Journal Article | Cardio-Metabolic, Others

April 20, 2021

Marie Angela Gochangco, MD



            Hyperlipidemia is one of the most common and established risk factors for cardiovascular disease (CVD). The American Heart Association (AHA) recommends the use of HMG-CoA reductase inhibitors commonly known as statins to lower lipid levels. Statins have remained to be the first-line and cornerstone of treatment for dyslipidemia because of their ability to lower cholesterol and their protective effect against CVD.


            Statins are well tolerated, but are associated with possible side effects labelled as statin-associated symptoms (SAS). These SAS include statin-associated muscle symptoms (SAMS), diabetes mellitus, and central nervous system complaints.


Of all the SAS, SAMS is the most common. Patients with SAMS may present with myopathy, myalgia with normal level of creatinine kinase, myositis with creatinine kinase above the upper limit of normal, and rhabdomyolysis with creatinine kinase more than 10 times above the upper limit of normal.


Management of SAS include patient reassurance, statin discontinuation or rechallenge, and treatment using a different statin or different dosing regimens in combination with other lipid-lowering medications.


            The addition of bile acid sequestrants or niacin to statin treatment could help achieve lipid-lowering goals. However, these agents are limited by significant rates of treatment discontinuation due to their side effects. The European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guideline for the management of dyslipidemias in 2016 recommended combination therapy with statins and other lipid-lowering drugs in cases of statin intolerance or insufficiency3.


            Alternatives for a safe and well-tolerated lipid-lowering agent as an add-on agent to statins have been limited until the advent of ezetimibe. Ezetimibe inhibits cholesterol absorption from the small intestines via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1), thus reduces plasma cholesterol in humans by 15 to 20%. It is effective for both monotherapy and combination therapy with statins in patients with hypercholesterolemia.


            The MRS-ROZE (Multicenter Randomized Study of Rosuvastatin and Ezetimibe) was a multicenter eight-week randomized clinical trial done by Kim, K., et al in 2016. The study compared the effects of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin with rosuvastatin alone in patients with primary hypercholesterolemia, including patients with diabetes mellitus or metabolic syndrome.


Fixed-dose combinations of ezetimibe and rosuvastatin showed a significant difference in lowering LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone.


            Baigent, C., et al in 2011 conducted the SHARP (Study of Heart and Renal Protection) trial, a randomized double-blind clinical trial in 9,270 patients with chronic kidney disease with no known history of myocardial infarction or coronary revascularizaton.  They were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus placebo. LDL cholesterol (LDL-C) reduction with simvastatin 20 mg plus ezetimibe 10 mg daily reduced the incidence of major atherosclerotic events by 17% in patients with chronic kidney disease.


            The research done by Giugliano, R., et al in 2018 discussed the outcomes of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study. The study evaluated the beneficial effect of reduction in major cardiovascular events from the addition of 40 mg ezetimibe and simvastatin versus 40 mg placebo and simvastatin therapy in 18,144 patients who present with acute coronary syndromes and have low-density lipoprotein cholesterol (LDL-C) of 50 to 125 mg/dl.


Results from the IMPROVE-IT showed that adding ezetimibe to statin therapy was beneficial in patients with diabetes mellitus and high-risk patients without diabetes mellitus. Subsequent reductions of myocardial infarction and ischemic stroke were found in these patients.



            Studies have demonstrated the effect of statins as first-line treatment for dyslipidemia. High-dose statins have several side effects such as myopathy, elevated liver enzymes, and new-onset diabetes. It is imperative therefore to look into drugs with a safer profile. Ezetimibe has shown to be a promising lipid-lowering drug with few side effects and protection against cardiovascular events and is usually given as an add-on therapy with statins.




            The single center, open-label, randomized controlled study by Hwang Y., et al. aims to determine the effect of rosuvastatin 20 mg monotherapy with rosuvastatin 5 mg and ezetimibe 10 mg combination therapy on lipid parameters in patients with type 2 diabetes mellitus.




            Patients with type II diabetes mellitus, aged ≥20 years old with LDL-C ≥130 mg/dL at baseline were included in the study. Excluded in the trial were those treated with a lipid lowering drug, thiazolidinediones or insulin within 3 months, experienced major cardiovascular events within 3 months, serum creatinine level of ≥1.5 mg/dL, liver transaminases ≥2x upper normal limit, uncontrolled hyperthyroidism or hypothyroidism, and women who were pregnant or lactating.


Forty-two patients were enrolled in the study. Among the 42 patients, six were lost to follow-up. A total of 36 subjects completed the study. 21 subjects were enrolled in the rosuvastatin monotherapy group (20 mg/day) and 21 subjects were enrolled in the rosuvastatin (5 mg/day) and ezetimibe (10 mg/day) combination therapy. The study was approved by the Internal Review Board (IRB) of Kyung Hee University Hospital at Gangdong, Seoul, South Korea.


The study lasted for 7 weeks, comprising of a 1-week screening period and a 6-week active treatment phase. Medical histories and physical examinations were conducted at baseline. Waist circumference, blood pressure, plasma glucose, plasma insulin, glycosylated hemoglobin, total cholesterol, triglycerides, HDL-C, LDL-C, plasma apoB and apoA1, high-sensititivity CRP, and plasma free fatty acid concentrations were measured in the study.


            The mean age of the study population was 51.7 years old and 64.2% were male. There were no differences in the initial variables at baseline between two groups, except triglycerides.


            After 6 weeks of treatment, there were no significant differences in blood pressure, fasting plasma glucose, plasma insulin, HbA1C, total cholesterol, triglycerides, HDL-C, LDL-C, apoB, apo-B/apoA1 ratio, and high-sensitivity CRP between the two groups.


Significant differences were noted in the reduction of triglycerides (–6.6% in the rosuvastatin group and -32.6% in the rosuvastatin and ezetimibe group) and free fatty acid levels (0.0% in the rosuvastatin group and -25.9% in the rosuvastatin and ezetimibe group) between the two groups.


A non-significant mild increase in liver enzymes (≤2.5x upper normal limit) was observed in both groups, and muscle enzyme levels in four subjects in the rosuvastatin group (≤2.5x upper normal limit).  No significant side effects were noted in both treatments.


            Long-term studies in a larger population, as well as studies of other statin and ezetimibe combination therapies on lipid parameters may be recommended to further investigate the clinical significance of ezetimibe as an add-on therapy.



            This study showed that combination therapy of low-dose rosuvastatin and ezetimibe showed a decrease in LDL-C, apoB, and apoB/A1 ratio similar to that of high-dose rosuvastatin monotherapy in patients with type 2 diabetes mellitus. Reductions in triglyceride and free fatty acids were greater with the combination therapy of low-dose rosuvastatin and ezetimibe than with rosuvastatin monotherapy.



  1. Grundy, S.,et al. 2018. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/

ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary.American Heart Association Journal.2018.

  1. Thompson, P., et al. Statin-Asociated Side Effects. Journal of the American College of Cardiology. 2016.
  2. Hong, S., et al. A Phase III, Multicenter, Randomized, 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. Clinical Therapeutics. 2018.
  3. Hyungsub, K., et al.Pharmacokinetic interactions and tolerability of rosuvastatin and ezetimibe: an open-label, randomized, multiple-dose, crossover study in healthy male volunteers. Drug, Design, Development and Therapy. 2018.
  4. Kim, K., et al. Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hyperchlesterolemia: MRS-ROZE (Multicenter Randomized Study of Rosuvastatin and Ezetimibe). Cardiovascular Therapeutics. 2018.
  5. Baigent, 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 randomized placebo-controlled trial. The Lancet. 2011.
  6. Giugliano, R., et al.Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in PatientsWith Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018.
  7. Vavlukis, M., et al.Adding ezetimibe to statin therapy: latest evidence and clinical implications. Drugs in Context. 2018.

Read more about

Was this article helpful? Rate us!

Suggested For You

Comprehensive Overview: Efficacy, Tolerability, and Cost-effectiveness of Irbesartan

Fotini Gialama and Nikos Maniadakis

3 min read

integrative med


3 min read


10 pieces of advice for new physicians

1 min read


Be The first to know