Review of Side-Effect Profile of Combination Ezetimibe and Statin Therapy in Randomized Clinical Trials

doi:10.1016/j.amjcard.2008.01.041

The American Journal of Cardiology

Volume 101, Issue 11, 1 June 2008, Pages 1606-1613

https://doi.org/10.1016/j.amjcard.2008.01.041 Get rights and content

Effective treatment to achieve target lipid parameters in high-risk patients may require combination drug therapies. Concerns regarding risks associated with such combination therapies may limit their use. A systematic overview of randomized controlled trials to assess risks associated with combination statin and ezetimibe therapy was performed. Eighteen trials were identified, including 14,471 patients. Follow-up ranged from 6 to 48 weeks. Compared with statin monotherapy, combination therapy did not result in significant absolute increases in risks of myalgias (risk difference −0.033, 95% confidence interval [CI] −0.06 to −0.01), creatine kinase increases (risk difference 0.011, 95% CI −0.02 to 0.04), rhabdomyolysis (risk difference −0.003, 95% CI −0.01 to 0.004), transaminase increases (risk difference −0.003, 95% CI −0.01 to 0.005), gastrointestinal adverse events (risk difference 0.005, 95% CI −0.03 to 0.04), or discontinuations because of an adverse event (risk difference −0.005, 95% CI −0.03 to 0.02). In conclusion, based on available randomized trials, the addition of ezetimibe to statin therapy did not increase the risk of myalgias, creatine kinase increases, rhabdomyolysis, transaminase increases, gastrointestinal adverse events, or discontinuations because of an adverse event. Additional trials are necessary to ensure that results of clinical trials are consistent with routine clinical practice, particularly in older patients with more co-morbid conditions and patients on higher statin doses.

Section snippets

Methods

We performed this study in accordance with the Quality of Reporting of Meta-analyses Statement and recommendations for assessing harm in randomized clinical trials.² Eligible studies were identified by searching MEDLINE (1966 to July 2006), EMBASE (1980 to July 2006), the Cochrane Library, the National Institutes of Health Clinical Trials Website, and relevant bibliographies. A combination of medical subject headings and text terms ezetimibe, zetia, and vytorin was used.

We included

Results

We identified 312 potentially relevant studies. Of these, 18 studies met our inclusion/exclusion criteria and were assessed in this study. A total of 14,471 patients were evaluated: 503 were randomly assigned to ezetimibe monotherapy; 7,911, to ezetimibe-statin combination therapy; and 6,057, to statin monotherapy. The method quality of the studies included was high, with an average Jadad score of 4.6 points.³ The statins assessed were atorvastatin (4 trials; 22%; n = 1,885), lovastatin (1

Discussion

Ezetimibe was touted as a novel LDL-lowering agent that provided substantial LDL lowering and, when used in combination with a statin, could achieve lower LDL targets through the complimentary mechanism of action of these 2 drugs.8, 15, 26 In 1 study, 86% of patients on combination therapy versus 68% of patients on statin monotherapy (p <0.01) reached National Cholesterol Education Program Adult Treatment Panel III²⁷–recommended LDL targets.²⁶ In addition, ezetimibe may be used to achieve LDL

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Cited by (89)

PCSK9 inhibitor, ezetimibe, and bempedoic acid: Evidence-based therapies for statin-intolerant patients
2023, Progress in Cardiovascular Diseases
Statins are first-line therapy for treating dyslipidemia because of their low-density lipoprotein cholesterol (LDL-C) lowering efficacy, superior event-reduction data and unrivaled cost-effectiveness. Yet, many people are intolerant of statins, whether due to true adverse events or the nocebo effect, so within one year about two-thirds of primary prevention patients and one-third of secondary prevention patients are no longer taking their prescription. Statins still dominate this landscape, but other agents, often used in combination, potently reduce LDL-C levels, regress atherosclerosis and lower risk of major adverse cardiovascular events (MACE). Ezetimibe lowers LDL-C by reducing intestinal absorption of cholesterol. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower LDL-C by increasing the number and durability of hepatic LDL receptors. Bempedoic acid reduces hepatic cholesterol synthesis. Ezetimibe, PCSK9i and bempedoic are evidence-based, non-statin therapies that synergistically lower LDL-C and reduce risk of MACE; they also have benign side-effect profiles and are generally well tolerated.
Special Patient Populations: Children and Adolescents
2023, Clinical Lipidology: A Companion to Braunwald's Heart Disease
Cardiovascular disease begins in childhood. To identify youth at increased risk, selective and universal screening is recommended, beginning at age 2 years for those with certain factors or between ages 9 to 11 and 17 to 21 years if not at risk. Treatment of dyslipidemia is nearly always initially dietary changes, decreasing sedentary time, and increasing physical activity. In those who adhere to these changes, lipid abnormalities are often resolved. However, some children with inherited forms of dyslipidemia or risk factors that are unmodifiable require lipid-lowering medication. First-line therapy for low-density lipoprotein cholesterol (LDL-C) reduction is statins, beginning at age 8 to 10 years. High-dose omega-3 fatty acids may be used for significantly elevated triglycerides and/or moderately elevated triglycerides and elevated non–high-density lipoprotein cholesterol (non–HDL-C) if there is no improvement in lipid levels after diet and lifestyle modification. Early identification of dyslipidemia is necessary to prevent morbidity and mortality of early-onset cardiovascular disease in adulthood.
Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial
2022, The Lancet
Citation Excerpt :
Considering a 15% loss to follow-up, a total of 3780 patients were required to prove our hypothesis. For the secondary objective, the achievement of LDL cholesterol of less than 70 mg/dL at 1 year was 31% in the simvastatin and 51% in the simvastatin–ezetimibe groups, in the IMPROVE-IT trial, and the LDL cholesterol-lowering effect of simvastatin–ezetimibe 40–10 mg was known to be similar to that of rosuvastatin 20 mg.22,24 Therefore, as a clinically important difference, the proportion of participants achieving LDL cholesterol of less than 70 mg/dL was presumed to be 70% in the combination therapy group and 50% in the high-intensity statin monotherapy group.
Drug combinations rather than increasing doses of one drug can achieve greater efficacy and lower risks. Thus, as an alternative to high-intensity statin monotherapy, moderate-intensity statin with ezetimibe combination therapy can lower LDL cholesterol concentrations effectively while reducing adverse effects. However, evidence from randomised trials to compare long-term clinical outcomes is needed.
In this randomised, open-label, non-inferiority trial, patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea were randomly assigned (1:1) to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%. This trial is registered with ClinicalTrials.gov, NCT03044665 and is complete.
Between Feb 14, 2017, and Dec 18, 2018, 3780 patients were enrolled: 1894 patients to the combination therapy group and 1886 to the high-intensity statin monotherapy group. The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference −0·78%; 90% CI −2·39 to 0·83). LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p<0·0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p<0·0001).
Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction.
Hanmi Pharmaceutical.
Lipid-Modifying Agents, From Statins to PCSK9 Inhibitors: JACC Focus Seminar
2020, Journal of the American College of Cardiology
Citation Excerpt :
Ezetimibe at the recommended 10-mg daily dose produces a mean reduction in LDL cholesterol (net of placebo) of 19% as monotherapy and 23% from the on-statin baseline when added to statin treatment (35). Several large long-term cardiovascular outcome studies (4,36,37), as well as earlier studies, demonstrated a safety and tolerability profile not detectably different from placebo (38). Specifically, muscle injury (myopathy, or its more severe form, rhabdomyolysis) does not appear to be an adverse effect of ezetimibe: there has been no excess over placebo of cases in large RCTs, and most cases reported during post-marketing surveillance have been in patients also treated with a statin.
Mendelian randomization studies and randomized trials have conclusively demonstrated that lower low-density lipoprotein (LDL) cholesterol results in fewer cardiovascular events. This review describes key stages in the evolution of LDL cholesterol–lowering treatment. Data from over 25 cardiovascular outcome trials confirm that, within a few years, statins lower the relative risk of major atherosclerotic events by about 22% per 38.7 mg/dl (1 mmol/l) reduction in LDL cholesterol, with similar benefit across patient subgroups. Meta-analyses of these trials have established the safety of statins with regard to nonvascular mortality and cancer. Other agents available for prescription include ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which both reduce major atherosclerotic events in proportion to their effects on LDL cholesterol and have good safety profiles, though PCSK9 inhibitors remain costly. Investigational LDL cholesterol–lowering agents currently being tested in cardiovascular outcome studies are bempedoic acid, an adenosine triphosphate–citrate lyase inhibitor that reduces cholesterol synthesis, and inclisiran, a double-stranded small interfering ribonucleic acid that inhibits PCSK9 synthesis.
LDL-cholesterol: The lower the better
2019, Clinica e Investigacion en Arteriosclerosis
La disminución del colesterol de las lipoproteínas de baja densidad (c-LDL) se asocia a un descenso de la morbilidad y la mortalidad cardiovascular. Se ha demostrado que no existe un valor de c-LDL por debajo del cual deje de obtenerse un beneficio preventivo con su disminución, y tampoco se ha observado una mayor incidencia de efectos secundarios asociada a las concentraciones más bajas de c-LDL. Disponemos de un amplio arsenal terapéutico hipolipidemiante, sin embargo, en un elevado porcentaje de pacientes no se alcanzan los objetivos de c-LDL. Las estatinas de alta potencia disminuyen el c-LDL por encima del 50%, y al asociar ezetimiba se consigue un descenso adicional del c-LDL de un 15-30% y puede doblar el porcentaje de pacientes que alcanzan los objetivos. Dicha combinación se ha mostrado segura y eficaz en prevención primaria y secundaria de la enfermedad cardiovascular. Otra opción es la combinación de estatinas con resinas de intercambio, aunque requiere un manejo algo más complejo. La inhibición de la proteína PCSK9 con anticuerpos monoclonales disminuye el c-LDL por encima del 60% y es eficaz en la prevención de la enfermedad cardiovascular. Sin embargo, debido a su coste, su uso queda restringido a los pacientes isquémicos o con hipercolesterolemia familiar que no alcanzan los objetivos con los fármacos convencionales.
La base de evidencias sobre el beneficio y la seguridad de lograr los objetivos de control del c-LDL es muy amplia y va en aumento. En los próximos años va a ser necesario adecuar la intensidad del tratamiento de la hipercolesterolemia al grado de riesgo vascular de los pacientes y al grado de descenso necesario para lograr los objetivos terapéuticos. Ello redundará en una prevención cardiovascular más eficaz y en una mayor calidad de vida, en particular en el amplio colectivo de pacientes de mayor riesgo vascular.
The reduction of low density lipoprotein-cholesterol (LDL-chol) has been associated with a decrease in cardiovascular morbidity and mortality. It has been demonstrated that there is no value of LDL-chol below which there ceases to be a preventive benefit with its reduction, and neither has it been observed that there is a higher incidence of secondary effects associated with lower concentrations of LDL-chol. Although there is a wide range of lipid-lowering drugs available, a high percentage of patients do not achieve the desired LDL-chol levels. The high-potency statins reduce the LDL-chol by 15-30%, and can double the percentage of patients that reach their desired level. This combination has shown to be safe and effective in the primary and secondary prevention of cardiovascular disease. Another option is the combination of statins with exchange resins, although this requires a more complex management. The inhibition of PCSK9 protein with monoclonal antibodies reduces the LDL-chol by more than 60%, and is effective in the prevention of cardiovascular disease. However, due to its cost, its use is restricted to patients with ischaemia or familial hypercholesterolaemia that do not achieve the desired levels with conventional drugs.
The evidence base as regards the benefit and safety of achieving the desired levels of LDL-chol is very wide and is still increasing. In the next few years, it may be necessary to adjust the intensity of the hypercholesterolaemia treatment to the level of vascular risk of the patients, and to the level of reduction necessary to achieve the therapeutic targets. This will result in a more effective cardiovascular prevention and in a better quality of life, particularly in the large group of patients at higher vascular risk.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines
2019, Journal of the American College of Cardiology

View all citing articles on Scopus

: Dr. Foody is on the advisory boards for Merck, Pfizer, and BMS/Sanofi and has received speaker honoraria from the same. Dr. Mann is supported by grants from the National Institutes of Health, Bethesda, Maryland, is a consultant for Acorn Cardiovascular, St. Paul, MN, and Medtronic, Minneapolis, MN, and holds Medtronic stocks.

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Preventive cardiologyReview of Side-Effect Profile of Combination Ezetimibe and Statin Therapy in Randomized Clinical Trials

Section snippets

Methods

Results

Discussion

Risks associated with statin therapy: a systematic overview of randomized clinical trials

Circulation

Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statementQuality of Reporting of Meta-analyses

Lancet

Assessing the quality of reports of randomized clinical trials: is blinding necessary?

Control Clin Trials

Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin

Am Heart J

LDL-C goal attainment with the addition of ezetimibe to ongoing simvastatin treatment in coronary heart disease patients with hypercholesterolemia

Curr Med Res Opin

Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin 10/20 mg/day compared to doubling the dose of atorvastatin in hypercholesterolaemic patients with atherosclerosis or coronary heart disease

Int J Clin Pract

Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia

Am J Cardiol

Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia

J Am Coll Cardiol

Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia

Int J Clin Pract

Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease

Int J Cardiol

Efficacy and safety of ezetimibe co-administered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in patients with hypercholesterolemia and coronary heart disease

Int J Clin Pract

Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial

Eur Heart J

A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the Ezetimibe Add-on to Statin for Effectiveness (EASE) Trial

Mayo Clin Proc

Long-term safety and tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study

Clin Ther

Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial

Circulation

Preventive cardiology
Review of Side-Effect Profile of Combination Ezetimibe and Statin Therapy in Randomized Clinical Trials