Comparison of Low-Intensity Statin Plus Ezetimibe Versus High-Intensity Statin Therapy on Risk of New-Onset Diabetes Mellitus (PROVE-DM)

December 7, 2023 updated by: Seung-Whan Lee, M.D., Ph.D.

Comparison of Low-Intensity Statin Plus Ezetimibe Versus High-Intensity Statin Therapy on Risk of New-Onset Diabetes Mellitus in Prediabetic Patients With Atherosclerotic Cardiovascular Disease

This study is to evaluating the impact of low-intensity statin plus ezetimibe versus high-intensity statin therapy on risk of new-onset diabetes mellitus in patients with atherosclerotic cardiovascular disease who have prediabetes.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The PROVE-DM trial is a multi-center, open-labeled, randomized controlled trial comparing two different lipid lowering strategies in patients with prediabetes and established atherosclerosis. Patients with prediabetes and documented atherosclerosis, either clinical or unequivocal on imaging are eligible for enrollment. The detailed information for inclusion and exclusion criteria is described below in the session 4. Patients meeting inclusion criteria without any exclusion criteria are assessed to be able to tolerate high-intensity statin therapy while achieving the target LDL level (LDL cholesterol < 70 mg/dL for established atherosclerotic cardiovascular disease or LDL cholesterol < 100 mg/dL for mild to moderate coronary artery disease) through a run-in period of 2 to 6 months. (Run in period was set as a screening process to reduce drop-out cases that cannot withstand high-intensity statins or cannot accomplished target LDL levels) Eligible patients will be randomized to high-intensity statin (rosuvastatin 20 mg qd) or low-intensity statin plus ezetimibe (rosuvastatin/ezetimibe 5/10 mg qd). Patients will be followed-up clinically at 6, 12 months and then annually up to 3 years after randomization. Follow-up measurement of DM diagnostic criteria (fasting plasma glucose, plasma Hb A1c, oral glucose tolerance test) and lipid profile is intended to 1) provide evidence of new onset DM, 2) evaluate effectiveness of lowering LDL cholesterol. To ensure the accurate assessment of the clinical outcomes, cardiovascular safety end point (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke), any arterial revascularization, any potential side effects of statin and all-cause mortality were also investigated.

Study Type

Interventional

Enrollment (Estimated)

4000

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Korea, Republic of
      • Bucheon, Korea, Republic of
        • Not yet recruiting
        • Bycheon Sejong Hospital
        • Contact:
        • Principal Investigator:
          • Ha-Wook Park, MD
      • Changwon, Korea, Republic of
        • Not yet recruiting
        • Gyeongsang National University Changwon Hospital
        • Principal Investigator:
          • Jae Seok Bae, MD
        • Contact:
      • Cheonju, Korea, Republic of
        • Not yet recruiting
        • Chungbuk National University Hospital
        • Contact:
        • Principal Investigator:
          • Sang Min Kim, MD
      • Chuncheon, Korea, Republic of
        • Recruiting
        • Gangwon National University Hospital
        • Principal Investigator:
          • Bong-Ki Lee, MD
        • Contact:
      • Daegu, Korea, Republic of
        • Not yet recruiting
        • Keimyung University Dongsan Medical Center
        • Contact:
        • Principal Investigator:
          • Hyuck-Jun Yoon, MD
      • Daegu, Korea, Republic of
        • Recruiting
        • Daegu Catholic University Medical Center
        • Contact:
        • Principal Investigator:
          • Jin-bae Lee, MD
      • Daejeon, Korea, Republic of
        • Not yet recruiting
        • Chungnam National University Sejong Hospital
        • Principal Investigator:
          • Jae-Hwan Lee, MD
        • Contact:
      • Gangneung, Korea, Republic of
        • Not yet recruiting
        • Gangneung Asan Hospital
        • Principal Investigator:
          • Han-bit Park, MD
        • Contact:
      • Incheon, Korea, Republic of
        • Not yet recruiting
        • Gachon University Gil Medical Center
        • Contact:
        • Principal Investigator:
          • Kyoung-Hun Lee, MD
      • Jeju, Korea, Republic of
        • Not yet recruiting
        • Jeju National University Hospital
        • Contact:
        • Principal Investigator:
          • Jae-Geun Lee, MD
      • Pusan, Korea, Republic of
        • Recruiting
        • Dong-A Medical Center
        • Principal Investigator:
          • Yong-rak Cho, MD
        • Contact:
      • Pusan, Korea, Republic of
        • Not yet recruiting
        • Inje University Busan Paik Hospital
        • Principal Investigator:
          • Tae Hyun Yang, MD
        • Contact:
      • Pusan, Korea, Republic of
        • Not yet recruiting
        • Kosin University Gospel Hospital
        • Contact:
        • Principal Investigator:
          • Jung Ho Heo, MD
      • Pusan, Korea, Republic of
        • Not yet recruiting
        • Pusan National University Yangsan Hospital
        • Principal Investigator:
          • Kook Jin Chun, MD
        • Contact:
      • Seoul, Korea, Republic of
        • Recruiting
        • Asan Medical Center
        • Contact:
        • Principal Investigator:
          • Seung-Whan Lee, MD
        • Sub-Investigator:
          • Tae Oh Kim, MD
        • Sub-Investigator:
          • Cheol whan Lee, MD
        • Contact:
      • Seoul, Korea, Republic of
        • Recruiting
        • Korea University Anam Hospital
        • Contact:
        • Principal Investigator:
          • Soon Jun Hong, MD
      • Seoul, Korea, Republic of
        • Not yet recruiting
        • Hallym University Medical Center-Kangdong
        • Contact:
        • Principal Investigator:
          • Sung-Eun Sung-Eun, MD
      • Seoul, Korea, Republic of
        • Not yet recruiting
        • The Catholic Univ. of Korea Eunpyeong St. Mary's Hospital
        • Contact:
        • Principal Investigator:
          • Yeon-Jik Choi, MD
      • Suwon, Korea, Republic of
        • Not yet recruiting
        • The Catholic University of Korea, St. Vincent's Hospital
        • Contact:
        • Principal Investigator:
          • Seong-Ho Heo, MD
      • Ulsan, Korea, Republic of
        • Not yet recruiting
        • Ulsan University Hospital
        • Principal Investigator:
          • Gyung-Min Park, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Men or women between the ages of 18 and 75 years who have prediabetes

    -Prediabetes consists of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or HbA1c

    1. IFG: fasting plasma glucose (FPG) 100 to 125 mg/dL
    2. IGT: 2 hours post-load glucose on the 75g OGTT (oral glucose tolerance test) 140 to 199 mg/dL
    3. HbA1c: 5.7 to 6.4%

  2. Patient requiring high-intensity statin due to high risk of a future cardiovascular event if at least one of the following criteria is present via patient history, physical examination, or medical records at the time of screening (Clinically documented ASCVD)

    • acute coronary syndrome (MI or unstable angina)
    • stable angina
    • coronary revascularization (PCI, CABG, and other arterial revascularization procedure)
    • stroke or TIA

    • peripheral arterial disease (<0.9 performed by a vascular lab or angiogram (including CTA) showing ≥ 50%) Unequivocally documented ASCVD on imaging

      • significant plaque on coronary angiography on CT (mild, moderate, severe coronary artery disease)
      • significant plaque on carotid ultrasound (mild, moderate, severe carotid disease)
  3. Patients who have never taken a statin or who do not have problems adhering to statin therapy
  4. Patient must have been on a stable diet prior to randomization and willing to follow the NCEP (national Cholesterol Education Program) TLC (therapeutic lifestyle changes) diet, or equivalent diet, throughout the study.
  5. The patient or guardian agrees to the study protocol and the schedule of clinical follow-up, and provides informed, written consent, as approved by the appropriate Institutional Review Board/Ethical Committee of the respective clinical site.

Exclusion Criteria:

  1. Patient's pregnant or breast-feeding or child-bearing potential.
  2. Concomitant administration of potent inhibitors of CYP3A4 (itraconazole, ketoconazole, protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) or CYP2C9 (relative contraindication not dependent on CYP450 statins).
  3. Chronic kidney disease (eGFR<30 ml/min/1.73m2) or dialysis-dependent renal failure
  4. Uncontrolled hypothyroidism.
  5. Personal or family history of hereditary muscular disorders.
  6. History of muscular toxicity with a statin
  7. Alcoholism.
  8. Hypersensitivity to any of statin and ezetimibe.
  9. Hemodynamic unstable conditions at the time of inclusion: cardiogenic shock at the time of randomization, refractory ventricular arrhythmias, or congestive heart failure (New York Heart Association class IV).
  10. Any history of hemorrhagic stroke or intracranial hemorrhage within the past 6 months
  11. Any surgery requiring discontinuation of statin and/or ezetimibe is planned within 6 months after randomization
  12. A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) in the past 3 years or current treatment for the active cancer.
  13. Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the Investigator, would preclude safe completion of the study.
  14. Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (ALT or AST > 3 times upper limit of normal) or (Total bilirubin> 2 times upper limit of normal).
  15. Life expectancy < 1 years for any non-cardiac or cardiac causes
  16. Unwillingness or inability to comply with the procedures described in this protocol.
  17. Patients who are actively participating in another drug or device investigational study, which have not completed the primary endpoint follow-up period.
  18. People who have previously been diagnosed with diabetes and are taking lifestyle modification and oral hypoglycemic agent (OHA) or insulin (In woman, gestational diabetes is included)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: high-intensity statin arm
(high-intensity statin arm): rosuvastatin 20 mg PO qd, once daily
Drug: high-intensity statin arm
•high-intensity statin strategy (standard arm): rosuvastatin 20 mg PO qd, once daily
Active Comparator: low-intensity statin plus ezetimibe arm
(low-intensity statin plus ezetimibe arm ): rosuvastatin 5mg /ezetimibe 10mg PO qd), once daily
Drug: low-intensity statin plus ezetimibe
•low-intensity statin plus ezetimibe strategy (experimental arm): rosuvastatin 5mg /ezetimibe 10mg PO qd), once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants with New-onset-DM
Time Frame: 36months after randomization

New onset DM was defined on the the basis of the American Diabetes association guideline if two abnormal test results of following criteria are existed from the same sample or in two separate test samples.

  1. fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours OR
  2. 2 hour plasma glucose during a 75 g oral glucose tolerance test (OGTT) ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water OR
  3. HbA1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP (National Glycohemoglobin Standardization Program) certified and standardized to the DCCT (Diabetes Control and Complication Trial) assay.
36months after randomization
Number of Participants with death
Time Frame: 36months after randomization
Major adverse cardiac events are defined as all-cause death
36months after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Composite cardiovascular safety
Time Frame: 36months after randomization
death from cardiovascular cause, non fatal myocardial infarction of nom fatal stroke
36months after randomization
Any arterial revascularization
Time Frame: 36months after randomization
Any arterial revascularization (carotid, coronary aorta or peripheral artery) Any arterial revascularization (carotid, coronary aorta or peripheral artery)
36months after randomization
Any potential side effect
Time Frame: 36months after randomization
Any potential side effect
36months after randomization
Each component of the diabetes-mellitus diagnosis criteria
Time Frame: 36months after randomization
Each component of the diabetes-mellitus diagnosis criteria
36months after randomization
All cause mortality
Time Frame: 36months after randomization
All cause mortality
36months after randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Seung-Whan Lee, M.D., Ph.D.

Collaborators

Yuhan Corporation

Investigators

  • Principal Investigator: Seung-Whan Lee, MD, Asan Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 14, 2023

Primary Completion (Estimated)

December 30, 2027

Study Completion (Estimated)

December 30, 2027

Study Registration Dates

First Submitted

October 11, 2022

First Submitted That Met QC Criteria

October 12, 2022

First Posted (Actual)

October 14, 2022

Study Record Updates

Last Update Posted (Estimated)

December 13, 2023

Last Update Submitted That Met QC Criteria

December 7, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2022-1275

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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