Safety and Effectiveness of High‐Intensity Statins Versus Low/Moderate‐Intensity Statins Plus Ezetimibe in Patients With Atherosclerotic Cardiovascular Disease for Reaching LDL‐C Goals: A Systematic Review and Meta‐Analysis

ABSTRACT Background It remains controversial whether adding ezetimibe to low/moderate‐intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high‐intensity statin regimens. Hypothesis A combination of low/moderate‐intensity statins plus ezetimibe might be more effective and safer than high‐intensity statin monotherapy. Methods We searched databases for randomized controlled trials comparing lipid profile alterations, drug‐related adverse events, and MACE components between high‐intensity statin monotherapy and low/moderate‐intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random‐effects model. Results Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low‐density lipoprotein cholesterol (LDL‐C) levels compared to monotherapy (MD = −6.6, 95% CI: −10.6 to −2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13–0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51–0.74). The occurrence of MACE was similar between the two treatment groups. Conclusions Adding ezetimibe to low/moderate‐intensity statins resulted in a greater reduction in LDL‐C levels, a lower rate of myalgia, and less drug discontinuation compared to high‐intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta‐analysis, the observed reduction in LDL‐C levels in the combination group did not correlate with a reduction in MACE compared to the high‐intensity statin group.


| Introduction
Cardiovascular disease (CVD) is the leading cause of global mortality and disability, with elevated serum lipid levels, particularly low-density lipoprotein cholesterol (LDL-C) as one of its major risk factors [1,2].Lowering LDL-C is crucial in mitigating the negative outcomes of CVD, especially in patients with a history of atherosclerotic cardiovascular disease (ASCVD).Statins are the first-line therapy for patients with ASCVD for LDL-C elevations, but many patients on low/ moderate-intensity statin regimens fail to attain target LDL-C levels [3,4].Contemporary guidelines recommend highintensity statins for hyperlipidemia treatment, but they come with challenges such as drug interactions and dose-dependent adverse events [5,6].An alternative approach is combining ezetimibe, a non-statin drug, with tolerated stain dosage [7,8].Ezetimibe has shown efficacy in lowering LDL-C alongside a more favorable safety profile [9,10].However, previous metaanalyses have shown conflicting information regarding the superiority in efficacy or safety profile of high-intensity statin monotherapy compared to low/moderate-intensity statin combined with ezetimibe therapy [11,12].Given the recent randomized controlled trials (RCTs), we aimed to conduct a comprehensive systematic review and meta-analysis comparing the efficacy and safety of these two lipid-lowering strategies in ASCVD patients [13][14][15].

| Protocol
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform the study [16], and the study protocol was registered in the International Prospective Register for Systematic Reviews (PROS-PERO) (registration number: CRD42023463729) [17].

| Search Strategy and Study Selection
To identify relevant studies, we searched PubMed, Embase, and Web of Science databases from inception to July 2023.No language restrictions were applied.We also searched ClinicalTrials.govand screened reference lists of eligible studies and relevant reviews.Detailed search terms are provided in Supporting Information S1: Table 1.
We included all RCTs comparing high-intensity statin monotherapy with low/moderate-intensity statin and ezetimibe combination therapy in ASCVD patients.We excluded conference abstracts, research letters, animal studies, non-English publications, studies lacking RCT design, studies with the same dosage of statin in both arms, and studies without full text.For studies with multiple publications, we included the publication with the most detailed information.

| Risk of Bias Assessment
Two authors (A.M. and S.S.) independently screened titles and abstracts, and discrepancies were resolved through discussion with senior authors (K.H. and H.S.).The risk of bias of the included studies was assessed using RoB2 instructions, with discrepancies resolved by consulting the senior authors [18].Results are provided in Supporting Information S1: Table 2.

| Data Extraction
We extracted relevant data including author, publication year, study location, statin type and dose, treatment duration, sample sizes, demographics (including age, sex, background disease, and cardiovascular risk factors including hypertension and diabetes), and outcome data (serum lipid profile including LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], and triglyceride [TG]; high-sensitivity C-reactive protein [hs-CRP] biomarker; drug-related adverse events such as elevation of liver enzymes, myalgia, discontinuation due to adverse events; and composite MACE and its components including hospitalization, revascularization, non-fatal myocardial infarction [MI], stroke, all-cause mortality, and cardiovascular mortality).

| Data Preparation and Statistical Analyses
For analysis, we calculated pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CIs) using a random-effects model.Heterogeneity was assessed using I 2 statistics, and subgroup analyses were conducted based on statin type and treatment duration to find the source of heterogeneity.Publication bias was assessed using funnel plots and Egger's regression (if ≥ 10 studies).Analyses were performed using R (version 4.1.3for Windows, Vienna, Austria) and R studio (version 1.1.463,Posit PBC, Boston, MA) with "tidyverse" and "meta" packages.

| Results
The search strategy yielded a total of 3060 articles.After removing duplicates and screening of articles, 32 trials were included in the meta-analysis (Figure 1).Inter-reader agreement was high (κ coefficient = 0.9).

Summary
Combination therapy of low/moderate-intensity statin with ezetimibe led to a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy, but no significant effect on MACE components.

| Laboratory Data
Twenty-one studies compared high-intensity statin monotherapy with low/moderate-intensity statin with ezetimibe combination therapy on LDL-C levels in ASCVD patients.The combination therapy demonstrated a greater reduction in LDL-C levels compared to monotherapy (MD = −6.6,95% CI: −10.6 to −2.5).However, a high degree of heterogeneity was noted among the included studies (I 2 = 84%, p < 0.01) (Figure 2A).The preliminary inspection of the funnel plot and Egger's regression showed no statistical evidence of publication (Supporting Information S1: Figure 1A).The observed effects remained consistent when considering treatment durations of less than 12 months or more than 12 months (Supporting Information S1: Figure 2A).The reduction in LDL-C levels was exclusively observed in atorvastatin and rosuvastatin subgroups (p < 0.001) (Supporting Information S1: Figure 2B).Considering different subgroups, the heterogeneity of effect was not due to variations in used statins or treatment durations across the included studies.
The difference between the effect of high-intensity statin monotherapy and low/moderate-intensity statin with ezetimibe combination therapy on HDL-C, TG, TC, and hs-CRP was evaluated in 18, 16, 17, and 14 studies, respectively.All of the analyses demonstrated no significant difference in terms of HDL-C (MD = 3.1, 95% CI: −1.5 to 7.7), TG (MD = −4.7,95% CI: −16.5 to 6.1), TC (MD = −0.6,95% CI: −13.1 to 11.9), and hs-CRP (MD = 0, 95% CI: −0.0 to 0.0) levels between the treatment arms.Considerable heterogeneity was noted among the studies, with I 2 values of 99% (p = 0) for HDL-C, 78% (p < 0.01) for TG, 99% (p < 0.01) for TC, and 31% (p = 0.13) for hs-CRP (Figure 2B-E).Although no significant publication bias was observed for HDL-C, TG, and hs-CRP, the inspection of the funnel plot and Egger's test demonstrated the existence of publication bias for TC (Supporting Information S1: Figure 1B-E).Subgroup analyses based on the statin class (Supporting Information S1: Figures 3B, 4B, 5B, and 6B) and treatment duration (Supporting Information S1: Figures 3A, 4A, 5A, and 6A) did not reveal any significant differences between the efficacy of the two treatment arms.Among the studies analyzing HDL-C subgroups, heterogeneity was attributed to the atorvastatin subgroup.In the case of TC, heterogeneity was influenced by studies involving multiple statins and atorvastatin.Subgroup analyses of different statins used and treatment periods are summarized in Supporting Information S1: Table 4.

| Drug-Related Adverse Events
Discontinuation due to adverse events in both treatment arms was evaluated in 14 studies.The risk of discontinuation due to adverse events was significantly lower in the combination therapy group compared to the monotherapy treatment arm (RR = 0.61, 95% CI: 0.51-0.74).The studies showed low heterogeneity (I 2 = 0%, p = 0.61) (Figure 3A).Subgroup analysis based on drug type demonstrated that the observed effect was exclusive to the Rosuvastatin subgroup, whereas no significant differences were observed in others (p = 0.04) (Supporting Information S1: Figure 7B).Interestingly, further subgroup analysis of the included studies demonstrated that the risk of discontinuation due to adverse events was approximately twofold in the monotherapy arm after 12 months of treatment (Supporting Information S1: Figure 7A).Examining other adverse events, the analysis indicated a lower risk of myalgia in the combination therapy group compared to the monotherapy arm (RR = 0.27, 95% CI: 0.13-0.57)based on the findings of five studies.Conversely, there was no significant difference between the two treatment modalities regarding liver enzyme elevations based on 10 included studies (RR = 0.65, 95% CI: 0.37-1.16).No heterogeneity was observed among studies in both parameters (Figure 3B,C).Additionally, no significant publication was observed for discontinuation due to adverse events and liver enzyme elevations (Supporting Information S1: Figure 8A,B).Subgroup analyses of the different statins used are presented in Supporting Information S1: Table 5.

| Discussion
Approximately 25% of high-risk and very high-risk ASCVD patients achieve the LDL-C goals recommended by the 2019 ECS/EAS guidelines [47,48].Although ezetimibe plus low/ moderate-intensity statin therapy has been shown to reduce CVD event rates and increase LDL-C goal attainment, its utilization remains low.In a recent study, only 4% of high-risk and 9% of very high-risk patients were on combination therapy [49].Furthermore, ezetimibe combined with low/moderate-intensity statin is available, affordable, and cost-effective [50].Our study has significant implications for ezetimibe in LDL-C goal attainment.In the present study, we showed that low/ moderate-intensity statin with ezetimibe combination therapy has a greater depreciating impact on LDL-C levels compared to high-intensity statin monotherapy in ASCVD patients.Moreover, we found that patients undergoing combination therapy experience fewer drug-related myalgia and discontinuation due to adverse events.Nevertheless, the occurrence of MACE between the two treatment groups was similar despite a more pronounced decrease in LDL-C levels in the combination therapy arm.
Although previous studies have examined the efficacy and safety of these therapies, to our knowledge, this is the most comprehensive systematic review and meta-analysis comparing the efficacy of these two treatment approaches on lipid and hs-CRP biomarkers, adverse events, and MACE components altogether.Our study supports the increased utilization of ezetimibe to improve LDL-C guideline goal attainment.

| Laboratory Data
Our findings demonstrated that the combination therapy approach was more effective in reducing LDL-C levels compared to statin monotherapy; however, no significant difference was noted in other lipid parameters.Our results aligned with a previous meta-analysis study conducted by Ah et al., which reviewed all studies until 2021 [11].Their study, which included 18 publications, showed that adopting low/moderate-intensity statin plus ezetimibe was more effective in reducing not only LDL-C but also other lipid parameters and hs-CRP.However, their data were older, and many recent studies were omitted from the analysis, especially those published in the last 2 years.In contrast to the aforementioned systematic review, our study focuses exclusively on patients with a history of CVD to minimize the confounding effect of non-cardiovascular conditions such as metabolic syndrome, diabetes, and hypercholesterolemia on outcomes.Furthermore, unlike the previous study, we conducted a subgroup analysis to investigate the effect of low/moderate-intensity statin plus ezetimibe therapy in different statin types and treatment durations.
The meta-analysis by Zhu et al. published in 2020 compared high-intensity statin monotherapy with low/moderate-intensity statin and ezetimibe combination therapy in patients with high cardiovascular risk [12].Consistent with the present study, it reported that the combination therapy was more efficient in reaching target LDL-C levels compared to statin monotherapy by including 14 studies.However, in contrast to our findings, a greater reduction in non-HDL and TC levels was observed in the combination therapy group.The findings of this metaanalysis have been updated through our meta-analysis by including a larger number of recent studies.Additionally, the results of the aforementioned study were limited to treatment durations under 1 year, whereas our study demonstrated that the benefits of combination therapy on LDL-C levels persist even in longer treatment durations.It is worth noting that LDL-C reduction is the primary treatment goal for patients with CVD.By combining a low/moderate-intensity statin with ezetimibe, clinicians can achieve more LDL-C reduction, which may translate to improved long-term cardiovascular outcomes.However, the lack of significant difference in other lipid parameters suggests that the benefits of combination therapy may be primarily driven by the enhanced LDL-C lowering effect.One reason for this observation is that the regulation of LDL-C is more directly linked to the cholesterol biosynthesis pathway inhibited by statins [51].Additionally, patients with different baseline lipid abnormalities may respond differently to statin therapy.For example, individuals with predominantly elevated LDL-C may experience more robust LDL-C reduction, whereas those with hypertriglyceridemia may have more variable effects on TG levels [52].

| Drug-Related Adverse Event
Our analysis suggested that a combination of low/moderateintensity statin and ezetimibe carries lower risks of discontinuation due to adverse events and myalgia compared to high-intensity statin monotherapy.In contrast to our findings, Zhan et al. found no difference in regard to treatment discontinuation due to adverse events by evaluating 10 RCTs [53].However, their results were mainly based on low-quality studies, and did not contain more recent publications.Chaiyasothi et al. found no difference in treatment discontinuation due to drug-related adverse events [54], but they comprised both moderate and high-intensity in the monotherapy group.
In our study, the risk of elevated liver enzymes was comparable between the two treatment groups.Previous meta-analyses also demonstrated that there was no significant difference in terms of elevated liver enzymes in both treatment methods [11,12,53].Nevertheless, it's worth noting that these earlier meta-analyses did not include more recent RCTs with longer treatment durations.It is essential to note that treatment adherence and persistence are crucial for achieving long-term cardiovascular benefits.The improved tolerability of the combination therapy may lead to better patient compliance and, ultimately, improved clinical outcomes.The comparable risk of elevated liver enzymes between the two treatment groups is also reassuring, as this adverse event is a common concern with statin use.

| MACE
We did not find a meaningful difference in MACE between the two treatment methods.The results of the meta-analysis conducted by Zhan et al. in 2018 also corroborate comparable allcause mortality and cardiovascular mortality between the two treatment groups.However, patients have a lower risk of nonfatal MI and stroke in the combination therapy group [53].The findings of the cohort study conducted by Kim et al. were also in agreement with our finding by showing that there was no significant difference in the risk of non-fatal MI, repeat revascularization, stroke, and all-cause mortality between two treatment groups after 5-year follow-up [13,14].
There are two main hypotheses to elucidate the conflicting outcomes.First, most analyses on MACE outcomes didn't comprise patients who discontinued their treatment due to adverse events and were more susceptible to cardiovascular outcomes [13,14,[19][20][21][22].Second, the different dosages and types of statins used in various therapies among the related studies could be an underlying cause of these conflicting results.Although our study did not demonstrate a clear superiority of combination therapy in reducing MACE, the significant reduction in LDL-C levels and improved tolerability profiles observed with this approach may still provide important clinical benefits.Clinicians should consider these factors when weighing the risks and benefits of statin monotherapy versus combination therapy for individual patients.

| Limitations
The primary limitation of our study is the inherent heterogeneity among the included studies.Variations in statin classifications, dosages, and follow-up durations may have contributed to the heterogeneities observed.Additionally, because this was a study-level meta-analysis lacking patient-level data, we were unable to perform more in-depth subgroup analyses or metaregressions.The second limitation is due to the publication bias.Despite our efforts to minimize publication bias by conducting a comprehensive search and including unpublished studies, the possibility of bias can't be completely ruled out.In addition, our outcomes for TC have been influenced by publication bias and, therefore, needed to be interpreted with caution.It is worth noting that publication bias was not assessed for some of our outcome parameters, as Egger's test and funnel plots are not appropriate in analyses containing less than 10 studies.The third limitation was about limited assessment of adverse events and MACE.Although we assessed the MACE components in both treatment groups, it is important to note that our analysis may have been limited by the availability of data reported in the included studies.Although most of the RCTs in our analysis were blinded, the types of blindness were not mentioned in these studies.Variations in the definitions and of adverse events and MACE components across studies may have affected the accuracy and comparability of the data.It would be nice if our findings were supported by large-scale, blinded RCTs with longer follow-up durations to better evaluate the long-term impact of statin plus ezetimibe combination therapy on hard cardiovascular events, patient-reported quality of life, and treatment satisfaction to better understand the real-world impact of the two treatment strategies on the overall wellbeing of ASCVD patients.

| Conclusions
In conclusion, this comprehensive systematic review and metaanalysis evaluated the efficacy and safety of the combination therapy versus monotherapy in terms of lipid levels, hs-CRP biomarkers, adverse events, and MACE in patients with existing CVD.Based upon the overall analysis of our study, the combination therapy of low/moderate-intensity statins with ezetimibe led to a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy, but no significant effect on MACE components.

FIGURE 2
FIGURE 2 (A) Mean difference in LDL-C, (B) mean difference in HDL-C, (C) mean difference in TG, (D) mean difference in TC, and (E) mean difference in hs-CRP.