Despite a sustained effort to treat dyslipidemia, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide [1]. Until 2010, ASCVD mortality decreased in South Korea, followed by a steady increase, reaching 123 per 100,000 persons in 2018 [2]. Dyslipidemia, a major risk factor for metabolic diseases and ASCVD, is characterized by an abnormal lipid profile, including high levels of low-density lipoprotein cholesterol (LDL-C) (≥ 160 mg/dL), low levels of high-density lipoprotein cholesterol (HDL-C) (< 40 mg/dL), or high levels of triglycerides (≥ 200 mg/dL). A high LDL-C level is the main risk factor for ASCVD [3]. The prevalence of dyslipidemia has increased by eightfold from 1.5 million in 2002 to 11.6 million in 2018 [4]. The most recent international guidelines for managing dyslipidemia recommend reducing LDL-C based on the principle of “lower is better” [5–8]. Recent epidemiological studies and clinical trials have consistently demonstrated that reductions of LDL-C level lower the risk of ASCVD in both primary and secondary settings [9,10]. Among lipid-lowering drugs, statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (an early enzyme in the cholesterol biosynthetic pathway), are the most cost-effective drugs for preventing ASCVD; they are commonly prescribed worldwide, including in Korea [11]. However, the proportion of patients achieving their target LDL-C goal remains low, and only a small percentage of very high-risk patients reach their target LDL-C goal during treatment with statins [12]. Despite sufficient reduction in LDL-C, patients experience an elevated risk of ASCVD, which is attributed to changes in lipid components such as triglycerides, lipoprotein (a), HDL-C, and chylomicrons [13–15]. Therefore, high-intensity statin therapy or combination therapy involving ezetimibe is increasingly prescribed [16]. Previous studies have shown that the effects of statin/ezetimibe combinations are superior to statin monotherapy in terms of achieving target LDL-C goals in patients with ASCVD or ASCVD risk equivalents. Furthermore, an updated consensus addressed evidence concerning novel medications beyond statin or ezetimibe combination therapy. This review evaluated alternative therapeutic options for non-statin treatments with a focus on ezetimibe, based on the most recent and relevant evidence.

Global clinical guidelines recommend statins as first-line treatment for reducing the LDL-C level, which is a major target of lipid-lowering therapy. Many studies have established an association between reducing LDL-C and preventing ASCVD, thereby emphasizing LDL-C management as the primary strategy. Although there are some similarities among clinical guidelines for dyslipidemia, the recommendations display substantial variation. The 2018 American College of Cardiology and American Heart Association (ACC/AHA) guidelines prioritize statin therapy to reduce LDL-C levels, without emphasizing specific lipids or lipoprotein targets [17]. However, for patients with very high ASCVD risk, an LDL-C threshold of 70 mg/dL is recommended as an indicator of the need for additional non-statin therapy. The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines [18], the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE) guidelines [19], and the Endocrine Society Clinical Practice Guidelines [20] encourage reducing LDL-C and non-HDL-C levels to targeted thresholds based on a patient’s cardiovascular risk profile. However, the most reliable risk estimate system should be based on specific population characteristics and corresponding data. The ESC/EAS guidelines utilize the Systematic Coronary Risk Estimation (SCORE) system, whereas the AHA/ACC guidelines use the Framingham Risk Score (FRS). Nevertheless, most guidelines define the very high-risk group as individuals with documented ASCVD, including acute myocardial infarction, ischemic stroke, and peripheral arterial disease. Numerous lipid experts suggest targeting LDL-C levels below 70 mg/dL and non-HDL-C levels below 100 mg/dL in patients with clinical ASCVD across all levels of baseline LDL-C or in patients with very high risk. The AACE and ESC/EAS guidelines recommend even lower LDL-C levels, below 55 mg/dL, for patients with very high ASCVD risk. The high-risk group is characterized by chronic kidney disease, diabetes mellitus (DM) with target organ damage, type 1 DM with duration > 10 years, familial hypercholesterolemia, SCORE ≥ 5%, and FRS ≥ 20%. The goal for the high-risk group should be an LDL-C level of < 100 mg/dL and a non-HDL-C level of < 130 mg/dL. The ESC/EAS recommended target LDL-C level for high-risk groups is < 70 mg/dL. Thus, the European guidelines establish a more stringent LDL-C target, compared with other guidelines. In Korea, the delineation of target LDL-C levels based on the presence of cardiovascular disease (CVD) risk factors is consistent with international guidelines. The recommended target LDL-C levels vary according to the level of risk: for the very high-risk group with CVD, the target LDL-C is < 70 mg/dL; for the high-risk group with carotid disease or DM, it is < 100 mg/dL; for the moderate-risk group with more than two major risk factors, it is < 130 mg/dL; and for the low-risk group with one or no major risk factors, it is < 160 mg/dL. However, immediate statin therapy is indicated for acute myocardial infarction, regardless of the baseline LDL-C level [21].

In the last few years, complementary therapies for HMG-CoA reductase inhibitors have emerged as additional options for LDL-C reduction. These therapies include the use of ezetimibe, an inhibitor of the Niemann-Pick C1-Like 1 (NPC1L1) transporter responsible for cholesterol absorption [21], and the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, which interferes with the degradation of LDL receptors in hepatocytes [22]. By targeting different metabolic pathways, these therapies offer new treatment options for patients with dyslipidemia who have a high ASCVD risk. Recent studies regarding the addition of ezetimibe to statin therapy, including Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) [23], and studies focused on PCSK9 inhibitors [24–26] revealed further decreases in LDL-C levels and CVD events. Current guidelines recommend these non-statin therapies when maximally tolerable statin dosage has been reached or when a switch to another class has not achieved sufficient reduction in LDL-C; thus, the strength of the recommendation is increased. Among newly developed treatments, ezetimibe and/or PCSK9 inhibitors have emerged as the primary non-statin therapies. In 2022, the ACC released the expert decision pathway for non-statin therapy, which recommends novel therapies (e.g., bempedoic acid, inclisiran [small interfering RNA], and evinacumab) but prioritizes ezetimibe and/or PCSK9 inhibitors because of their superior outcome data [6]. Global perspectives based on all clinical guidelines are consistent in recommending statins as first-line treatment; non-statin therapies, such as ezetimibe and/or PCSK9 inhibitors, remain second-line options. More options are available to achieve target LDL-C levels and improve CVD outcomes with the emergence of novel therapies for dyslipidemia.

Considering the large amount of data supporting the clinical effectiveness of statin therapy and the current guidelines that prioritize statin prescriptions, the number of clinical trials assessing ezetimibe monotherapy has been relatively limited. A meta-analysis of eight randomized controlled trials (RCTs) regarding the clinical effectiveness of ezetimibe monotherapy (10 mg/d) for 12 weeks demonstrated a mean LDL-C level reduction of 18.58%. Additionally, there were substantial reductions in total cholesterol (13.49%) and triglycerides (8.6%), compared with the placebo group [27]. According to a recent meta-analysis, the pooled prevalence of statin intolerance is 9.1% [28]. In patients who cannot tolerate statin therapy, non-statins are recommended as alternative treatment options. In confirmed CVD cases with statin intolerance or contraindications, ezetimibe monotherapy is cost-effective relative to no treatment. Ezetimibe monotherapy reduces LDL-C levels by 18.56% relative to no treatment [29]. The GAUSS-3 trial investigated the effectiveness of two non-statin therapies, ezetimibe (10 mg/d) and evolocumab (a PCSK9 inhibitor, 420 mg/mo), in 419 patients with statin intolerance [30]. At week 24, the average percentage changes in LDL-C level were −16.7% with ezetimibe and −52.8% with evolocumab. One study (EWTOPIA 75), conducted among Japanese patients aged ≥ 75 years, demonstrated the effectiveness of non-statin monotherapy using a 10 mg dose of ezetimibe to prevent CVD. The study revealed a hazard ratio of 0.66 (95% confidence interval [CI] 0.50–0.86), indicating a reduced risk of CVD, along with a substantial reduction (25.9%) in LDL-C levels [31]. Nevertheless, evidence regarding ezetimibe monotherapy as first-line treatment for primary prevention and its effectiveness in preventing ASCVD is insufficient, compared with statin therapy. Consequently, further research is needed to better understand the potential benefits and efficacy of ezetimibe in these areas.

LDL-C levels are affected by endogenous cholesterol synthesis, cholesterol absorption, and clearance [32]. Statin-mediated inhibition of hepatic cholesterol synthesis can paradoxically enhance cholesterol absorption, leading to a smaller lipid-lowering effect of statin therapy [33]. This problem can be overcome by incorporating a cholesterol-absorbing inhibitor, such as ezetimibe, to complement the statin treatment. As previously noted, ezetimibe monotherapy reduces LDL-C levels by 13–20%. The combination of ezetimibe with statin therapy results in an additional 21–27% decrease in LDL-C levels [34,35]. Several meta-analyses have consistently shown that combination therapy with ezetimibe and a statin is more effective in reducing LDL-C, compared with a twofold increase in the statin dose [36]. In terms of preventing major adverse cardiovascular events (MACEs), most clinical trials focused on secondary prevention among patients with a history of ASCVD (Table 1). Combination therapy demonstrated a superior drop in LDL-C levels and a 17% proportional decrease in MACEs in the Study of Heart and Renal Protection (SHARP) trial, which included individuals with chronic kidney disease who had no history of ASCVD [37]. These results are consistent with previous findings that combination therapy in the vascular surgical setting is protective against MACEs during the first year of follow-up [38]. The IMPROVE-IT study, which is the largest and longest study (enrolling 18,144 participants over 6 yr), showed that the MACE rate in the combined group was lower than the rate in the simvastatin monotherapy group, with absolute risk reduction of 2% (hazard ratio 0.936) [23]. The results concerning MACE risk were inconsistent in Asian patients with ASCVD [39–43]. The Heart Institute of Japan-Proper Level of Lipid Lowering with Pitavastatin and Ezetimibe in Acute Coronary Syndrome (HIJ-PROPER) trial and post hoc analysis of that study demonstrated different results. In HIJ-PROPER, combination therapy did not improve MACE outcomes compared with monotherapy, despite reduction of LDL-C levels [40]. Post hoc analysis of 1,702 patients with ASCVD revealed a significant benefit of combination therapy regarding single vessel disease (hazard ratio 0.72, 95% CI 0.55–0.94) [43]. In a recent large, randomized, open-label study (the randomized comparison of efficacy and safety of lipid lowering with statin monotherapy versus statin–ezetimibe combination for high-risk cardiovascular disease [RACING] trial), combination therapy in patients with high ASCVD risk was non-inferior to high-intensity statin monotherapy (absolute difference −0.78%; 90% CI −2.39 to 0.83) [44]. The previous trials were based on the additive effect of ezetimibe while maintaining a single statin dosage, whereas the RACING trial compared the efficacies of combination therapy comprising moderate-intensity statin with ezetimibe (10 mg rosuvastatin with 10 mg ezetimibe) and monotherapy involving high-intensity statin (20 mg rosuvastatin). Although clinical trials have shown heterogeneous results, pooled analysis of MACEs using a fixed-effects model indicated that combination therapy with ezetimibe resulted in a lower risk of MACEs, compared with the control group. The risk ratio was 0.94 (95% CI 0.90–0.98), indicating a significant benefit [45]. These trial results indicate that patients with higher risk can achieve risk reduction by adding ezetimibe to a statin therapy regimen. Overall, the findings support ezetimibe as a second-line treatment option.

Clinical trials spanning over one year revealed diverse benefits of Ezetimibe, encompassing anti-atherosclerotic effects, anti-inflammation, impact on lipoprotein oxidation, and involvement in glucose metabolism and insulin resistance. These findings provide insights into the multifaceted advantages of Ezetimibe therapy (Table 2).

The use of high-intensity statins is often linked to statin intolerance, which is frequently associated with muscle-related adverse events. Although various interpretations of statin intolerance have been described in the literature, the definition most widely used by the EAS focuses on the probability of statin-associated muscle symptoms (SAMS) linked to statin usage. This likelihood assessment considers the nature of the muscle symptoms; the elevation of creatine kinase (CK) levels; and temporal relationships with the initiation, discontinuation, and re-initiation of statin therapy [84]. Comprehensive large-scale clinical studies regarding alternatives to statin therapies have demonstrated substantial reduction in statin-associated side effects, including SAMS, accompanied by improvements in clinical outcomes [24,30,85].

In contrast to statins, ezetimibe has not been associated with an increase in muscle toxicity. An analysis of eight RCTs indicated that ezetimibe therapy did not consistently lead to a clinical increase in CK level (≥ 10 times the upper limit of normal); the incidence was < 1% [27]. A comprehensive pooled safety analysis, involving 17 RCTs and 4,558 patients, conclusively showed that combination therapy involving ezetimibe does not worsen SAMS or increase their incidence [86]. Furthermore, a subanalysis from the RACING trial indicated that the rate of SAMS-related discontinuation or therapeutic reduction was lower in the combination therapy group (4.5%) than in the statin monotherapy group (7.9%) [87]. An RCT involving ezetimibe monotherapy demonstrated that myopathy was slightly more common in the ezetimibe group than in the placebo group (5 vs. 4%) without an increase in CK level [88]. However, some case reports of myopathy (muscle pain with increased CK levels) have been linked to the addition of ezetimibe to statin therapy [89,90]. In these cases, ezetimibe withdrawal led to normalization of the CK level and reduction of muscle pain. One plausible mechanism involves glucuronidation. Statins undergo cytochrome P450 hydrolysis and glucuronidation; ezetimibe can also undergo glucuronidation [91]. Another possible underlying mechanism is the obstruction of fatty acid oxidation by ezetimibe [89]. Fatty acids are crucial constituents for energy production and the maintenance of muscle function. Therefore, the effects of ezetimibe on fatty acid oxidation may lead to changes in energy metabolism and function within muscle. The exact mechanisms by which ezetimibe causes muscle-related side effects are currently under investigation.

Ezetimibe is metabolized in the small intestine and liver [91]. Nevertheless, the incidence of increased serum transaminases (≥ 3 times the upper limit of normal) was not affected by ezetimibe monotherapy [27]. Current guidelines indicate that ezetimibe can be used without dose modification in patients with mild hepatic insufficiency. However, these guidelines may not support the use of ezetimibe for individuals with moderate or severe hepatic insufficiency [92].

Current guidelines recommend ezetimibe as cost-effective second-line therapy. The addition of ezetimibe to statin therapy produces favorable outcomes in terms of further decreases in LDL-C levels and MACE risks in patients with established ASCVD or high ASCVD risk. The pleiotropic effects of ezetimibe in clinical trials may be linked to improvements in ASCVD outcomes. These effects include protection against atherosclerosis; reduction of inflammation; modulation of lipoprotein oxidation; and potential benefits regarding glucose metabolism, insulin resistance, and NAFLD. However, the long-term pleiotropic effects of ezetimibe remain controversial because clinical trial data have been limited. Further research is needed to explore the benefits of ezetimibe beyond LDL-C reduction.