Effect of Ezetimibe on Gut Microbiota

Gut Microbiota Alteration With Atorvastatin/Ezetimibe Combination in Patients With Atherosclerotic Cardiovascular Disease

Ezetimibe exerts its primary effects by inhibiting intestinal cholesterol absorption through the NPC1L1 protein. Beyond this, its impact on gut microbiota remains an area of interest. Gut microbiota has been implicated in cholesterol metabolism and CVD pathogenesis through metabolic and non-metabolic pathways. Modulating gut microbiota has been explored as a potential strategy to prevent CVDs.

Despite its intestinal mechanism, the influence of ezetimibe on gut microbiota composition has not been thoroughly investigated. Future studies are needed to elucidate its potential interactions with gut microbial communities and their implications for cholesterol metabolism and cardiovascular health.

Study Overview

• Status: Recruiting
• Conditions: Atherosclerotic Cardiovascular Disease With Dyslipidemia
• Intervention / Treatment: Drug: Atorvastatin 40mg; Drug: Atorvastatin 20mg+Ezetimibe 10mg

Detailed Description

1. Study Period The clinical trial spans 12 weeks to analyze baseline data and changes after treatment.

   The study starts upon IRB approval, with participant recruitment concluding within 24 months and the entire study wrapping up within 48 months.

2. Study Design This is an investigator-initiated, prospective, single-center, open-label, randomized clinical trial.

   It involves 110 coronary artery disease (CAD) patients in need of lipid-lowering therapy, divided into two groups:

   Experimental Group (n=55): Moderate-intensity statin (Atorvastatin 20 mg) combined with Ezetimibe 10 mg.

   Control Group (n=55): High-intensity statin monotherapy (Atorvastatin 40 mg). Primary Outcome: Changes in gut microbiota composition. Secondary Outcomes: Changes in blood lipid levels and inflammatory biomarkers.

3. Methods 3.1. Screening and Enrollment Participants are screened for eligibility based on inclusion and exclusion criteria.

   After providing informed consent, participants are randomized into two groups (1:1 ratio) using a permuted block randomization method.

   For those on prior statin or Ezetimibe therapy, a 2-week washout period is required before enrollment.

   3.2. Study Medication

   Participants receive their assigned treatment for 12 weeks, with medications administered orally once daily at consistent times, irrespective of meals:

   High-Intensity Statin Group: Atorvastatin 40 mg. Combination Therapy Group: Atorvastatin 20 mg + Ezetimibe 10 mg. 3.3. Follow-Up Baseline data, including demographic details, blood tests, and stool samples, are collected at enrollment.

   After 12 weeks of treatment, follow-up includes clinical evaluations, blood tests, and stool sample collection for post-treatment analysis.

4. Efficacy Evaluation 4.1. Primary Endpoint

Gut Microbiota Analysis:

Stool samples are analyzed using 16S rRNA sequencing.

Statistical tests compare microbiota differences:

Between groups at baseline (T-test or Mann-Whitney test). Pre- and post-treatment within groups (Paired t-test or Wilcoxon test). Intergroup changes over time (ANOVA test). 4.2. Secondary Endpoint Similar statistical methods are applied to assess changes in blood lipid levels and inflammatory biomarkers.

4.3. Subgroup Analysis

Specific subgroups undergo additional analysis:

Subgroup 1: Low-risk CAD patients (10-year ASCVD risk <7.5%). Subgroup 2: Patients with poor response to therapy (LDL >70 mg/dL after 12 weeks).

Subgroup 3: Recurrent CAD patients despite optimal therapy. Subgroup stool samples are analyzed using shotgun metagenomic sequencing for detailed microbial insights.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: jong won ha, MD,PhD; Phone Number: 82-2-2228-8460; Email: jwha@yuhs.ac

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • Severance hospital, Yonsei university college of medicine
    • Contact: jongwon ha, M.D., Ph.D.; Phone Number: 82-2-2228-8460; Email: jwha@yuhs.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: 19 to 80 years old
• Criteria for Diagnosis of Coronary Artery Disease:

Patients diagnosed with coronary artery disease through coronary angiography, or

Patients who require high-intensity lipid-lowering therapy according to current guidelines:

Clinical atherosclerotic cardiovascular disease, LDL cholesterol ≥ 190 mg/dL, LDL 70-189 mg/dL in diabetic patients, 10-year calculated atherosclerotic cardiovascular disease risk ≥ 7.5%

- Voluntary Consent: Individuals who have voluntarily agreed to participate in the study and signed the consent form.

Exclusion Criteria:

• Patients with active liver disease or liver disease with AST/ALT levels elevated more than twice the upper limit of normal.
• Individuals with allergies or hypersensitivity to HMG-CoA reductase inhibitors or ezetimibe.
• Individuals with a history of adverse reactions to HMG-CoA reductase inhibitors or ezetimibe.
• Pregnant, breastfeeding, or women of childbearing potential.
• Organ transplant recipients or individuals scheduled for organ transplantation.
• Patients with active malignant tumors.
• Patients with inflammatory bowel disease.
• Patients with wasting diseases, autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis), or connective tissue diseases (e.g., systemic sclerosis, polymyositis, and dermatomyositis).
• Patients with a history of taking antibiotics, probiotics, or ezetimibe within 3 months prior to study screening.
• Patients who have undergone gastrointestinal surgery within the past year.
• Patients who do not understand the study content or are unable to provide consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atorvastatin 40mg	Drug: Atorvastatin 40mg; High intensity HMG-CoA reductase inhibitor
Experimental: Atorvastatin 20mg+Ezetimibe 10mg	Drug: Atorvastatin 20mg+Ezetimibe 10mg; Moderate intensity HMG-CoA reductase inhibitor plus NPC1L1 antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Gut Microbiota After 12 Weeks of Treatment	Gut Microbiota difference after intervention Stool samples are analyzed using 16S rRNA sequencing. Statistical tests compare microbiota differences: Between groups at baseline (T-test or Mann-Whitney test). Pre- and post-treatment within groups (Paired t-test or Wilcoxon test). Intergroup changes over time (ANOVA test).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Blood Lipid Levels and Inflammatory Biomarker Levels After 12 Weeks of Treatment	Similar statistical methods are applied to assess changes in blood lipid levels and inflammatory biomarkers.	12 weeks

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: December 30, 2024
• First Submitted That Met QC Criteria: January 16, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 16, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Metabolic Diseases; Lipid Metabolism Disorders; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Dyslipidemias; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Ezetimibe
• Other Study ID Numbers: 4-2023-0161

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No