The Effect of Different Statin‐Based Lipid‐Lowering Strategies on C‐Reactive Protein Levels in Patients With Stable Coronary Artery Disease

ABSTRACT Background Statins are lipid‐lowering drugs with favorable anti‐inflammatory effects. This study aimed to explore different statin‐based lipid‐lowering strategies to reduce high‐sensitivity C‐reactive protein (hs‐CRP). Hypothesis The hypothesis is that different statin‐based lipid‐lowering strategies might reduce hs‐CRP. Methods This retrospective study included 3653 patients who underwent percutaneous coronary intervention (PCI). Three statin‐based lipid‐lowering strategies were investigated, including different types of statins (atorvastatin vs. rosuvastatin), statin combined with ezetimibe therapy (vs. without), and intensive statin therapy (vs. regular). The hs‐CRP levels and blood lipid indicators were measured at baseline and after 1‐month lipid‐lowering therapy. Multivariable linear regression analysis and structural equation mode analysis were conducted to verify the association between different lipid‐lowering strategies, Δhs‐CRP (%) and ΔLDL‐C (%). Results Totally, 3653 patients were enrolled with an average age of 63.81 years. Multivariable linear regression demonstrated that statin combined with ezetimibe therapy was significantly associated with decreased Δhs‐CRP (%) (β = −0.253, 95% CI: [−0.501 to −0.005], p = 0.045). The increased ΔLDL‐C (%) was an independent predictor of elevated levels of Δhs‐CRP (%) (β = 0.487, 95% CI: [0.15−0.824], p = 0.005). Furthermore, structural equation model analysis proved that statin combined with ezetimibe therapy (β = −0.300, p < 0.001) and intensive statin therapy (β = −0.032, p = 0.043) had an indirect negative effect on Δhs‐CRP via ΔLDL‐C. Conclusions Compared with routine statin use, statin combined with ezetimibe therapy and intensive statin therapy could further reduce hs‐CRP levels.


| Introduction
Coronary artery disease (CAD) is the most prevalent cause of mortality worldwide, and stable coronary artery disease (SCAD) is one of the most common clinical manifestations [1].For decades, lipid-lowering therapy has been a mainstay for CAD patients [2].American College of Cardiology/ American Heart Association (ACC/AHA) 2019 guidelines recommended lipid-lowering therapy as the primary and secondary prevention of CAD [3].Statins are the commonly used lipid-lowering drugs, which primarily reduce the lowdensity lipoprotein cholesterol (LDL-C), delay arteriosclerosis, and decrease the risk of cardiovascular adverse events [4].In addition to the lipid-lowering effect, statins have pleiotropic vasculoprotective properties, such as reducing inflammation and improving endothelial function [5].The anti-inflammatory effect of statins is currently a hot research topic.
Inflammation plays a crucial role in the pathogenesis of atherosclerosis, so anti-inflammatory therapy is vital for a good prognosis in CAD patients [6,7].C-reactive protein (CRP) is a widely used inflammatory biomarker, and elevated CRP is related to the higher incidence of cardiovascular diseases [8].High-sensitivity CRP (hs-CRP) has been reported to be a better predictor of inflammatory response and vascular disorders than CRP [9].Numerous studies have demonstrated that statins have an anti-inflammatory property that significantly reduces hs-CRP levels [10,11].Previous research solely focused on validating that different stain-based lipid-lowering therapies involving different types of statins, such as statin combined with ezetimibe, could decrease the levels of CRP or hs-CRP [12,13].However, it has not been adequately studied whether such an effect on hs-CRP differs significantly between different statin-based lipid-lowering strategies.It is also unclear whether statin-based lipid-lowering strategies directly reduce hs-CRP levels or are indirectly mediated by LDL-C.Therefore, the purpose of this study is to compare the effect of different statin-based lipid-lowering strategies, including different types of statins (atorvastatin vs. rosuvastatin), statin combined with ezetimibe therapy (vs.without), and intensive statin therapy (vs.regular), on the decrease of hs-CRP in patients treated with statins after percutaneous coronary intervention (PCI) and to further explore whether this effect on hs-CRP decrease is mediated by LDL-C.

| Study Design
This research was an observational retrospective study that followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [14].From May 2013 to October 2018, CAD patients who underwent PCI following treatment with statins in Sir Run Run Shaw Hospital were studied.The inclusion criteria were as follows: (1) patients of SCAD who underwent PCI and were treated with oral lipid-lowering medications (atorvastatin or rosuvastatin with/without ezetimibe) after discharge, (2) hs-CRP and LDL-C were evaluated on admission and 1-month follow-up after discharge, and (3) data of demographic, laboratory examination, and medication was available for analysis.A total of 4937 individuals were available for analysis according to the above inclusion criteria.The exclusion criteria were as follows: (1) patients who were treated with other statins such as simvastatin and pravastatin (N = 977), (2) patients with hs-CRP > 10 mg/L at baseline or follow-up (N = 69), (3) patients with clinically apparent infectious diseases during hospitalization or 1-month follow-up (N = 37), (4) patients with familial hyperlipidemia (N = 178), and (5) patients who died during 1-month follow-up (N = 23).Finally, a total of 3653 patients were enrolled.

| Definitions
According to the 2019 ACC/AHA guideline [3], regular statin therapy was defined as the administration of atorvastatin 20 mg per day or rosuvastatin 10 mg per day, and intensive statin therapy was defined as the administration of atorvastatin (40 mg or greater) or rosuvastatin (20 mg or greater).Statin combined with ezetimibe therapy was defined as the regular dose of statin with ezetimibe of 10 mg or greater per day.
This study elected Δhs-CRP (%) and ΔLDL-C (%) to represent the change of hs-CRP levels.Δhs-CRP (%) and ΔLDL-C (%) were the ratio of change in hs-CRP and LDL-C from baseline to 1-month follow-up, calculated as the (follow-up minus baseline) divided by baseline, respectively.

| Data Collection
The data were collected from the hospital information system.The demographic information included age, gender, comorbidity, medication at discharge, and follow-up records.During treatment, hs-CRP, LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), and triglycerides (TG) were measured at baseline and 1 month of lipid-lowering therapy.Besides, the levels of creatine kinase (CK) and creatinine (Cr) were also recorded at baseline and 1-month follow-up.All blood samples were obtained after fasting overnight for at least 12 h and measured by experienced operators in a central laboratory.

| Statistical Analysis
Continuous variables were shown as the mean ± standard deviation and were compared by Mann−Whitney U tests.
Categorical variables were represented as counts (proportions) and were compared by the χ 2 test or Fisher's exact test (if the expected cell value was <5).Spearman's correlation analysis was determined and visualized by a correlation matrix plot.A loess smooth curve was depicted to visualize the relationship between ΔLDL-C (%) and Δhs-CRP (%).The univariable and multivariable linear regression analyses were performed to assess the influence of different lipidlowering strategies on both ΔLDL-C (%) and Δhs-CRP (%), respectively.Furthermore, the structural equation model was conducted to determine the direct and indirect effects through ΔLDL-C (%) of lipid-lowering strategies on the Δhs-CRP (%) levels.
A two-tailed p < 0.05 was considered significant.Statistical analysis was performed using SPSS software, version 18.0 (SPSS Inc., Chicago, IL, USA), and R, version 3.5.1 (The R Foundation for Statistical Computing, Vienna, Austria).

| Population Characteristics on the Baseline and 1-Month Follow-up
A total of 3653 patients were enrolled.The average age was 63.81 years, and the male population accounted for 69.4%.According to the median change in Δhs-CRP (%) levels, patients were divided into the following two groups: high-effective Δhs-CRP (%) group (n = 1828) and low-effective Δhs-CRP (%) group (n = 1825).

| Discussion
The current study demonstrated that different statin-based lipid-lowering strategies exhibited different effects on decreasing hs-CRP levels.The LDL-C partly mediated the relationship between statin-based lipid-lowering strategies and hs-CRP levels.We found that hs-CRP reduction and LDL-C reduction occur simultaneously and in parallel correlation when statins are combined with ezetimibe therapy, and our hypotheses and conclusions partially demonstrate a possible mediating effect.However, it is important to note that our study was not about LDL-C and hs-CRP but about the potential effect of lipidlowering strategies on the presence of hs-CRP, and therefore, this paper cannot prove a causal relationship between LDL-C and hs-CRP.Compared to routine statin use, statin combined with ezetimibe therapy and intensive statin therapy could further reduce hs-CRP levels.There was no significant difference in the effects on hs-CRP among different types of statins.Lipid-lowering therapy, particularly statin therapy, has been the cornerstone of CAD prevention due to its potent lipidlowering effect [15].Recently, researchers found that statin therapy was also a promising anti-inflammatory therapy [16].
The JUPITER trial, a landmark trial, proved that statin therapy contributed to a significant reduction in hs-CRP level, decreasing the risk of cardiovascular events [12].Tan et al. reported that the combination therapy with atorvastatin and ezetimibe

Note:
Variables to be entered into the multivariable linear regression analysis were chosen on the basis of the results of univariable analysis (p < 0.1).Abbreviations: hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein-cholesterol.
a Multivariable linear regression excluded the ΔLDL-C (%) for further analysis.
efficiently controlled the variation of LDL-C and, in the meantime, alleviated the inflammation, becoming an alternative approach in clinical practice [17].This study further compared the efficacy of different stain-based lipid-lowering strategies on hs-CRP levels based on previous research.This study demonstrated that compared to statin monotherapy, statin combined with ezetimibe therapy was significantly associated with reducing hs-CRP.Therefore, statin combined with ezetimibe therapy in clinical practice might be a more encouraging option for downregulating inflammation in patients after PCI.However, no differences were observed among different types of statins or between intensive statin therapy and regular statin therapy.
More importantly, LDL-C partly mediated the relationship between statin-based lipid-lowering strategies and hs-CRP levels, as hs-CRP reduction and LDL-C reduction occur simultaneously, and in parallel correlation, when statins are combined with ezetimibe therapy as shown in Supporting Information S1: Figure 3, the association of therapy, LDL-C, and hs-CRP was significant.LDL-C is the important determinant of arteriosclerosis in various lipid markers with a proinflammatory effect [18,19].Miller et al. found that oxidized LDL-C can result in severe inflammatory processes [20].
Consistently, this study established a close relationship between hs-CRP and LDL-C.The multivariable linear regression analysis showed that statin combined with ezetimibe therapy was significantly associated with the Δhs-CRP (%), while this association was absent when incorporating ΔLDL-C (%) into the model, suggesting that the decrease of LDL-C strongly influenced such effects on hs-CRP reduction.Structural equation model analysis also proved that ΔLDL-C (%) played an intermediary role.In this study, although intensive statin therapy also had the indirect pathway (intensive statin therapy → ΔLDL-L [%] → Δhs-CRP [%]), the correlation between intensive statin therapy and LDL-C was weak, which might explain why intensive statin therapy was not significantly linked with the decrease of hs-CRP levels when compared with regular statin therapy.
Based on the available studies, the effect of statin-based lipidlowering strategies on lowering hs-CRP levels may be clarified by the following mechanisms.First, the inflammation usually cooccurs with oxidative stress, an important component of atherosclerosis pathogenesis [21,22].Hyperlipidemia exacerbates this oxidative stress, thereby aggravating the inflammatory status and promoting the progression of atherosclerotic plaques [23].Consequently, applying lipid-lowering strategies can lower blood lipid levels and reduce the hs-CRP levels by improving oxidative stress.Second, PCI procedures may cause mechanical injury to the coronary vessels, leading to a sharp increase of hs-CRP in the short term [24].To narrow down the effect of PCI surgery on hsCRP, we included all SCAD patients after PCI and used △hsCRP (%) from baseline as an endpoint to convert the absolute value of the change into a relative value, taking into account the individual variability that exists at baseline.Lipid-lowering drugs, especially statins, can improve vascular endothelial function by activating the endothelial nitric oxide synthase (eNOS) system and increasing the production of nitric oxide (NO) [25].NO is regarded as an important vascular protective molecule and an important mediator of inflammatory reactions, which can promote the health of blood vessels [26].Therefore, lipidlowering treatment may induce NO production and endothelial repair by employing the anti-inflammatory effect.Third, the inflammation of atherosclerosis is a chronic systemic inflammatory response rather than a local vascular inflammation [27].The LDL-C circulating in the bloodstream can enhance the activation of toll-like receptors, which subsequently mediate immunological response and increase hs-CRP levels [28].It can be speculated that due to the application of lipid-lowering drugs, the decrease in LDL-C contributes to preventing the activation of the inflammatory cytokine and alleviating inflammatory reactions [29].
Although important findings were presented here, some limitations still deserve attention.First, as a retrospective study, the inherent selection and follow-up bias were unavoidable.Second, hs-CRP may not be a reliable diagnostic marker as various factors can affect the hs-CRP levels, especially infection or injury.Therefore, this study excluded patients with clinically apparent infectious diseases or abnormally elevated hs-CRP levels (hs-CRP > 10 mg/L).Third, we only analyzed the effect of statin and ezetimibe, and other lipid-lowering drugs had not been investigated.Fourth, the effect of lipid-lowering strategies on hs-CRP was studied only at 1 month, and it is unclear whether long-term efficacy remains unchanged.

| Conclusions
Compared with routine statin use, statin combined with ezetimibe therapy and intensive statin therapy could further reduce hs-CRP levels.There was no significant difference in the effects on hs-CRP between different types of statins.*p < 0.05.

TABLE 2 |
The outcome of 1-month follow-up.

TABLE 4 |
Linear regression results of lipid-lowering strategies on ΔLDL-C (%).Note: Variables to be entered into the multivariable linear regression analysis were chosen on the basis of the results of the univariable analysis.Abbreviation: LDL-C, low-density lipoprotein cholesterol.*p < 0.05.