entered LDL-C in the covariance analysis (Model 2) as an additional potential confounder, FMD (p = 0.057) and hsCRP (p = 0.083) tended to be lower in the E + group (Table 2). The difference in bIMT was no longer significant after adjusting for the mentioned parameters (p = 0.191, Table 2).

In the present study we analysed the impact of ezetimibe therapy on endothelial function in patients with established CV disease. Our main result was that endothelial function is better preserved in high-risk patients with preexisting CV disease if treated with ezetimibe along with statin, compared to high risk patients treated with statin only. Of note, endothelial dysfunction causes vasoconstriction, leads to arterial stiffness and ultimately increases future CV events. [9, 10, 16]

In our study we assessed endothelial function with the UNEX system, which is a semi-automatic system and less prone to errors compared to previous hand-held ultrasound systems. [17] FMD is one of the most widely assessed parameters for the analysis of endothelial function and impaired FMD has been shown to be a predictor for CV events in both patients with CV disease and healthy subjects. [18–20] Our group was amongst the first to show that statin treatment improves vascular function in patients with increased LDL-C and we were also able to show that an improvement in endothelial function with statin therapy is linked with an improvement of pulse wave velocity. [21–23] Most recently our group has shown that in patients with established CV diseases, evolocumab in addition to statin treatment leads to an improvement of endothelial function, despite the treatment with statins and ACE-inhibitors or AT-1-receptor-blockers. [24] In the present study patients with ezetimibe, in addition to high-potent statin treatment, had a higher FMD indicative of a more intact endothelial function compared to patients with statin-monotherapy. This result remained significant after adjusting for the potential confounders age, systolic office BP and HbA1c, and was observed despite the fact that coronary artery diseases and peripheral arterial diseases were more frequent in this group. The IMPROVE-IT study showed that ezetimibe added to statin therapy reduces cardiovascular events in high-risk patients. [6] Thus, our results support the explanation that the lower CV endpoint rates achieved by ezetimibe in the IMPROVE-IT study may be related to improved endothelial function by ezetimibe. [6]

Several studies reported that lowering LDL-C levels are the key to achieve better outcomes, and the pleiotropic effects of statins are of minor importance. [26–28] The results of the IMPROVE-IT trial provide strong support that the lower LDL-C levels achieved by adding ezetimibe are the key mediators that lead to better CV outcomes. [27] In support to that, we found an association between FMD and total cholesterol and a trend for LDL-C in the overall cohort.

In a small study Settergren et al. found an increase in FMD in both treatment groups in patients with stable coronary artery disease treated with the combination therapy of statin and ezetimibe once daily or with simvastatin monotherapy once daily. [25] However, in contrast to our study design, low potent statin in a dose i.e. simvastatin 10 mg was used in combination with ezetimibe. As a result the LDL-cholesterol level after treatment was comparable between the two groups. In our present study we had significantly different LDL-C levels in the E + and E- group and therefore adjusted not only for age, office systolic BP and HbA1c, but also for LDL-C (model 2). After adjustment there was still a trend for a better FMD in the E + group. This observation does not allow any conclusion but the observed signal of better FMD in patients treated with ezetimibe may suggest potential pleiotropic effects of ezetimibe itself. There are still only limited data about possible pleiotropic effects of ezetimibe beyond its inhibition of intestinal cholesterol absorption. Tie et al. reported that ezetimibe may have extra-intestinal effects by inhibition of macrophage migration. [29] Another study suggested that ezetimibe may reduce acute inflammatory response (mediated by macrophages) and reduce plaque size trough the inhibition of macrophages. [30] However, in a small study, patients with heart failure were randomized to simvastatin (N = 10) or ezetimibe monotherapy (N = 10) and only patients with the simvastatin monotherapy had an increase in flow-dependent dilatation. Unfortunately, they did not examine the combination of statin therapy combined with ezetimibe. Thus, the results are not conflicting to our findings. [31] In support of our results that ezetimibe therapy leads to an improvement of endothelial function, we also found a lower hsCRP in patients in the E + group. Elevated hsCRP is a marker for inflammation, is related to impaired endothelial function and associated with an increase of CV event. [32–34] Thus, the lower hsCRP may indicate less inflammation in these patients with combined treatment of ezetimibe with statins and partially explain the better FMD in the E + group.

Limitations

Our study has several limitations. It is a single-center, cross-sectional post-hoc analysis with a small sample size and therefore just allows us to generate hypothesis that require longitudinal examinations of endothelial parameters in patients with or without ezetimibe in addition to statin treatment.

In conclusion, we observed that endothelial function is better in high-risk patients with preexisting CV disease treated with ezetimibe along with statin than in patients with statin monotherapy. The results may explain to some extent lower CV endpoint rates achieved by ezetimibe in the IMPROVE-IT study.

Ethics approval and consent to participate

Written informed consent was obtained from each patient before study inclusion. The study protocol was approved by the Local Ethics Committee (University of Erlangen- Nuremberg), and the studies were conducted in accordance with the Declaration of Helsinki and the principles of good clinical practice guidelines.

Consent for publication

All authors gave full consent for publication.

Competing interests

MGA and other authors except RES declare that they have no conflict of interest with respect to this study. RES has conflict of interests with respect to this study: Amgen, Boehringer Ingelheim, AstraZeneca (grants to the institution, speaker and adviser)

Funding

No funding received.

Author Contributions:

Merve Günes-Altan analyzed data, contributed to the discussion and wrote the manuscript.

Agnes Bosch, Kristina Striepe, Mario Schiffer and Peter Bramlage collected data, contributed to the discussion and reviewed the manuscript.

Roland E. Schmieder analyzed data, contributed to the discussion and reviewed/edited the manuscript.

Dennis Kannenkeril designed the study, analyzed data, contributed to the discussion and reviewed/edited the manuscript.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the
corresponding author on reasonable request.

Acknowledgements

We gratefully acknowledge the expert technical assistance of Dorothea Bader-Schmieder, Ingrid Fleischmann, Kerstin Fröhlich-Endreß, Ulrike Heinritz, Simone Pejkovic, Wiebke Maurer and Theresa Federlein.

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No competing interests reported.

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Endothelial function in high-risk patients with ezetimibe therapy

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Abstract

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Introduction

Methods

Study design

Study cohort

Assessments

Statistical analysis

Results

Baseline characteristics

Lipid status

Endothelial function

Coviariance analysis

Discussion

Limitations

Conclusion

Declarations

References

Additional Declarations

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