Vascular Effects of Ezetimibe/Simvastatin and Simvastatin on Atherosclerosis

Rho-kinase in Patients With Atherosclerosis: Effects of Statins A Randomized Clinical Trial Comparing Ezetimibe/Simvastatin and Simvastatin

Multiple clinical trials, using 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins), have shown benefit in the primary and secondary prevention of atherosclerotic complications. However, till now, there is an incomplete understanding of all the mechanisms of the biologic effects of statins beyond LDL cholesterol (LDL-C) reduction, but there is accumulating evidence that the Rho-GTP/Rho-Kinase pathway (Rho/Rho-K) plays an important role and may be a strategic therapeutic target in cardiovascular diseases. With similar LDL-C reduction ability, the availability of Ezetimibe offers the potential to begin to address the question whether some of the benefits conferred by statins may accrue independently of their effects on LDL-C lowering. A better understanding of the role of the Rho/Rho-kinase signaling pathway in the pathogenesis of atherosclerosis in human is essential. Inhibition of Rho/Rho-kinase by statins may explain some of the biological beneficial effects of statins observed in clinical trials. This study aims to translate into patients important experimental discoveries regarding the initiation of inflammation in atherosclerosis in an attempt to improve upon the present treatment of cardiovascular diseases.

Study Overview

• Status: Completed
• Conditions: Atherosclerosis
• Intervention / Treatment: Drug: Simvastatin (Zocor); Drug: 10mg/10mg of Ezetimibe/Simvastatin (Vytorin)

Detailed Description

Study Design:

A single-blind controlled trial with two arms will be conducted at National Chen-Kung University Hospital (NCKUH). We will screen subjects with stable atherosclerosis to complete enrollment of 40 subjects in the study (see inclusion and exclusion criteria section below). A central pharmacist at NCKUH will randomize the patients to 40mg or Simvastatin (n=20) or 10mg/10mg of Ezetimibe/Simvastatin (n=20) for 28 days. If the patient is already on a statin a two-week washout period will be 2 weeks prior to trial initiation.

Primary Outcomes and measurement:

The primary outcomes are the mean changes in the Rho-kinase expression and activity in leukocytes in response to 40mg or Simvastatin (n=20) or 10mg/10mg of Ezetimibe/Simvastatin (n=20) over 28 days.

Secondary Outcomes and measurement:

The secondary outcomes are the correlation between the mean changes in Rho-kinase expression and activity in leukocytes and vascular tissue with the mean changes in LDL-C, hsCRP, and BAFMD, as well as its relation with clinical characteristics.

Subjects:

Participants will be recruited from the ambulatory clinics at the NCKUH Clinic.

Inclusion Criteria:

1. Male or female subjects aged 40 to 80 years
2. Documented stable atherosclerosis by angiography or vascular ultrasound (more that 20% luminal narrowing), peripheral arterial disease or type 2 diabetes mellitus (coronary heart disease (CHD) risk equivalent - Adult Treatment Program (ATP)-III guidelines)
3. LDL-cholesterol >100mg/dL (indication to treat with statin)
4. Written informed consent
5. Primary care physician authorization letter to participate in the study.

Exclusion criteria:

1. Inability to give consent
2. Pre-menopausal women
3. Current use of antibiotics, anti-inflammatory or immunosuppressant drugs
4. History of LFT >2 times the upper normal limit
5. History of myopathy / myositis or CPK > 10 times the upper normal limit
6. CPK above normal limits at study onset
7. Any evidence of inflammatory, infectious or neoplastic disease
8. History of CABG, PCI or acute ischemic syndrome in the preceding 3 months.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Inclusion Criteria:

  1. Male or female subjects aged 40 to 80 years
  2. Documented stable atherosclerosis by angiography or vascular ultrasound (more that 20% luminal narrowing), peripheral arterial disease or type 2 diabetes mellitus (coronary heart disease (CHD) risk equivalent - Adult Treatment Program (ATP)-III guidelines)
  3. LDL-cholesterol >100mg/dL (indication to treat with statin)
  4. Written informed consent
  5. Primary care physician authorization letter to participate in the study.

• Exclusion criteria:

  1. Inability to give consent
  2. Pre-menopausal women
  3. Current use of antibiotics, anti-inflammatory or immunosuppressant drugs
  4. History of LFT >2 times the upper normal limit
  5. History of myopathy / myositis or CPK > 10 times the upper normal limit
  6. CPK above normal limits at study onset
  7. Any evidence of inflammatory, infectious or neoplastic disease
  8. History of CABG, PCI or acute ischemic syndrome in the preceding 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: high dose statin; 40mg of Simvastatin (n=20)	Drug: Simvastatin (Zocor); 40mg of Simvastatin (n=20) orally per-day for 28 days; Other Names: Zocor
Active Comparator: combination arm; 10mg/10mg of Ezetimibe/Simvastatin (n=20)	Drug: 10mg/10mg of Ezetimibe/Simvastatin (Vytorin); 10mg/10mg of Ezetimibe/Simvastatin (n=20) orally per-day for 28 days; Other Names: Vytorin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
changes in the lipid profile change and Rho-kinase expression and activity	28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
correlation between changes in Rho-kinase expression and activity with the changes in LDL-C, hsCRP and BAFMD	28 days

Collaborators and Investigators

• Sponsor: National Cheng-Kung University Hospital
• Investigators: Principal Investigator: Jyh-Hong Chen, MD, PhD, National Cheng-Kung University Hospital

Publications and helpful links

General Publications

• Liu PY, Liu YW, Lin LJ, Chen JH, Liao JK. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation. 2009 Jan 6;119(1):131-8. doi: 10.1161/CIRCULATIONAHA.108.813311. Epub 2008 Dec 15.

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): January 1, 2008
• Study Completion (Actual): February 1, 2008

Study Registration Dates

• First Submitted: November 16, 2007
• First Submitted That Met QC Criteria: November 16, 2007
• First Posted (Estimate): November 19, 2007

Study Record Updates

• Last Update Posted (Estimate): February 24, 2010
• Last Update Submitted That Met QC Criteria: February 23, 2010
• Last Verified: February 1, 2010

More Information

Terms related to this study

• Keywords: endothelial function; HMG-CoA Reductase Inhibitors; HMG-CoA Reductase Inhibitors on vascular protection
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Ezetimibe; Ezetimibe, Simvastatin Drug Combination
• Other Study ID Numbers: NCKUH-01/HR-95-112