If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Effects of Fixed-dose Combination of Low-intensity Rosuvastatin and Ezetimibe Versus Moderate-intensity Rosuvastatin Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia: A Randomized, Double-blind, Multicenter, Phase III Study
Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
Division of Cardiology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Division of Cardiovascular Medicine, Department of Internal Medicine, Dankook University Hospital, Dankook University School of Medicine, Chungcheongnam-do, Republic of Korea
Address correspondence to: Cheol Whan Lee, MD, Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
We investigated whether the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy in patients requiring cholesterol-lowering therapy.
Methods
This was a multicenter randomized, double‐blind study to investigate the safety and efficacy of a fixed-dose combination of rosuvastatin 2.5 mg and ezetimibe 10 mg (R2.5+E10) compared to those of ezetimibe 10 mg monotherapy (E10), rosuvastatin 2.5 mg (R2.5), and rosuvastatin 5 mg monotherapy (R5) in patients with hypercholesterolemia. A total of 348 patients at 15 centers in Korea were screened, and 279 patients were randomized to different groups in the study. Clinical and laboratory examinations were performed at baseline and 4 and 8 weeks after intervention. The primary endpoint was the percentage change of low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up.
Findings
Baseline characteristics were similar among the four groups. There were significant changes in lipid profiles at the 8-week follow-up. A greater decrease in the LDL cholesterol levels (primary endpoint) were found in the R2.5+E10 group (−45.7±18.6%) than in the E10 group (−16.7±14.7%, p<0.0001), R2.5 group (−32.6±15.1%, p<0.0001), and R5 group (−38.9±13.9%, p=0.0003). Similar outcomes were observed regarding the decrease in total cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B protein. In addition, changes in the triglyceride and HDL levels in the R2.5+E10 group were significantly different compared with those in the E10 group; however, the changes were similar to those in the other treatment groups. In patients with low and moderate risk, all patients achieved the target LDL cholesterol levels in the R2.5+E10 group (100%) compared to 13.0% in the E10 group, 47.6% in the R2.5 group, and 65.2% in the R5 group. Adverse effects were rare and similar in the four groups.
Implications
Fixed-dose combination of low-intensity rosuvastatin and ezetimibe was more effective in lowering LDL cholesterol and achieving LDL cholesterol goals than moderate-intensity rosuvastatin monotherapy. These findings suggest that the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy for cholesterol management, particularly in patients with low and moderate risk. ClinicalTrials.gov identifier: NCT04652349.
Cholesterol Treatment Trialists Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.
High-intensity statins decrease LDL-C levels by ≥50%, whereas moderate-intensity statins reduce LDL-C levels by 30% to 49%. Statins are generally well tolerated and have an excellent safety profile. However, statin-associated adverse effects are not uncommon; in particular, statin-associated muscle symptoms or hepatic toxicity are usually dose dependent.
Ezetimibe inhibits the uptake of biliary and dietary cholesterol into the enterocytes, and the combination therapy of statins and ezetimibe synergistically lowers LDL-C levels.
Efficacy of combination therapy with ezetimibe and statins versus a double dose of statin monotherapy in participants with hypercholesterolemia: a meta-analysis of literature.
In real-world clinical practice, low-intensity statins combined with ezetimibe are occasionally used due to concerns regarding statin-associated adverse effects. However, it remains unclear whether this combination therapy has similar effects on lipid profiles and fewer adverse effects compared with standard-intensity statin therapy.
In the present study, we compared the effects of a fixed-dose combination of low-intensity rosuvastatin and ezetimibe (2.5/10 mg) with those of ezetimibe 10 mg, low-intensity rosuvastatin 2.5 mg, or moderate-intensity rosuvastatin 5 mg on the lipid profiles of patients requiring cholesterol-lowering therapy.
Patients and Methods
Study Design
This multicenter, randomized, double-blind Phase III clinical trial was conducted to compare the effect of combination therapy with rosuvastatin and ezetimibe (2.5/10 mg) versus that of ezetimibe 10 mg, rosuvastatin 2.5 mg, or rosuvastatin 5 mg on lipid levels and their safety profile in patients with hypercholesterolemia (ClinicalTrials.gov identifier, NCT04652349). Patients who voluntarily signed the consent form at Visit 1 and satisfied the inclusion/exclusion criteria during screening were advised therapeutic lifestyle changes, including diet, exercise, and weight loss for at least 4 weeks (see Supplemental Figure 1 in the online version at doi:10.1016/j.clinthera.2021.07.016). During this period, the subjects had a washout period with no lipid medications (at least 4 weeks from Pre–Visit 2 for statins and omega-3 supplements, and at least 6 weeks from Pre–Visit 2 for fibrates). At Pre–Visit 2, the patients were screened again based on their fasting serum lipid levels and the inclusion/exclusion criteria. Eligible patients were stratified according to the cardiovascular risk category at Visit 2 (see Supplemental Table I in the online version at doi:10.1016/j.clinthera.2021.07.016) and randomly assigned to 1 of 4 treatment groups (1:1:1:1).
The risk of cardiovascular diseases was determined based on the 10-year risk calculated by using the Systematic Coronary Risk Evaluation (SCORE) method and other risk factors (diabetes, chronic renal disease, lipid level, atherosclerotic cardiovascular disease, and familial dyslipidemia). Patients were prescribed the investigational drugs corresponding to their treatment group. They visited the research institution every 4 weeks for efficacy and safety assessments.
Participants
Patients aged ≥19 years were eligible if they provided written informed consent, had fasting serum levels of LDL-C ≤250 mg/dL and triglyceride levels <500 mg/dL at Visit 1, and had appropriate ranges of LDL-C levels according to the defined risk category at Visit 2 (see Supplemental Tables I and II in the online version at doi:10.1016/j.clinthera.2021.07.016). We excluded patients with acute coronary syndrome, advanced heart failure, history of percutaneous coronary intervention, or coronary bypass graft surgery within the last 6 months; history of stroke; type 1 diabetes or uncontrolled type 2 diabetes (glycosylated hemoglobin values >9%); uncontrolled hypertension; comorbidities such as active liver disease, chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2), hyperthyroidism, hypothyroidism, or malignant tumors within the last 5 years; impaired drug absorption or history of alcohol abuse; history of fibromyalgia, myopathy, or rhabdomyolysis; and female patients who were pregnant or breastfeeding.
Study Treatment
Participants were randomly assigned in a 1:1:1:1 ratio to the following groups: combination therapy of rosuvastatin (2.5 mg) and ezetimibe (10 mg), ezetimibe 10 mg, rosuvastatin 2.5 mg, and rosuvastatin 5 mg. The randomization was performed by using a Web-based interactive response system. The allocation to each treatment group was computer generated and stratified according to the cardiovascular risk categories. The packaging manager of Hanmi Pharmaceutical Co, Ltd packaged the investigational drugs according to the randomization list. The patients were prescribed oral administration of the appropriate investigational drugs daily (4 pills: 1 actual medication, 3 placebos) for 8 weeks. Patients and researchers were double-blinded to the group allocation using a placebo throughout the treatment period. All patients underwent therapeutic lifestyle changes throughout the study period.
Study End Points
The primary efficacy end point was the percent change in LDL-C levels at the 8-week follow-up. Secondary efficacy end points were the percent changes in the following variables: (1) LDL-C at 4-week follow-up; and (2) total cholesterol, HDL-C, triglyceride, non–HDL-C, apolipoprotein A1, apolipoprotein B (apoB), high-sensitivity C-reactive protein, and LDL-C goal achievement at 4- and 8-week follow-up. The treatment goal of LDL-C was individualized according to the risk category (see Supplemental Table II in the online version at doi:10.1016/j.clinthera.2021.07.016). Safety was assessed by monitoring adverse events, clinical evaluation, and laboratory data. All investigator-reported adverse events were adjudicated by a core laboratory. All adverse events were classified into preexisting adverse events and treatment-emergent adverse events based on the time of occurrence; the findings were summarized in a list.
Statistical Analysis
This trial was designed to show the superiority of combination therapy with rosuvastatin and ezetimibe (2.5/10 mg) over low-dose rosuvastatin (2.5 mg) and ezetimibe (10 mg) on the percent reduction in LDL-C levels. Rosuvastatin 5 mg as the reference standard of moderate-intensity statin was used to assess the utility of the combination of rosuvastatin and ezetimibe (2.5/10 mg) in lowering LDL-C levels. A sample size of 240 subjects (60 per group) was calculated to have 98% power to detect a change of –13.8% in LDL-C levels from the baseline between the combination therapy and ezetimibe 10 mg with a 5% significance level,
Efficacy of combination therapy with ezetimibe and statins versus a double dose of statin monotherapy in participants with hypercholesterolemia: a meta-analysis of literature.
Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of Rosuvastatin and Ezetimibe).
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.
assuming an SD of 17.3% and a 20% dropout rate. The significance of differences in the baseline characteristics among groups was assessed by analysis of variance (Kruskal-Wallis test) for the continuous variables and the χ2 test or Fisher's exact test for the categorical variables.
The full analysis set was used for the efficacy assessment and the safety analysis set for the safety assessment. The full analysis set included patients who have undergone a primary end point assessment at least once after administration of an investigational drug, and the safety analysis set included those who have undergone a safety assessment at least once after the administration of an investigational drug. Type I error for the primary end point was controlled by using a stepwise, hierarchical testing procedure (overall power, 94%). Comparisons were made between rosuvastatin and ezetimibe (2.5/10 mg) in the first step and between the combination of rosuvastatin and ezetimibe (2.5/10 mg) and rosuvastatin 2.5 mg in the next step. The percent changes in LDL-C and other lipid parameters among the groups were evaluated by using ANCOVA or Wilcoxon rank-sum tests according to the normality distribution. The last-observation-carried-forward was used to impute missing values for the primary and secondary end points in the full analysis set. Statistical significance was defined as a two-sided P value <0.05. All statistical analyses were conducted by using SAS version 9.4 (SAS Institute, Inc, Cary, NC, USA).
Results
Baseline Characteristics
From June 2020 through October 2020, a total of 348 patients at 15 centers in the Republic of Korea were screened, and 279 patients were randomized to the 4 treatment groups (68 received 2.5/10 mg of rosuvastatin and ezetimibe, 70 received 10 mg of ezetimibe, 67 received 2.5 mg of rosuvastatin, and 70 received 5 mg of rosuvastatin). Three patients did not continue the follow-up laboratory examination because of withdrawal of informed consent (n = 1) or the occurrence of adverse events (n = 2). The remaining 276 patients (98.9%) completed the follow-up to assess the efficacy outcomes (Figure 1). The mean (SD) age of the patients was 62.3 (10.5) years, and men comprised 60.4% of the patient population. At the time of randomization, 83 patients (30.2%) had diabetes, 167 (60.7%) had hypertension, and 180 (67.6%) belonged to the high- or very-high-risk group. Baseline demographic characteristics and risk categories were not significantly different between the groups (Table I).
Changes in the lipid parameters and high-sensitivity C-reactive protein levels during treatment are summarized in Figure 2, Supplemental Figure 2 (in the online version at doi:10.1016/j.clinthera.2021.07.016), and Supplemental Table III (in the online version at doi:10.1016/j.clinthera.2021.07.016). The decrease in LDL-C levels at the 8-week follow-up (primary end point) was significantly greater in the combination therapy group than in the other groups. Similar findings were observed regarding the decrease in total cholesterol, non–HDL-C, and apoB protein levels. In addition, changes in the triglyceride and HDL levels in the combination therapy group were significantly different compared with those in the ezetimibe group but were similar compared with those in the other treatment groups. No significant change was observed in high-sensitivity C-reactive protein levels in any of the groups during the study period. In the subgroup analysis according to sex, the change in LDL-C level at 8 weeks of treatment was also notably greater in the combination therapy group than in the other groups, as shown in Supplemental Figure 3 (see the online version at doi:10.1016/j.clinthera.2021.07.016).
Figure 2Percent changes in the lipid parameters. E = ezetimibe; NS = not significant (P ≥ 0.05); R = rosuvastatin; TG = triglyceride. ****P < 0.0001; *** P < 0.001; **P < 0.01; *P < 0.05.
The percentage of patients achieving LDL-C goals at the 8-week follow-up according to the SCORE risk category is shown in Figure 3. Overall, the target achievements were significantly higher in the combination therapy group (51.5%) than in the ezetimibe 10-mg (5.7%; P < 0.0001), rosuvastatin 2.5-mg (22.4%; P < 0.0001), or rosuvastatin 5-mg (32.9%; P = 0.0092) group. In patients with low and moderate risk, all patients achieved target LDL-C levels in the combination therapy group (100%) compared with those in the ezetimibe 10-mg (13.0%), rosuvastatin 2.5-mg (47.6%), and rosuvastatin 5-mg (65.2%) groups. The percentage of patients achieving LDL levels <70 mg/dL or a reduction of LDL ≥50% was significantly higher in the combination therapy group than other groups (P < 0.001) (see Supplemental Figure 4 in the online version at doi:10.1016/j.clinthera.2021.07.016).
Figure 3LDL-C goal achievement according to Systematic Coronary Risk Evaluation (SCORE) risk category at 8 weeks. E = ezetimibe; NS = not significant (P ≥ 0.05); R = rosuvastatin. *P < 0.05; †P < 0.01; ‡P < 0.001; §P < 0.0001.
Adverse events occurred in 7 (2.5%) patients, and there were no differences in adverse effects between the treatment groups (Table II). Most adverse events were mild, and the most common adverse effects were dyspepsia and pruritus in 2 patients each. Adverse events leading to treatment discontinuation occurred in 1 patient (1.4%) in the combination therapy group and 1 (1.5%) in the rosuvastatin 2.5-mg group. One patient each in the rosuvastatin 5-mg group experienced a significant elevation in liver transaminase (>3 upper limits of normal) and creatine kinase (>10 upper limits of normal) levels during the study.
Table IITreatment-related side effects. Values are given as no. (%).
In the present study, the fixed-dose combination therapy of low-intensity rosuvastatin 2.5 mg with ezetimibe 10 mg showed a greater decrease in LDL-C, non–HDL-C, and apoB protein, and beneficial changes in lipid ratios, than the moderate-intensity rosuvastatin 5-mg monotherapy in patients with varied profiles, which resulted in a higher percentage of patients attaining the target LDL-C goal. Overall, 100% of the patients in the low- and moderate- risk categories achieved the target levels of LDL-C with a combination of low-intensity rosuvastatin and ezetimibe; however, this outcome was not seen in those in the high- and very-high-risk category (31.8%). Adverse side effects were largely similar and very low in all treatment groups. These findings suggest that combination therapy with low-intensity rosuvastatin 2.5 mg with ezetimibe 10 mg is a more effective strategy compared with rosuvastatin 5 mg for cholesterol management in patients with low and moderate risk.
Statins are the basis of lipid management due to their proven benefits. They are classified into 3 categories according to cholesterol‐lowering efficacy3: high-intensity statins (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) achieve at least a 50% reduction in LDL-C; moderate-intensity statins (atorvastatin 10–20 mg or rosuvastatin 5–10 mg) achieve a 30% to 49% reduction in LDL-C; and low-intensity statins (pravastatin 10–20 mg, simvastatin 10 mg, or rosuvastatin 2.5 mg) achieve an LDL-C reduction of <30%. High-intensity statin therapy is recommended for patients with high and very high risk of cardiovascular disease, whereas moderate-intensity statin therapy is indicated for those with low and moderate risk. Although high- and moderate-intensity statins remain the standard therapy to reduce cardiovascular events, some patients are unable to tolerate statin therapy. In fact, the use of statins is considered to be suboptimal in real-world practice, and low-intensity statins are occasionally used, especially for patients with a low risk of cardiovascular disease. Therefore, there is a wide gap between guideline-based optimal care and actual care in clinical practice. These might be due to concerns about the statin-associated adverse effects. Statin-associated muscle symptoms are the most common of the statin-associated adverse effects, which are usually dose dependent.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
One rational approach is using 2 cholesterol-lowering agents, such as a low-intensity statin and ezetimibe, which may alleviate the concerns regarding statin-associated adverse effects and lead to achievement of LDL-C goals.
It is recommended to use combination therapy with complementary mechanisms of action to maximize the effect with a lower dose and reduce the risk of several adverse reactions. Inhibition of cholesterol synthesis in the liver by rosuvastatin can enhance cholesterol absorption, while paradoxically decreasing the lipid-lowering effect. The addition of a cholesterol absorption inhibitor, ezetimibe, can provide a complementary action and increase the LDL-C–reducing efficacy of statins.
Ezetimibe inhibits cholesterol absorption in the intestine and decreases LDL-C by ∼20%. When coadministered with a statin, ezetimibe led to a significant additional reduction in LDL-C levels, with a higher proportion of patients achieving the target goals. In the present study, the low-intensity rosuvastatin/ezetimibe combination therapy decreased LDL-C levels by 45.7%, which was superior to that achieved with moderate-intensity rosuvastatin therapy (ie, 38.9%). These findings are compatible with those of the previous studies showing that adding ezetimibe 10 mg to any statin dose reduced LDL-C levels by an additional 25%, compared with the usual 6% achieved by doubling the statin dose.
Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of Rosuvastatin and Ezetimibe).
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.
In addition, low-intensity rosuvastatin/ezetimibe versus moderate-intensity rosuvastatin led to significantly greater improvements in total cholesterol, non–HDL-C, and apoB protein. In contrast, the decrease in LDL-C was <20% with ezetimibe alone, which is considerably below the current recommended limits for cholesterol treatment. The clinical benefit of LDL-C–lowering therapy depends on the intensity of therapy, the baseline LDL-C level, and the baseline risk of cardiovascular disease.
LDL-C goals were attained with low-intensity rosuvastatin/ezetimibe combination therapy in most patients with low and moderate risk. However, it did not achieve the target goals in the majority of patients with high risk or very high risk and may not be appropriate in these patient populations. Although the relative efficacy of statin/ezetimibe combination therapy compared with that of equivalent statin monotherapy remains unclear, the risk reduction of cardiovascular events is known to be proportional to the degree of decrease in LDL-C.
Cholesterol Treatment Trialists Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.
Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial Mendelian randomization study.
These findings suggest that the addition of ezetimibe to low-intensity rosuvastatin therapy may be a useful alternative to moderate-intensity rosuvastatin therapy in patients with low and moderate risk.
Ezetimibe combination with low-intensity rosuvastatin was well tolerated, with an excellent safety profile. Most of the adverse events were mild, and no serious adverse events were reported in any patients. The adverse event profiles observed in the low-intensity rosuvastatin/ezetimibe group were similar to those in the low-intensity rosuvastatin group and the ezetimibe group. Few patients discontinued treatment as a result of adverse events. In the combination therapy group, 1 patient experienced myalgia without an elevation of creatine kinase level during the study. For the most part, abnormal laboratory test results were unremarkable.
Several potential limitations need to be addressed. First, the small sample size and the use of surrogate markers are significant drawbacks of our study. It remains uncertain whether our findings would ultimately translate into reduced cardiovascular events in clinical practice, and this needs to be verified through trials with large sample sizes. Second, patients with a broad range of baseline risks were included in this study. The fixed-dose combination of low-intensity rosuvastatin and ezetimibe has a moderate potency to decrease LDL-C by 30% to 50%, and our findings may not be applicable for patients with high or very high risk. Third, the incidence of adverse events and discontinuation was low in each group, and there were no statistically significant differences between groups. This study was not designed with sufficient statistical power to prove the tolerability of a low-dose statin versus a standard dose of statin, and larger scale studies are needed. Finally, our study only involved an Asian population; thus, the extrapolation of these data to other ethnic groups may be limited. Overall, the rate of LDL goal attainment was lower in the high- and very-high-risk groups. The lower rate could have originated from insufficient validation of the SCORE risk algorithm in the Asian population, and the possibility of ethnic or geographic differences cannot be ruled out.
Conclusions
Low-intensity rosuvastatin (2.5 mg) with ezetimibe 10 mg resulted in more significant reductions in LDL-C and beneficial changes in lipid ratios than moderate-intensity rosuvastatin 5 mg monotherapy among a broad range of patients requiring cholesterol-lowering therapy.
Acknowledgment
The Hanmi Pharmaceutical Company supported the supply of the study drug, laboratory tests, data collection, clinical research coordinator expenses, and data analysis.
The funding body had no role in data interpretation or the writing of the manuscript based on the data.
Cheol Whan Lee contributed to the design and implementation of this study, the analysis of the results, the writing and critical revision of the manuscript, and obtaining the fund and supervision of this research. Seung-Ah Lee carried out the acquisition, analysis, and interpretation of data, participated in statistical analysis, and drafted the manuscript with support from Cheol Whan Lee. All listed authors have performed the data collection and supervised this trial, and revised the manuscript for important intellectual content.
DISCLOSURES
The authors have indicated that they have no conflicts of interest regarding the content of this article.
References
Cholesterol Treatment Trialists Collaboration
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.
Efficacy of combination therapy with ezetimibe and statins versus a double dose of statin monotherapy in participants with hypercholesterolemia: a meta-analysis of literature.
Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of Rosuvastatin and Ezetimibe).
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.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial Mendelian randomization study.
00261-7&id=gr1.jpg){kind=link}
00261-7&id=gr2.jpg){kind=link}
00261-7&id=gr3.jpg){kind=link}