Fixed-dose combination of rosuvastatin and ezetimibe: treating hypercholesteremia according to cardiovascular risk

Vivencio Barrios & Carlos Escobar

To cite this article: Vivencio Barrios & Carlos Escobar (2021) Fixed-dose combination of rosuvastatin and ezetimibe: treating hypercholesteremia according to cardiovascular risk, Expert Review of Clinical Pharmacology, 14:7, 793-806, DOI: 10.1080/17512433.2021.1925539
To link to this article: https://doi.org/10.1080/17512433.2021.1925539

Published online: 24 May 2021. Image Submit your article to this journal
Article views: 62
View related articles Image View Crossmark data
Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierj20

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 2021, VOL. 14, NO. 7, 793–806

https://doi.org/10.1080/17512433.2021.1925539

REVIEW Image
Fixed-dose combination of rosuvastatin and ezetimibe: treating hypercholesteremia according to cardiovascular risk
Vivencio Barriosa and Carlos Escobarb
aCardiology Department, University Hospital Ramón Y Cajal. Alcalá University, Madrid, Spain; bCardiology Department, University Hospital La Paz, Madrid, Spain

ABSTRACT
Introduction: Reducing low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies has been associated with a decrease in the frequency of cardiovascular events.Areas covered: A systematic search was conducted on PubMed (MEDLINE), using the MeSH terms [Rosuvastatin] + [Ezetimibe] + [Dyslipidemia] + [treatment]. Original data from clinical trials, prospectiveand retrospective studies and more useful reviews were selected.Expert opinion: While statins continue to be the cornerstone of dyslipidemia management, many patients do not attain LDL-C targets with high-intensity statins alone. Rosuvastatin is a high-intensity statin with a low risk of adverse effects and drug–drug interactions and proven benefits in the prevention of cardiovascular disease. Rosuvastatin and ezetimibe have complementary mechanisms of action that enhance their ability to reduce LDL-C levels. Various studies have shown that the combination of rosuvastatin 10–40 mg and ezetimibe 10 mg enables considerable reductions in LDL- C (up to 60–75%) with a good safety profile in a broad spectrum of patients with hypercholesterolemia, including those at high risk and those with atherosclerotic cardiovascular disease. In addition, a fixed- dose combination of rosuvastatin and ezetimibe may improve adherence to medication. In this review, the available evidence on the combination of rosuvastatin and ezetimibe is updated.

ARTICLE HISTORY
Received 8 March 2021
Accepted 30 April 2021
KEYWORDS
Cholesterol; combined therapy; ezetimibe; rosuvastatin

1. Introduction
Cardiovascular disease (CVD) is the leading cause of death worldwide [1]. Elevated low-density lipoprotein cholesterol (LDL-C) levels represent not only a major modifiable risk factor for CVD but also the underlying etiologic and patho- genic cause [2]. Reducing LDL-C with lipid-lowering thera- pies has been associated with a decrease in cardiovascular events in both primary and secondary prevention [3]. Of note, the beneficial effects of lipid-lowering drugs are inde- pendent of age, and favorable findings have even been reported for elderly people [4]. In addition, it was recently reported that early (versus delayed) primary prevention of CVD with lipid-lowering therapy is associated with a sub- stantial reduction in expected atherosclerotic CVD risk in the following years [5].

Statins are the cornerstone of management of dyslipide- mia. Based on a step-by-step approach, European guidelines recommend prescription of a high-intensity statin up to the highest tolerated dose to reach treatment goals according to cardiovascular risk (LDL-C < 55 mg/dL and ≥50% from baseline in very high-risk patients; LDL-C < 70 mg/dL and ≥50% from baseline in high risk patients); if targets are not achieved, then ezetimibe should be added [2]. Unfortunately, despite these recommendations, a large pro- portion of patients do not achieve their therapeutic goals. For example, the EUROASPIRE V study, which included patients with chronic ischemic heart disease from 27

European countries, showed that only 29% of patients achieved the previous LDL-C goal of 70 mg/dL (32% in patients taking lipid-lowering drugs). Of note, 20% of patients were not taking statins, and the use of ezetimibe was marginal [6].
Therefore, prescribing high-intensity statins in monother- apy to patients with a high or very high cardiovascular risk may attain current LDL-C targets in only a small percentage. In this context, a recent consensus promoted by the Spanish Society of Cardiology provides 3 simple and feasi- ble decision-making algorithms that cover most clinical sce- narios in patients with ischemic heart disease. The algorithms have the double aim of achieving LDL-C goals as soon as possible, since the magnitude of the benefit is risk- and time-dependent. This consensus states that in some high-/very-high-risk patients, it is necessary to start with the combination of a high-intensity statin plus ezeti- mibe directly to attain LDL-C goals [7].

The aim of this review was to update available evidence on the combination of rosuvastatin, a high-intensity statin, plus ezetimibe and its role in the treatment of hypercholesterole- mia. For this purpose, a systematic search was conducted on PubMed (MEDLINE), using the MeSH terms [Rosuvastatin] + [Ezetimibe] + [Dyslipidemia] + [treatment]. Original data from clinical trials, prospective and retrospective studies and more useful reviews were selected.

CONTACT Vivencio Barrios [email protected] Cardiology Department, University Hospital Ramón Y Cajal. Alcalá University, Madrid, Spain.

© 2021 Informa UK Limited, trading as Taylor & Francis Group

Article highlights

⦁ Attaining LDL-C goals is necessary in order to decrease cardiovascular burden, especially in high-/very-high-risk patients.
⦁ Early primary prevention of cardiovascular disease with lipid-lowering therapy is associated with a substantial reduction in atherosclerotic cardiovascular risk in the following years.
⦁ Statins continue to be the cornerstone of management of dyslipide- mia, yet many patients do not attain recommended LDL-C targets with high-intensity statins alone.
⦁ Rosuvastatin and ezetimibe have complementary mechanisms of action that enhance their ability to reduce LDL-C levels.
⦁ The fixed-dose combination of rosuvastatin and ezetimibe may sim- plify treatment and improve adherence to medication, thus reducing the frequency of cardiovascular complications.
⦁ The combination of rosuvastatin and ezetimibe is cost-effective.

2. Rosuvastatin in the management of dyslipidemia
2.1. Efficacy of rosuvastatin with respect to lipid parameters
Rosuvastatin is a relatively hydrophilic, potent, and highly selective 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor that significantly reduces the generation of cholesterol. The absolute bioavailability of rosuvastatin is around 20%. Approximately 90% of the drug is bound to plasma proteins, mainly to albumin. Of note, rosuvastatin undergoes limited metabolism, as it is a poor substrate for cytochrome P450– based metabolism (~10%), which translates into a low risk of drug–drug interactions. Around 90% of rosuvastatin is excreted unchanged in feces and the remaining 10% in urine. The plasma elimination half-life is approximately 19 hours. Age does not have a relevant impact on the phar- macokinetics of rosuvastatin. Although mild to moderate renal insufficiency does not affect plasma concentrations, severe renal impairment markedly increases exposure to rosuvastatin [8–10].
The STELLAR (Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin) trial showed that after 6 weeks of treatment, a daily dose of rosuvastatin 10– 40 mg reduced LDL-C by 46%–55% (vs 37%–51% with ator- vastatin 10–80 mg, 28–39% with simvastatin 10–40 mg, 20%– 30% with pravastatin 10–40 mg). In addition, HDL cholesterol increased by 8%–10%, 2%–6%, 5%, and 3–6%, respectively, and triglycerides levels decreased by 20%–26%, 20%–28%, 12%–15%, and 8%–13%, respectively [11]. These results were confirmed in the VOYAGER (Individual Patient Data Metaanalysis Of Statin Therapy In At Risk Groups: Effects of Rosuvastatin, Atorvastatin and Simvastatin) study, a pooled analysis based on data from 32,258 individual patients from studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin (Table 1) [12]. A recent meta-ana- lysis of 50 studies with 51,956 patients showed that rosuvas- tatin is the statin with the greatest effect on reducing LDL-C and ApoB levels and on increasing ApoA1 levels (vs atorvas- tatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and sim- vastatin) [13]. Rosuvastatin also exhibits benefits beyond its effects on lipid profile, including anti-inflammatory, antioxi- dant, antithrombotic, and endothelial protective properties, and also reduces the lipid content of atherosclerotic plaques [8,9,14–17]. Moreover, it has been reported that rosuvastatin improves both quantitative and qualitative HDL cholesterol, thus contributing to its reverse cholesterol transport and anti- oxidant functions [18].

2.2. Efficacy of rosuvastatin on the prevention of outcomes in patients without established atherosclerotic cardiovascular disease
The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) demonstrated the marked benefits of rosuvastatin on primary prevention of CVD. The study population comprised 17,802 subjects with LDL-C < 130 mg/dL, high-sensitivity C-reactive protein ≥2.0 mg/L, but no known CVD. Patients received rosuvastatin 20 mg or placebo. The study was stopped pre- maturely owing to the beneficial effects of rosuvastatin on outcomes after a median follow-up of only 1.9 years. During this period, rosuvastatin provided sustained reductions in LDL- C (50%) and in high-sensitivity C-reactive protein (37%). Of note, compared with placebo, rosuvastatin 20 mg significantly reduced the risk of the primary combined endpoint of myo- cardial infarction, stroke, arterial revascularization, hospitaliza- tion for unstable angina, and cardiovascular death by 44%, the risk of major adverse cardiovascular events (MACE) by 47%, nonfatal myocardial infarction by 65%, any myocardial infarc- tion by 54%, nonfatal stroke by 48%, any stroke by 48%, arterial revascularization by 46%, and all-cause death by 20% (Figure 1) [19]. The 5-year number needed to treat in the JUPITER trial for the primary endpoint was only 20 [20]. The results were consistent according to the subgroups of patients. With regard to adverse effects, while rosuvastatin did not increase the risk of myopathy or cancer, it was asso- ciated with a significant but not clinically relevant higher incidence of physician-reported diabetes, as the baseline HbA1c of 5.7% increased to 5.9% with rosuvastatin and to 5.8% with placebo; P = 0.001 [19,21]. In addition, a number of substudies of the JUPITER trial have analyzed the role of rosuvastatin in different subgroups of patients (Table 2) [22–29].More recently, the HOPE (Heart Outcomes Prevention Evaluation)-3 trial, showed in primary prevention patients at intermediate cardiovascular risk that treatment with Efficacy of rosuvastatin (vs placebo) in patients without prior cardiovascular disease. data from the JUPITER trial MACE: major cardiovascular event; MI: myocardial infarction.. Primaryend point: myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death; MACE: MI, stroke, or CV death.. Figurebased on data from reference #19.rosuvastatin 10 mg daily was associated with a significant reduction of 24% in the risk of major cardiovascular events compared with placebo [30]. Therefore, rosuvastatin can be considered a first-line ther- apeutic choice in the management of dyslipidemia in subjects with no established CVD.

2.3. Efficacy of rosuvastatin on the prevention of cardiovascular events in patients with atherosclerotic cardiovascular disease
A number of studies have analyzed the efficacy and safety of rosuvastatin in patients with atherosclerotic CVD [31]. Various clinical trials have shown that in patients with coronary artery disease, rosuvastatin is safe, significantly decreases LDL-C levels in a dose-dependent way, and increases HDL cholesterol levels, leading to a complete improvement in the lipid profile. Of note, clinical trials have also shown that administration of high doses of rosuvastatin regresses coronary atherosclerosis, reduces atheromatous plaque volume, stabilizes coronary pla- que through the reduction of lipid-rich necrotic core, and may reduce the progression of carotid intima-media thickness (Table 3; Figure 2) [32–40].

Additionally, real-life studies have confirmed the role of rosuvastatin in reducing LDL-C levels with a low risk of adverse effects in this population [16,41]. Moreover, rosuvastatin is associated with a reduction in inflammatory markers and pre- vents ventricular remodeling and myocardial fibrosis [15,42,43].The abovementioned data clearly illustrate the beneficial impact of rosuvastatin on outcomes in this population. Thus, a retrospective analysis performed in 549 patients with coronary heart disease showed that improvement in exercise tolerance was more intense in patients taking rosuvastatin than in those taking atorvastatin [44]. In a randomized clinical trial that included elderly patients with ST-elevation acute myocardial infarction who underwent percutaneous coronary intervention and were treated with low or high doses of atorvastatin, rosuvastatin, and simvastatin, MACE were less frequent in patients with higher doses [45]. A recent retrospective obser- vational study did not find significant differences between high doses of rosuvastatin and atorvastatin in the recurrence of atherosclerotic CVD, indicating a similar effect on the pre- vention of cardiovascular complications [46]. Another retro- spective cohort study performed in secondary prevention patients aged ≥75 years showed that rosuvastatin 10 mg reduced the risk of ischemic cardiovascular and cerebrovascu- lar events to a greater extent than atorvastatin 10 mg (HR 0.79; 95% CI: 0.64–0.98; p = 0.029) [47].

3. Ezetimibe in the management of dyslipidemia
Ezetimibe selectively inhibits the intestinal absorption of cho- lesterol and related plant sterols by blocking the sterol trans- porter, Niemann-Pick C1-Like 1 (NPC1L1), with no significant effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat-soluble vitamins A and
D. Ezetimibe is rapidly absorbed after oral ingestion, reaching maximum plasma concentrations at 1 to 2 hours, and its oral bioavailability is not affected by food. Ezetimibe is extensively bound to plasma proteins and is metabolized primarily in the small intestine and liver via glucuronide conjugation with subsequent biliary excretion. Metabolism via the cytochrome P450 system has not been described. Therefore, the risk of

● In this analysis, participants were stratified on the basis of having none or ≥1 risk factor for developing diabetes (metabolic syndrome, impaired fasting glucose, body-mass index ≥30 kg/m2, or HbA1c >6%).
⦁ Among patients at risk of diabetes, rosuvastatin significantly reduced the risk of the primary endpoint by 39% and that of total mortality by 17%.
⦁ Among patients with no risk of diabetes, these percentages were 52% and 22%, respectively, with no increase in the incidence of diabetes.
⦁ In those patients who developed diabetes, rosuvastatin reduced the risk of the primary endpoint by 37%. Compared with placebo, rosuvastatin accelerated the average time to diagnosis of diabetes by 5.4 weeks.
LDL-C < 50 mg/dL ● Among patients attaining LDL-C < 50 mg/dL with rosuvastatin, cardiovascular events and mortality were reduced to a greater extent than in patients with LDL-C > 50 mg/dL or those treated with placebo, with no significant increase in the frequency of adverse events, including myalgia, muscle weakness, neuropsychiatric conditions, cancer, and diabetes.
Gender ● The JUPITER trial included 6,801 women ≥60 years and 11,001 men ≥50 years.
⦁ Rosuvastatin reduced cardiovascular events in women with a relative risk reduction similar to that observed in men.
⦁ Rosuvastatin significantly reduces cardiovascular outcomes and total mortality independently of the risk or status of diabetes.
⦁ Rosuvastatin only accelerates the development of diabetes by less than 2 months in those patients at high risk of diabetes. However, it is very likely that these patients would develop diabetes even without treatment with rosuvastatin.
⦁ This study confirms that marked reductions in LDL-C with rosuvastatin are associated with a lower risk of outcomes, with no increase in the frequency of adverse effects.
⦁ The beneficial effects of rosuvastatin are independent of sex and can be equally used in men and women.
Chronic kidney diseaseFramingham and SCORE risk
⦁ While patients with moderate chronic kidney disease (eGFR
<60 ml/min/1.73 m2), had higher vascular event rates than those with normal renal function, treatment with rosuvastatin was associated with a 45% reduction in the risk of the primary endpoint and a 44% reduction in all-cause mortality.
⦁ The risk of adverse effects of rosuvastatin did not increase in patients with chronic kidney disease.
⦁ Rosuvastatin 20 mg significantly reduced major cardiovascular events among patients with elevated hsCRP and ‘intermediate risk’, defined either as a 10-year Framingham risk of 5% to 10% or 10% to 20%.
⦁ In primary prevention, rosuvastatin 20 mg significantly reduced major cardiovascular events among patients with elevated hsCRP and a high global cardiovascular risk (10-year Framingham risk score >20% or SCORE risk ≥5%).
⦁ The risk-benefit profile of rosuvastatin is independent of renal function. The drug can be safely used among patients with chronic kidney disease.
⦁ In primary prevention, rosuvastatin 20 mg significantly reduces the risk of MACE in patients at intermediate, high, and very high cardiovascular risk.

Age ● In the JUPITER trial, almost one-third of patients were aged
≥70 years.
⦁ Although outcomes were more common in elderly patinets, no significant heterogeneity was found in treatment effects by age, and, consequently, absolute reductions in event rates were greater in elderly patients.
⦁ The frequency of adverse events with rosuvastatin was similar to that of placebo in elderly patients.
⦁ The beneficial effects of rosuvastatin in primary prevention is independent of age. The drug can be safely used in elderly patients.

hsCRP: high-sensitivity C-reactive protein; LDL-C: LDL cholesterol; eGFR: estimated glomerular filtration rate; MACE: major adverse cardiovascular events. Table constructed based on data from references #2229 drug–drug interactions is low. The half-life is approximately 22 hours. Approximately 78% of ezetimibe is eliminated in feces and 11% in urine. No dose adjustment is required according to age, sex, or renal function [8–10].
In monotherapy, ezetimibe reduces LDL-C by about 15– 20% [10]. A recent clinical trial with a PROBE design analyzed 3,411 patients aged ≥75 years with elevated LDL-C and no history of coronary artery disease. The authors found that compared with usual care (dietary counseling), treatment with ezetimibe 10 mg/d was associated with significant reduc- tions in the primary outcome, that is, a composite of sudden cardiac death, myocardial infarction, coronary revasculariza- tion, and stroke (HR 0.66; 95% CI: 0.50–0.86; p = 0.002), the composite of cardiac events (HR 0.60; 95% CI: 0.37–0.98;p = 0.039), and coronary revascularization (HR 0.38; 95% CI: 0.18–0.79; p = 0.007), with no significant increase in adverse events [48].
Ezetimibe and statins exhibit complementary mechanisms of action, leading to further reductions in LDL-C. Inhibition of cholesterol synthesis in the liver by statins results in enhanced cholesterol absorption; in contrast, inhibition of cholesterol absorption may enhance cholesterol synthesis. Therefore, the combination of both statins (endogenous cholesterol synth- esis) and ezetimibe (exogenous cholesterol absorption) seems to be a suitable approach that provides marked reductions in LDL-C [8,9,49,50]. Thus, a pooled analysis of over 21,000 sub- jects from 27 clinical trials showed that, whereas statins in monotherapy reduced LDL-C by 23.6%, the combination of Rosuvastatin in clinical trials of patients with atherosclerotic cardiovascular disease.Study (year) Design Main results PULSAR (2006) (Prospective study to evaluate the utility of low doses of the statins Atorvastatin and Rosuvastatin ASTEROID (2006) (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound- Derived Coronary Atheroma Burden) METEOR (2007) (Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin)
LUNAR (2012)
(Limiting Undertreatment of Lipids in Acute Coronary Syndrome with Rosuvastatin)
⦁ 996 patients with LDL-C > 130 and <220 mg/dL and atherosclerosis, coronary artery disease, or coronary artery disease-risk equivalent were treated with rosuvastatin 10 mg vs atorvastatin 20 mg for
6 weeks.

⦁ This study aimed to assess whether rosuvastatin 40 mg could regress coronary atherosclerosis, as determined by intravascular ultrasound (IVUS) imaging in 349 patients after 24 months of treatment.
⦁ Randomized double-blind placebo-controlled clinical trial, in which 984 individuals, with either age (mean 57 years) as the only risk factor for coronary heart disease or a 10-year Framingham risk score <10%, modest carotid intima-media thicknesss (1.2-
<3.5 mm), and elevated LDL-C (mean, 154 mg/dL), were randomized to rosuvastatin 40 mg or placebo over 2 years.
⦁ Carotid ultrasound was performed to assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness.
⦁ Randomized double-blind trial in which 43 patients (33 completed the trial) with LDL-C ≥ 100 and
<250 mg/dL and 16% to 79% carotid stenosis by duplex ultrasound were randomized to receive rosuvastatin 5 mg or rosuvastatin 40/80 mg.
⦁ Carotid atherosclerotic plaque was assessed using 1.5-Tesla magnetic resonance imaging.
⦁ Multicenter and open-label trial, in which 214 patients with stable coronary artery disease from Japan (124 were finally analyzed) received rosuvastatin 2.5 mg/day, which could be increased at 4-week intervals to ≤20 mg/day.
⦁ The effect of rosuvastatin on plaque volume was assessed using IVUS imaging
⦁ Investigator-led, open-label, blinded-endpoint, multicenter, randomized, controlled trial, in which treatment with rosuvastatin 10 mg was compared with simvastatin 40 mg in 1,263 patients with myocardial infarction over 3 months.
⦁ Randomized, double-blind, parallel-group trial, in which 753 patients with non-ST elevation acute coronary syndrome were treated with rosuvastatin 20 mg or atorvastatin 80 mg for 3 months.
⦁ Multicenter, randomized, double-blind clinical trial, in which 1,039 patients with coronary disease were treated with either atorvastatin 80 mg or rosuvastatin 40 mg, over 104 weeks.
⦁ IVUS imaging was performed to compare the effects of statins on the progression of coronary athero- sclerosis.
⦁ 825 patients with coronary artery disease who were hospitalized for acute coronary syndrome within
48 hours of the first symptoms were randomized to an open-label, treatment with rosuvastatin 20 mg, rosuvastatin 40 mg, or atorvastatin 80 mg for
12 weeks.
⦁ Rosuvastatin reduced LDL-C more than atorvastatin (44.6% vs 42.7%; p < 0.05).
⦁ More patients achieved LDL-C goals with rosuvasta- tin than with atorvastatin (69% vs 63%; p < 0.05).
⦁ HDL-C increased more with rosuvastatin than with atorvastatin (6.4% vs 3.1%; p < 0.001).
⦁ At study end, LDL-C decreased by 53.2%
(p < 0.001), and HDL-C increased by 14.7% (p < 0.001).
⦁ There was significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease bur- den (mean change in percent atheroma volume of entire vessel, mean change in atheroma volume in the 10-mm most diseased subsegment, and mean change in total atheroma volume).
⦁ At study end, rosuvastatin reduced LDL-C by 49%.
⦁ Rosuvastatin significantly reduced the rate of pro- gression of maximum carotid intima-media thick- ness, although this did not translate into regression.
⦁ At study end, both doses significantly reduced LDL- C (38.2% vs 59.9%).
⦁ Although the overall plaque burden remained unchanged, there was a 41.4% reduction in lipid-rich necrotic core.

⦁ At study end, LDL-C decreased by 38.6% and HDL-C increased by 19.8%.
⦁ Rosuvastatin significantly reduced plaque volume in the coronary artery, and plaque regression was observed in 60% of patients.

⦁ Compared with simvastatin, rosuvastatin was more effective for reducing LDL-C, and more patients achieved LDL-C targets.

⦁ At study end, rosuvastatin 20 mg decreased apoB/ apoA-1 ratio at 1 month more than atorvastatin 80 mg, although without significant differences at month 3.
⦁ LDL-C decreased by approximately 50% after 1 and 3 months of treatment in both groups.
⦁ At study end, rosuvastatin reduced LDL-C and increased HDL-C levels to a higher extent than atorvastatin.
⦁ Although both statins regressed the percent ather- oma volume, this was numerically greater with rosuvastatin.

⦁ At study end, reduction of LDL-C was greater with rosuvastatin 40 mg than with atorvastatin 80 mg (46.8% vs 42.7%; p = 0.02). LDL-C reduction was similar between atorvastatin 80 mg and rosuvastatin 20 mg.
⦁ Increases in HDL-C were significantly higher with rosuvastatin 40 mg (11.9%, p < 0.001) and rosuvas- tatin 20 mg (9.7%, p < 0.01) than with atorvastatin 80 mg (5.6%).

LDL-C: LDL cholesterol; HDL-C: HDL cholesterol; IVUS: intravascular ultrasound. Table based on data from references #3240.
Percent changes in adjusted mean LDL cholesterol levels (versus baseline) after treatment with rosuvastatin vs atorvastatin in clinical trials of patients with atherosclerotic vascular disease.R10: rosuvastatin 10 mg; A20: atorvastatin 20 mg; R20: rosuvastatin 20 mg; A80: atorvastatin 80 mg; R40: rosuvastatin 40 mg.. Figurebased on data from references #32,38,39,40. statins plus ezetimibe reduced LDL-C by 38.7% (treatment difference, 15.1%). Of note, the greater effect of combined therapy on LDL-C levels was independent of baseline LDL-C, age, sex, race, and history of diabetes mellitus [50]. In addition, combined treatment is associated with higher reductions in high-sensitivity C-reactive protein compared with statins alone [50,51] and even with an improvement in insulin resis- tance [52].

Various clinical trials have shown that the greater reduction in LDL-C levels achieved with combined therapy translates into a reduction in outcomes. Thus, the SHARP (Study of Heart and Renal Protection) study was a randomized double- blind clinical trial that included 9,270 patients with chronic kidney disease and no previous CVD. Patients were rando- mized to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo. After a median follow-up of 4.9 years, com- bined therapy was associated with a significant 17% reduction in the risk of major atherosclerotic events (RR 0.83; 95% CI: 0.74–0.94; p = 0.0021) [53]. The IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) study included 18,144 patients who had been hospitalized for acute coronary syndrome within the preceding 10 days and had baseline LDL-C between 50 and 100 mg/dL if they were taking lipid-lowering therapy or 50– 125 mg/dL if they were not. Patients were randomized to receive the combination of simvastatin 40 mg and ezetimibe 10 mg or simvastatin 40 mg and placebo. Median LDL-C during the study was 53.7 mg/dL with combined therapy and 69.5 mg/dL with monotherapy (p < 0.001). After a median follow-up of 6 years, combined therapy significantly reduced the risk of the combined primary endpoint (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke) by 6% (HR 0.94; 95% CI: 0.89–0.99; p = 0.016), MACE by 10%, any myocardial infarction by 13%, and ischemic stroke by 21% (Figure 3) [54]. The beneficial effects of combined therapy were consistent across different subgroups of patients, including elderly persons [53]. Adverse effect rates did not increase with combined therapy, even in the lowest LDL-C range [54,55].

4. Combination of rosuvastatin and ezetimibe in the management of dyslipidemia
Experimental data have demonstrated the underlying comple- mentary mechanisms that enable the combination of rosuvas- tatin with ezetimibe to markedly reduce LDL-C [56]. A number of clinical studies have analyzed the efficacy and safety profile of combining rosuvastatin and ezetimibe in patients with dyslipidemia in many clinical settings [8–10].

4.1. Pharmacokinetics of the combination of rosuvastatin with ezetimibe
Several studies have revealed a bioequivalent pharmacokinetic interaction between both drugs. In other words, no clinically significant pharmacokinetic interactions between rosuvastatin and ezetimibe were observed when the 2 drugs were admi- nistered concomitantly, leading to additional lipid-lowering effects, with a good safety profile. In addition, the fixed-dose combination of rosuvastatin and ezetimibe is bioequivalent to concomitantly administered single agents, without compro- mising lipid-lowering efficacy or safety [57–62].

4.2. Combination of ezetimibe and rosuvastatin in patients with hypercholesterolemia
The I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) study compared the efficacy and safety profile of the combination of ezetimibe and rosuvas- tatin with rosuvastatin in monotherapy in 396 patients (389 Efficacy of simvastatin plus ezetimibe (vs simvastatin) after acute coronary syndrome. data from the IMPROVE-IT trial. MI: myocardial infarction; MACE: major adverse cardiovascular events.Primary end point: CV death, major coronary event, or nonfatal stroke; MACE: MI,stroke, or CV death.. Figurebased on data from reference #54.were finally analyzed) with hypercholesterolemia in an 8- week, double-blind, multicenter, phase III randomized con- trolled trial. Patients received ezetimibe/rosuvastatin 10/ 20 mg, ezetimibe/rosuvastatin 10/10 mg, ezetimibe/rosuvas- tatin 10/5 mg, rosuvastatin 20 mg, rosuvastatin 10 mg, or rosuvastatin 5 mg. At the end of the study, the percent changes in adjusted mean LDL-C levels compared with baseline were higher in the total combined groups than in the monotherapy groups (–57.0% vs – 44.4%; p < 0.001), as was the proportion of patients reaching LDL-C goals (92.3% vs 79.9%; p < 0.001), with no increase in the frequency of adverse effects, including liver function and creatinine kinase levels (Figures 4 and Figures 5) [63].

The MRS-ROZE (Multicenter Randomized Study of Rosuvastatin and Ezetimibe) trial was a multicenter 8-week randomized double-blind phase III study that compared the effects of fixed-dose combinations of ezetimibe plus rosuvas- tatin (5, 10, or 20 mg daily) with rosuvastatin alone (5, 10, or 20 mg daily) in 407 patients with primary hypercholesterole- mia. At the end of the study, combined therapy reduced LDL-C (59.1% vs 49.4%; p < 0.001), total cholesterol (39.6% vs 32.9%;P < 0.001), and triglycerides (22.7% vs 13.4%; p = 0.003) to a greater extent than monotherapy. According to the dose of rosuvastatin, combined therapy reduced LDL-C, total choles- terol, and triglyceride levels by 56%–63%, 37%–43%, and 19%–24%, respectively [64].
In another 8-week multicenter, randomized, and double- blind study performed in patients with primary hypercho- lesterolemia that assessed the efficacy and safety of the combination of rosuvastatin (5, 10, and 20 mg) plus ezeti- mibe (10 mg) compared with rosuvastatin (5, 10, and 20 mg) alone, reductions in LDL-C were more pronounced with the combination than with monotherapy (56.5% vs 45.2%; p < 0.01), as was the proportion of patients achiev- ing LDL-C goals (94.2% vs 86.6%; p = 0.01) (Figures 4 and Figures 5). Improvements in other lipid variables (total cholesterol, HDL cholesterol, and triglycerides) were also greater with combined therapy. In the extension phase study (from week 8 to 20), ezetimibe was also added to subjects treated with rosuvastatin alone in the main study, and the same treatment was continued in the combined therapy group. Of note, the beneficial effects of combined therapy on lipid profile remained unchanged in the exten- sion phase. The drugs were well tolerated. In fact, no serious adverse drug reactions were observed during the study [65].

A recent phase III, multicenter, randomized, parallel, open-label, and noninferiority study including 129 patients with hypercholesterolemia or mixed dyslipidemia treated with a fixed-dose combination of rosuvastatin (10 or
20 mg) and ezetimibe revealed significantly higher LDL-C reductions than with simvastatin (20 or 40 mg) or ezetimibe, respectively. In fact, the LDL-C target of <100 mg/dL was achieved in a significantly greater proportion of rosuvasta- tin/ezetimibe patients at week 4 (84.8% vs 68.2%; p = 0.0257) and at week 9 (81.2% vs 73.0%; p = 0.23). In the case of the target LDL-C < 70 mg/dL, the percentages were 45.4% vs 15.9% (p = 0.003) and 40.9% vs 15.9% (p = 0.0017), respectively. The overall incidence of adverse events was similar in both groups [66].
Additionally, the combination of rosuvastatin and ezeti- mibe exhibits anti-inflammatory properties and improves hepatic steatosis in patients with dyslipidemia [67–69].

Percent changes in adjusted mean LDL cholesterol levels (versus baseline) after treatment with rosuvastatin/ezetimibe or rosuvastatin.
Figure based on data from references #63,65,74. Proportion of patients achieving LDL cholesterol goals after treatment with rosuvastatin/ezetimibe or rosuvastatin.Figure based on data from references #63,65,74.

4.3. Combination of ezetimibe and rosuvastatin in patients with diabetes and dyslipidemia
A randomized, multicenter, open-label, parallel-group study per- formed in 136 patients with diabetes and hypercholesterolemia treated with rosuvastatin/ezetimibe 5/10 mg or rosuvastatin 10 mg for 8 weeks showed a greater reduction in the apoB/A1 ratio with combined therapy than with rosuvastatin (–46.1% vs – 41.3; p = 0.03). In addition, more patients attained the compre- hensive lipid target (LDL-C < 70 mg/dL, non-HDL-cholesterol
<100 mg/dL, and apoB <80 mg/dL) with combined therapy (73.5% vs 45.6%; p < 0.001). Greater benefits were also obtained with rosuvastatin/ezetimibe on total cholesterol, non-HDL cho- lesterol, LDL-C, and apoB. Of note, the risk of adverse effects was low and similar between groups [70].
To ascertain whether it is more effective to add ezetimibe or to increase the statin dose in patients with type 2 diabetes who are already being treated with statins, a clinical trial including 79 subjects with type 2 diabetes treated with rosu- vastatin 2.5 mg and LDL-C ≥ 80 mg/dL randomized patients to add ezetimibe or increase their dose of rosuvastatin to 5 mg/ day, for 12 weeks. Compared with doubling the dose of rosuvastatin, adding ezetimibe was associated with greater reductions in LDL-C, small dense LDL-C, oxidized LDL, and remnant-like lipoprotein cholesterol [71].
In the MRS-ROZE study, the impact of combined therapy on lipid profile was even greater in patients with diabetes mellitus or metabolic syndrome than in the general study population [64].

4.4. Combination of ezetimibe and rosuvastatin in patients with hypercholesterolemia and high cardiovascular risk
The ACTE study (Efficacy and Safety of Ezetimibe Added On to Rosuvastatin Versus Uptitration of Rosuvastatin in Hypercholesterolemic Patients at Risk for Coronary Heart Disease) was a multicenter, 6-week, randomized, double- blind, parallel-group, clinical trial that assessed the efficacy and safety of adding ezetimibe to rosuvastatin (5 or 10 mg) compared with doubling the dose of rosuvastatin (from 5 to 10 mg or from 10 to 20 mg) in 440 subjects at moderately high/high risk of coronary heart disease with uncontrolled LDL-C. Pooled combined therapy reduced LDL-C to a greater extent than doubling the dose of rosuvastatin (21% vs 5.7%; p < 0.001). A higher proportion of patients on combined therapy attained LDL-C targets of <100/70 mg/dL (59.4%vs 30.9%; p < 0.001), and LDL-C < 70 mg/dL (43.8% vs 17.5%, p < 0.001). The incidence of adverse effects was low, with no significant differences between groups [72].The EXPLORER trial (Examination of Potential Lipid-mod- ifying Effects Of Rosuvastatin in Combination with Ezetimibe versus Rosuvastatin Alone) investigated the efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe 10 mg for 6 weeks in 469 patients at high risk of coronary heart disease. At the end of the study, the combi- nation of rosuvastatin/ezetimibe reduced LDL-C significantly more than rosuvastatin (–69.8% vs – 57.1%, p < 0.001) and more patients attained LDL-C < 100 mg/dL and <70 mg/dL (94.0% vs 79.1% [p < 0.001] and 79.6% vs 35.0% [p < 0.001],
respectively). Both treatments were well tolerated [73].

In a randomized, double-blind, placebo-controlled, multicen- ter study, 245 patients with high or moderately high risk were randomly assigned to receive rosuvastatin 5 mg, rosuvastatin/ ezetimibe 5/10 mg, rosuvastatin 10 mg, rosuvastatin/ezetimibe 10/10 mg, rosuvastatin 20 mg, or rosuvastatin/ezetimibe 20/ 10 mg for a period of 8 weeks. After 8 weeks of treatment, LDL- C decreased by 60% (range 58%–63%) in the pooled combined therapy group and by 51% (range 45%–56%) in the pooled monotherapy group (p < 0.001). Similarly, LDL-C targets were achieved in more patients who received combined therapy than in those who received monotherapy (91% [range 87%-95%] vs 73% [range 64%-87%]; p = 0.01) (Figures 4 and Figures 5). Adverse event rates were similar between the groups [74].

4.5. Combination of ezetimibe and rosuvastatin in patients with hypercholesterolemia and coronary heart disease
The GRAVITY study (Gauging the Lipid Effects of Rosuvastatin Plus Ezetimibe Versus Simvastatin Plus Ezetimibe Therapy) analyzed
833 patients with coronary heart disease or risk equivalent and reported that the combinations of rosuvastatin (10–20 mg) plus ezetimibe provided a further 10%-14% reduction in LDL-C than the combination of simvastatin (40–80 mg) plus ezetimibe [75]. In 125 Chinese patients with non-ST-elevation acute cor- onary syndrome, a higher proportion of patients achieved an LDL-C < 70 mg/dL with rosuvastatin/ezetimibe 10/10 mg than with rosuvastatin 20 mg or 10 mg after 12 weeks of follow-up (81.0% vs 68.3% vs 33.3%, respectively; p < 0.001). Similarly, the reduction in LDL-C was greater with the combination than with monotherapy (67.28% vs 52.80% vs 43.89%, respectively; p < 0.001). The incidence of drug-related adverse events was higher with rosuvastatin 20 mg than with rosuvastatin 10 mg or combined therapy [76]. The ROSEZE study demonstrated that the fixed-dose com- bination of rosuvastatin and ezetimibe significantly and per- manently decreased LDL-C, regardless of the timing of administration (morning or evening) [77]. In addition, various studies have reported that the combi- nation of rosuvastatin and ezetimibe can provide significant incremental reduction in the plaque volume of coronary arteries and also a decrease in plaque burden, leading to plaque stability and to a lower risk of outcomes, not only because of the combination’s lipid-lowering effect, but also because of its inflammatory properties [78–80].

5. Discussion
Reducing LDL-C levels to recommended targets is mandatory if we are to reduce the burden of cardiovascular disease [2]. Unfortunately, a large number of patients, particularly those at high or very high risk do not attain their LDL-C goals, mainly because of insufficient intensification of lipid-lowering therapy [6]. Moreover, there are many barriers to the use of statins in cardiovascular care, including underuse/underdosing of sta- tins, low adherence, and early discontinuation due to adverse effects, leading to an increased risk of cardiovascular out- comes [81]. In this context, rosuvastatin, a high-intensity statin with a low risk of adverse effects and drug-drug interactions could prove to be very helpful [82,83]. However, many studies have shown that uptitrating statin doses is less effective than adding ezetimibe, as combined therapy provides greater LDL- C reductions without increasing the risk of adverse events, because of the complementary mechanisms of action [84,85]. Of note, the combination of rosuvastatin and ezetimibe mark- edly reduces LDL-C levels (up to 60%-75% from baseline), leading to the achievement of LDL-C goals in a broad spec- trum of patients with hypercholesterolemia, along the cardio- vascular risk continuum, including those with established atherosclerotic CVD [7,63–80]. Table 4 summarizes the clinical profile of patients with coronary artery disease who may benefit from the combination rosuvastatin 10–40 mg plus ezetimibe 10 mg according to the consensus of the Spanish Society of Cardiology [7].In addition, fixed-dose combinations of rosuvastatin and
ezetimibe simplify treatment (vs free combinations) and may improve adherence to medication, thus reducing the fre- quency of cardiovascular complications [81]. In fact, a recent study showed that although the addition of ezetimibe in patients already prescribed a statin reduces LDL-C by an addi- tional 23.8%, this reduction is even greater when fixed-dose combinations are prescribed than when separate pills are prescribed (28.4% vs 19.4%; p < 0.0001) [86]. As a result, assuring a good medication adherence through the simplifica- tion of treatment with the used of fixed-dose combination (vs taking two pills separately) seems mandatory.

One of the concerns about the use of rosuvastatin in clinical practice is the potential risk of developing diabetes [87]. However, as the JUPITER trial demonstrated, although this may occur in specific cases where the patient is at risk of diabetes, it is not clinically relevant, as rosuvastatin only accelerates the diagnosis of diabetes for a few weeks [19,21,22]. Moreover, the addition of ezetimibe to rosuvastatin could not only reduce the risk of diabetes, given that lower doses of rosuvastatin are required, but also provides marked reductions in LDL-C levels in diabetic patients or in patients at risk of diabetes, thus leading to a reduction in cardiovascular complications [64,70,71].
Finally, different studies have shown that adding ezetimibe to rosuvastatin is a cost-effective approach, particularly in patients with atherosclerotic CVD, as well as in patients with elevated LDL-C levels and a high cardiovascular risk [88,89]. However, although compared with free combinations, the use of fixed-dose combinations improves medication adherence, and this may translate into a reduction of costs [88], this should be specifically investigated with the rosuvastatin-ezeti- mibe combination.

6. Conclusions
Elevated LDL-C is associated with an increased risk of cardio- vascular outcomes. As a result, attaining LDL-C goals is neces- sary in order to decrease cardiovascular burden. This is particularly important in high-/very-high-risk patients, in whom marked reductions in LDL-C levels are usually required. Clinical profile of patients who may benefit from the combination rosuvastatin 10–40 mg plus ezetimibe 10 mg according to the consensus of the spanish society of Cardiology. Follow-up visit if LDL-C targets The combination of rosuvastatin and ezetimibe provides important LDL-C reductions (up to 60–75%), with a good safety profile. Various clinical trials have demonstrated the beneficial effects of combining rosuvastatin with ezetimibe in a broad spectrum of patients with hypercholesterolemia, including those at high risk and those with atherosclerotic CVD. In addition, the fixed-dose combination may improve medication adherence, thus adding value in the treatment of these patients.

7. Expert opinion
Elevated low-density lipoprotein cholesterol (LDL-C) is a major modifiable risk factor for cardiovascular disease. Reducing LDL-C with lipid-lowering therapies is associated with a decrease in cardiovascular events in both primary and second- ary prevention, even in patients with a recent ischemic stroke or transient ischemic attack of atherosclerotic origin. Thus, the Treat Stroke to Target trial showed that after an atherosclero- tic cerebrovascular event, reducing LDL-C below 70 mg/dL through the use of a more intensive lipid lowering therapy, including the combination of a statin plus ezetimibe, was associated with a lower risk of subsequent cardiovascular events compared with an LDL-C between 90 and 110 mg/dL [89]. In addition, early primary prevention of cardiovascular disease with lipid-lowering agents is associated with a sub- stantial reduction in future atherosclerotic risk [5]. However, despite recommendations from guidelines, many patients do not achieve their therapeutic goals, and prescribing high- intensity statins in monotherapy may enable LDL-C targets to be reached by only a small percentage of patients. European guidelines recommend prescription of a high-inten- sity statin up to the maximum tolerated dose to reach treat- ment goals according to cardiovascular risk; if these targets are not reached, then ezetimibe should be added [2]. A recent consensus document from the Spanish Society of Cardiology provides three simple algorithms aimed at achieving LDL-C goals as soon as possible, since the magnitude of the benefit is both risk- and time-dependent [7]. Rosuvastatin is a high-intensity statin with a low risk of LDL-C target First visit are not achieved (4–6 weeks*/ 48 weeks**) adverse effects and drug-drug interactions. However, increas- ing its dose is not as effective as combining the drug with
⦁ On maximum high-intensity
tolerated dose of statin and LDL-C ≥ 55 mg/dL.
⦁ On non-maximum high- intensity tolerated dose of statin and LDL-C > 100 mg/ dL.
⦁ No prior statin treatment and LDL-C > 100 mg/dL
⦁ On maximum high-intensity tolerated dose of statin and LDL-C ≥ 70 mg/dL.
⦁ On non-maximum high- intensity tolerated dose of statin and LDL-C > 130 mg/ dL.
⦁ No prior statin treatment and LDL-C > 130 mg/dL.
⦁ On maximum high-intensity
tolerated dose of statin and LDL-C < 55 mg/dL.
⦁ On non-maximum high- intensity tolerated dose of statin and LDL-C < 100 mg/ dL.
⦁ No prior statin treatment and LDL-C ≤ 100 mg/dL.
⦁ On maximum high-intensity tolerated dose of statin and LDL-C < 70 mg/dL.
⦁ On non-maximum high- intensity tolerated dose of statin and LDL-C 70–130 mg/ dL.
⦁ No prior statin treatment and LDL-C ≤ 130 mg/dL.
ezetimibe. Combination therapy provides greater LDL-C reduc- tions without increasing the risk of adverse events, thanks to the complementary mechanisms of action [56]. In fact, the combination of rosuvastatin and ezetimibe markedly reduces LDL-C levels (60–75% from baseline), thus enabling patients with hypercholesterolemia, including those with established atherosclerotic cardiovascular disease, to achieve their LDL-C goals [7,63–80].
New lipid-lowering drugs in combinations with statins can play a key role in overcoming the many barriers to the use of statins in cardiovascular care (e.g. underuse/underdosing and potentially fatal poor adherence) [81]. Available data indicate that rosuvastatin could prove very useful owing to its low risk of adverse events and interactions. Fixed dose combinations

LDL-C: LDL cholesterol.
Table based on data from reference #7.
of rosuvastatin and ezetimibe seem promising with respect to improving adherence and reducing the frequency of cardiovascular complications [81,85], although further investi- gation, especially randomized control trials with large samples, are warranted to confirm current findings.
The fixed-dose combination of rosuvastatin and ezetimibe has been shown to be cost-effective in patients with athero- sclerotic cardiovascular disease and in patients with elevated LDL-C levels and a high cardiovascular risk [90,91].

Acknowledgments
Writing and editorial assistance were provided by Content Ed Net (Madrid, Spain) with funding from Viatris Spain.

Funding
This article was supported by Viatris Spain.

Declaration of interest
V. Barrios has declared receiving honoraria consultancies and/or lecturing fees from Mylan, MSD, Sanofi, Amgen, Servier, Almirall. C. Escobar has declared receiving honoraria for oral presentations and consultancy fees from Mylan, MSD, Sanofi, Amgen, Servier, Almirall. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures
One reviewer has declared consultancy to Astra Zeneca and Althera. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose

References
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
1. GBD 2017. Causes of death collaborators. global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 19802017: a systematic analysis for the global burden of disease study 2017. Lancet. 1. 2018;392 (10159):1736–1788.
2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2. 2020;41(1):111–188.
3. Silverman MG, Ference BA, Im K, et al. Association between low- ering LDL-C and Cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 3. 2016;316(12):1289–1297.
4. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual parti- cipant data from 28 randomised controlled trials. Lancet. 4. 2019;393 (10170):407–415.
5. Pencina MJ, Pencina KM, Lloyd-Jones D, et al. The expected 30-year benefits of early versus delayed primary prevention of Cardiovascular Disease by lipid lowering. Circulation. 5. 2020;142 (9):827–837.
6. Kotseva K, De Backer G, De Bacquer D, et al. Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: results from the European Society of Cardiology ESC- EORP EUROASPIRE V registry. Eur J Prev Cardiol. 6. 2019;26(8):824– 835.
7. Escobar C, Anguita M, Arrarte V, et al., Recommendations to improve lipid control. Consensus document of the Spanish
Society of Cardiology. Rev Esp Cardiol (Engl Ed). 2020;73(2):161– 167.
⦁ Not achieving target lipid levels is of particular concern in secondary prevention patients. Application of simple algo- rithms can cover most secondary prevention scenarios in clin- ical practice.
8. Strilchuk L, Tocci G, Fogacci F, et al. An overview of rosuvastatin/ ezetimibe association for the treatment of hypercholesterolemia and mixed dyslipidemia. Expert Opin Pharmacother. 2020;21 (5):531–539.
9. Lamb YN. Rosuvastatin/Ezetimibe: a review in Hypercholesterolemia. Am J Cardiovasc Drugs. 2020;20(4):381–392.
10. Rosuvastatin and ezetimibe. Summary of product characteristics. [cied 2020 Dec 18]. Available from: https://mri.cts-mrp.eu/human/ downloads/NL_H_3647_001_FinalSPC.pdf
11. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92 (2):152–160.
12. Nicholls SJ, Brandrup-Wognsen G, Palmer M, et al. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosu- vastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER. Am J Cardiol. 2010;105(1):69–76.
13. Zhang X, Xing L, Jia X, et al. Comparative lipid-lowering/increasing efficacy of 7 statins in patients with Dyslipidemia, Cardiovascular diseases, or diabetes mellitus: systematic review and network meta-analyses of 50 randomized controlled trials. Cardiovasc Ther. 2020;3987065:2020.
14. Athyros VG, Kakafika AI, Tziomalos K, et al. Pleiotropic effects of statins – clinical evidence. Curr Pharm Des. 2009;15(5):479–489.
15. Fan CH, Hao Y, Liu YH, et al. Anti-inflammatory effects of rosuvas- tatin treatment on coronary artery ectasia patients of different age groups. BMC Cardiovasc Disord. 2020;20(1):330.
16. Slhessarenko JR, Hirata M, Sousa A, et al. Effect of preloading with high dose of rosuvastatin on serum levels of inflammatory markers after percutaneous coronary intervention. J Invasive Cardiol. 2020;32(9):335–341.
17. Kini AS, Baber U, Kovacic J, et al. Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW Trial (reduction in yellow plaque by aggressive lipid-low- ering therapy). J Am Coll Cardiol. 2013;62(1):21–29.
18. Naresh S, Bitla AR, Rao PVLNS, et al. Efficacy of oral rosuvastatin intervention on HDL and its associated proteins in men with type 2 diabetes mellitus. Endocrine. 2021;71(1):76–86.
19. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive pro- tein. N Engl J Med. 2008;359(21):2195–2207.
20. Ridker PM, MacFadyen JG, Fonseca FA, et al. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipo- protein cholesterol and elevated high-sensitivity C-reactive pro- tein: justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER). Circ Cardiovasc Qual Outcomes. 2009;2(6):616–623.
21. Barrios V, Escobar C. Rosuvastatin and diabetes: when the evidences talk. Cardiovasc Hematol Agents Med Chem. 2013;11(2):115–124.
22. Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular ben- efits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565– 571.
23. Hsia J, MacFadyen JG, Monyak J, et al. Cardiovascular event reduc- tion and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. the jupiter trial (justification for the use of statins in prevention: an interven- tion trial evaluating rosuvastatin). J Am Coll Cardiol. 2011;57 (16):1666–1675.
24. Mora S, Glynn RJ, Hsia J, et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C- reactive protein or dyslipidemia: results from the Justification for

the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation. 2010;121(9):1069–1077.
25. Ridker PM, MacFadyen J, Cressman M, et al. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary ana- lysis from the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial. J Am Coll Cardiol. 2010;55(12):1266–1273.
26. Everett BM, Glynn RJ, MacFadyen JG, et al. Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER. Circulation. 2010;121(1):143–150.
27. Ridker PM, Macfadyen JG, Nordestgaard BG, et al. Rosuvastatin for primary prevention among individuals with elevated high-sensitiv- ity c-reactive protein and 5% to 10% and 10% to 20% 10-year risk. Implications of the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial for “inter- mediate risk”. Circ Cardiovasc Qual Outcomes. 2010;3(5):447–452.
28. Glynn RJ, Koenig W, Nordestgaard BG, et al. Rosuvastatin for pri- mary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010;152(8):488–496.
29. Koenig W, Ridker PM. Rosuvastatin for primary prevention in patients with European systematic coronary risk evaluation risk = 5% or Framingham risk >20%: post hoc analyses of the JUPITER trial requested by European health authorities. Eur Heart J. 2011;32 (1):75–83.
⦁ Rosuvastatin 20 mg significantly reduced major cardiovascular
events in primary prevention patients with elevated hsC-RP and a high global cardiovascular risk.
30. Yusuf S, Bosch J, Dagenais G, et al. HOPE-3 Investigators. choles- terol lowering in intermediate-risk persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2021–2031.
31. Wander GS, Hukkeri MYK, Yalagudri S, et al. Rosuvastatin: role in Secondary Prevention of Cardiovascular Disease. J Assoc Physicians India. 2018;66(3):70–74.
32. Clearfield MB, Amerena J, Bassand JP, et al., Comparison of the efficacy and safety of rosuvastatin 10 mg and atorvastatin 20 mg in high-risk patients with hypercholesterolemia–Prospective study to evaluate the Use of Low doses of the Statins Atorvastatin and Rosuvastatin (PULSAR). Trials. 7(1): 35. 2006.
⦁ Rosuvastatin was more efficacious than atorvastatin at redu-
cing LDL-C in high-risk patients with hypercholesterolemia, enabling more patients to achieve their LDL-C goals.
33. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556–1565.
34. Crouse JR 3rd, Js R, Wa R, et al. Effect of rosuvastatin on progres- sion of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA. 2007;297 (12):1344–1353.
35. Underhill HR, Yuan C, Zhao XQ, et al. Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic reso- nance imaging trial. Am Heart J. 2008;155(3):584.
36. Takayama T, Hiro T, Yamagishi M, et al. Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS). Circ J. 2009;73(11):2110–2117.
37. Hall AS, Jackson BM, Farrin AJ, et al. A randomized, controlled trial of simvastatin versus rosuvastatin in patients with acute myocardial infarction: the secondary prevention of acute coronary events– reduction of cholesterol to key European targets trial. Eur J Cardiovasc Prev Rehabil. 2009;16(6):712–721.
38. Lablanche JM, Leone A, Merkely B, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin in reducing
apolipoprotein B/apolipoprotein A-1 ratio in patients with acute coronary syndrome: results of the CENTAURUS study. Arch Cardiovasc Dis. 2010;103(3):160–169.
39. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365(22):2078–2087.
40. Pitt B, Loscalzo J, Monyak J, et al., Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study). Am J Cardiol. 2012;109(9):1239–1246.
⦁ Rosuvastatin more effectively decreased LDL cholesterol,
increased HDL cholesterol, and improved other lipid para- meters than atorvastatin in patients with acute coronary syndrome.
41. Zhang J, Feng R, Ferdous M, et al. Effect of 2 different dosages of rosuvastatin on prognosis of acute myocardial infarction patients with new-onset atrial fibrillation in Jinan, China. Med Sci Monit. 2020;26:e925666.
42. Luo R, Sun X, Shen F, et al. Effects of high-dose rosuvastatin on ventricular remodelling and cardiac function in st-segment ele- vation Myocardial infarction. Drug Des Devel Ther. 2020;14:3891–3898.
43. Calza L, Colangeli V, Borderi M, et al. Rosuvastatin decreases serum inflammatory markers and slows atherosclerosis progression rate in treated HIV-infected patients with metabolic syndrome. Infect Dis (Lond). 2021;53(2):81–88.
44. Liu D, Shen T, Ren C, et al. The effects of atorvastatin and rosuvas- tatin on exercise tolerance in patients with coronary heart disease. Expert Opin Drug Saf. 2020;19(9):1203–1208.
45. He W, Cao M, Li Z. Effects of different doses of atorvastatin, rosuvastatin, and simvastatin on elderly patients with ST-eleva- tion acute myocardial infarction (AMI) after percutaneous cor- onary intervention (PCI). Drug Dev Res. 2020;81(5):551–556.
46. Perez-Calahorra S, Laclaustra M, Marco-Benedi V, et al. Comparative efficacy between atorvastatin and rosuvastatin in the prevention of cardiovascular disease recurrence. Lipids Health Dis. 2019;18(1):216.
47. Kwak A, Kim JH, Choi CU, et al. Comparative effectiveness of statins in secondary prevention among the older people aged 75 years and over. Int J Clin Pharm. 2019;41(2):460–469.
48. Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe lipid-lowering trial on prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): a randomized, controlled trial. Circulation. 2019;140(12):992–1003.
49. Hammersley D, Signy M. Ezetimibe: an update on its clinical usefulness in specific patient groups. Ther Adv Chronic Dis. 2017;8(1):4–11.
50. Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identifica- tion of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012;223(2):251–261.
51. Ta P, Cm B, Veltri E, et al. Pooled analyses of effects on C- reactive protein and low density lipoprotein cholesterol in pla- cebo-controlled trials of ezetimibe monotherapy or ezetimibe added to baseline statin therapy. Am J Cardiol. 2009;103 (3):369–374.
52. Tsunoda T, Nozue T, Yamada M, et al. Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. Diabetes Res Clin Pract. 2013;100 (1):46–52.
53. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): a randomised placebo-controlled trial. Lancet. 2011;377 (9784):2181–2192.
54. Cp C, Ma B, Rp G, et al., Ezetimibe added to statin therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387–2397.
⦁ Adding ezetimibe to statin therapy results in incremental lowering of LDL-C and improves cardiovascular outcomes.
55. Bach RG, Cannon CP, Giugliano RP, et al. Effect of simvastatin- ezetimibe compared with simvastatin monotherapy after Acute Coronary Syndrome among patients 75 years or older: a secondary analysis of a randomized clinical trial. JAMA Cardiol. 2019;4(9):846– 854.
56. Verschuren L, Radonjic M, Wielinga PY, et al. Systems biology analysis unravels the complementary action of combined rosuvas- tatin and ezetimibe therapy. Pharmacogenet Genomics. 2012;22 (12):837–845.
57. Kim CH, An H, Kim SH, et al. Pharmacokinetic and pharmacody- namic interaction between ezetimibe and rosuvastatin in healthy male subjects. Drug Des Devel Ther. 2017;11:3461–3469.
58. Kim H, Choi HY, Kim YH, et al. Pharmacokinetic interactions and tolerability of rosuvastatin and ezetimibe: an open-label, rando- mized, multiple-dose, crossover study in healthy male volunteers. Drug Des Devel Ther. 2018;12:815–821.
59. Hwang I, Park SI, Lee SH, et al. Pharmacokinetics of fixed-dose combination of rosuvastatin 20 mg and ezetimibe 10 mg com- pared to concurrent administration of individual tablets in healthy Korean subjects. Transl Clin Pharmacol. 2018;26(1):16– 24.
60. Kang WY, Seong SJ, Ohk B, et al. Pharmacokinetics and bioequiva- lence of a rosuvastatin/ezetimibe fixed-dose combination tablet versus single agents in healthy male subjects. Int J Clin Pharmacol Ther. 2018;56(1):43–52.
61. Kosoglou T, Statkevich P, Yang B, et al. Pharmacodynamic interac- tion between ezetimibe and rosuvastatin. Curr Med Res Opin. 2004;20(8):1185–1195.
62. Rhee MY, Kim KJ, Kim SH, et al. Ezetimibe and rosuvastatin combina- tion treatment can reduce the dose of rosuvastatin without compro- mising its lipid-lowering efficacy. Clin Ther. 2019;41(12):2571–2592.
63. Hong SJ, Jeong HS, Ahn JC, et al., A phase III, multicenter, rando- mized, double-blind, active comparator clinical trial to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus rosuvastatin monotherapy in patients with hypercholesterolemia: i-ROSETTE (Ildong rosuvastatin & ezetimibe for hypercholesterolemia) randomized controlled trial. Clin Ther. 2018;40(2):226–241.
⦁ Fixed-dose combinations of rosuvastatin/ezetimibe signifi-
cantly improved lipid profiles in patients with hypercholester- olemia compared with rosuvastatin monotherapy.
64. Kim KJ, Kim SH, Yoon YW, et al. Effect of fixed-dose combina- tions of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROSE (Multicenter randomized study of ROsuvastatin and eZEtimibe). Cardiovasc Ther. 2016;34(5):371–382.
65. Kim W, Yoon YE, Shin S-H, et al., Efficacy and safety of ezetimibe and rosuvastatin combination therapy versus those of rosuvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther. 2018;40(6):993–1013.
⦁ The combination of ezetimibe with rosuvastatin enabled more
patients to reach their LDL-C goal in primary hypercholester- olemia than rosuvastatin alone.
66. Vattimo ACA, Fonseca FAH, Morais DC, et al. Efficacy and tolerabil- ity of a fixed-dose combination of rosuvastatin and ezetimibe compared with a fixed-dose combination of simvastatin and ezeti- mibe in Brazilian patients with primary hypercholesterolemia or mixed dyslipidemia: a multicenter, randomized trial. Curr Ther Res Clin Exp. 2020;93:100595.
67. Yamazaki D, Ishida M, Watanabe H, et al. Comparison of anti-inflam- matory effects and high-density lipoprotein cholesterol levels between therapy with quadruple-dose rosuvastatin and rosuvastatin combined with ezetimibe. Lipids Health Dis. 2013;12(1):9.
68. Ren Y, Zhu H, Fan Z, et al. Comparison of the effect of rosuvastatin versus rosuvastatin/ezetimibe on markers of inflammation in patients with acute myocardial infarction. Exp Ther Med. 2017;14 (5):4942–4950.
69. Lee WD, Kim BK, Park JY, et al. Combined use of rosuvastatin and ezetimibe improves hepatic steatosis in patients with dyslipidemia. Eur J Gastroenterol Hepatol. 2020;32(12):1538–1544.
70. Lee J, Hwang YC, Lee WJ, et al., Comparison of the efficacy and safety of rosuvastatin/ezetimibe combination therapy and rosuvas- tatin monotherapy on lipoprotein in patients with type 2 diabetes: multicenter randomized controlled study. Diabetes Ther. 2020;11 (4):859–871.
•• The combination of rosuvastatin and ezetimibe significantly
reduced the apoB/A1 ratio compared with rosuvastatin alone. Both treatments were well tolerated in patients with type 2 diabetes and hypercholesterolemia.
71. Torimoto K, Okada Y, Mori H, et al. Efficacy of combination of ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes. Lipids Health Dis. 2013;12(1):137.
72. Bays HE, Davidson MH, Massaad R, et al. Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE study). Am J Cardiol. 2011;108(4):523–530.
73. Ballantyne CM, Weiss R, Moccetti T, et al., Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol. 2007;99(5):673–680.
⦁ Rosuvastatin combined with ezetimibe may improve the man-
agement of high-risk patients who cannot achieve their LDL-C goals on maximum-dose statin monotherapy.
74. Yang Y-J, Lee S-H, Kim BS, et al. Combination therapy of rosuvas- tatin and ezetimibe in patients with high cardiovascular risk. Clin Ther. 2017;39(1):107–117.
75. Ballantyne CM, Hoogeveen RC, Raya JL, et al. Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein meta- bolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: results of the GRAVITY randomized study. Atherosclerosis. 2014;232 (1):86–93.
76. Ran D, Nie HJ, Gao YL, et al. A randomized, controlled comparison of different intensive lipid-lowering therapies in Chinese patients with non-ST-elevation acute coronary syndrome (NSTE-ACS): ezeti- mibe and rosuvastatin versus high-dose rosuvastatin. Int J Cardiol. 2017;235:49–55.
77. Obonska K, Kasprzak M, Tymosiak K, et al., Low dose of ROSuvastatin in combination with EZEtimibe effectively and per- manently reduce low density lipoprotein cholesterol concentra- tion independently of timing of administration (ROSEZE): a randomized, crossover study – preliminary results. Cardiol J. 2021;28(1):58–66.
⦁ The fixed-dose combination of rosuvastatin and ezetimibe
significantly and permanently decreases LDL-C regardless of the timing of administration.
78. Wang X, Zhao X, Li L, et al. Effects of combination of ezetimibe and rosuvastatin on coronary artery plaque in patients with coronary heart disease. Heart Lung Circ. 2016;25(5):459–465.
79. Masuda J, Tanigawa T, Yamada T, et al. Effect of combination therapy of ezetimibe and rosuvastatin on regression of coronary atherosclerosis in patients with coronary artery disease. Int Heart J. 2015;56(3):278–285.
80. Kouvelos GN, Arnaoutoglou EM, Matsagkas MI, et al. Effects of rosuvastatin with or without ezetimibe on clinical outcomes in patients undergoing elective vascular surgery: results of a pilot study. J Cardiovasc Pharmacol Ther. 2013;18(1):5–12.
81. Drexel H, Coats AJS, Spoletini I, et al., An expert opinion paper on statin adherence and implementation of new lipid-lowering med- ications by the ESC Working Group on Cardiovascular Pharmacotherapy: barriers to be overcome. Eur Heart J Cardiovasc Pharmacother. 2020;6(2):115–121.
•• Poor adherence is associated with dangerous and sometimes
fatal outcomes. Combination therapy with lower dosages of statins and new lipid-lowering agents could increase adher- ence and prevent poor outcomes.
82. Barrios V, Escobar C. Rosuvastatin along the cardiovascular conti- nuum: from JUPITER to AURORA. Expert Rev Cardiovasc Ther. 2009;7(11):1317–1327.
•• Early treatment with rosuvastatin can maximize benefits in terms of reduction of LDL-C levels, as well as levels of trigly- cerides, total cholesterol, and apolipoprotein B and the apoli- poprotein B:A-1 ratio.
83. Barrios V, Escobar C. Rosuvastatin and cardiovascular continuum when time is important. J Am Coll Cardiol. 2010;55(15): 1645–1646. author reply 1646.
84. Lorenzi M, Ambegaonkar B, Baxter CA, et al. Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy. Clin Res Cardiol. 2019;108(5):487– 509.
85. Yu M, Liang C, Kong Q, et al. Efficacy of combination therapy with ezetimibe and statins versus a double dose of statin monotherapy in participants with hypercholesterolemia: a meta-analysis of litera- ture. Lipids Health Dis. 2020;19(1):1.
86. Katzmann JL, Sorio-Vilela F, Dornstauder E, et al. Non-statin lipid- lowering therapy over time in very-high-risk patients: effectiveness of fixed-dose statin/ezetimibe compared to separate pill combina- tion on LDL-C. Clin Res Cardiol. Online ahead of print Sep 19 2020. 10.1007/s00392-020-01740-8
•• The reduction in LDL-C when a statin and ezetimibe were
prescribed in combination was considerably larger for fixed- dose combinations.
87. Barkas F, Elisaf M, Liberopoulos E, et al. Statin therapy with or without ezetimibe and the progression to diabetes. J Clin Lipidol. 2016;10(2):306–313.
88. Salam A, Huffman MD, Kanukula R, et al. Two-drug fixed-dose combinations of blood pressure-lowering drugs as WHO essential medicines: an overview of efficacy, safety, and cost. J Clin Hypertens (Greenwich). 2020;22(10):1769–1779.
89. Amarenco P, Kim JS, Labreuche J, et al. Treat stroke to target investigators. a comparison of two ldl cholesterol targets after ischemic stroke. N Engl J Med. 2020;382(1):9.
90. Davies GM, Vyas A, Baxter CA. Economic evaluation of ezetimibe treatment in Rosuvastatin combination with statin therapy in the United States. J Med Econ. 2017;20(7):723–731.
⦁ The combination of ezetimibe and a statin was cost-effective for primary and secondary prevention of coronary heart disease and stroke in patients with high LDL-C levels and patients with diabetes.
91. Yang H, Li N, Zhou Y, et al. Cost-effectiveness analysis of ezetimibe as the add-on treatment to moderate-dose rosuvastatin versus high-dose rosuvastatin in the secondary prevention of cardiovas- cular diseases in china: a Markov model analysis. Drug Des Devel Ther. 2020;14:157–165.