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

Last updated: January 2, 2025
Sponsor: Seung-Whan Lee, M.D., Ph.D.
Overall Status: Active - Recruiting

Phase

N/A

Condition

Diabetes Prevention

Diabetes And Hypertension

Treatment

high-intensity statin arm

low-intensity statin plus ezetimibe

Clinical Study ID

NCT05579626
2022-1275
  • Ages 18-75
  • All Genders

Study Summary

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.

Eligibility Criteria

Inclusion

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 glucosetolerance (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%

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

  • acute coronary syndrome (MI or unstable angina)

  • stable angina

  • coronary revascularization (PCI, CABG, and other arterial revascularizationprocedure)

  • stroke or TIA

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

  • ThoracoAbdominal Aortic Aneurysm

  • Unequivocally documented ASCVD on imaging

  • significant plaque on coronary angiography on CT (mild, moderate, severecoronary artery disease)

  • significant plaque on carotid ultrasound (mild, moderate, severe carotiddisease)

  1. Patients who have never taken a statin or who do not have problems adhering tostatin therapy

  2. Patient must have been on a stable diet prior to randomization and willing to followthe NCEP (national Cholesterol Education Program) TLC (therapeutic lifestylechanges) diet, or equivalent diet, throughout the study.

  3. The patient or guardian agrees to the study protocol and the schedule of clinicalfollow-up, and provides informed, written consent, as approved by the appropriateInstitutional Review Board/Ethical Committee of the respective clinical site.

Exclusion

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 andnefazodone) 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 thetime of randomization, refractory ventricular arrhythmias, or congestive heartfailure (New York Heart Association class IV).

  10. Any history of hemorrhagic stroke or intracranial hemorrhage within the past 6months

  11. Any surgery requiring discontinuation of statin and/or ezetimibe is planned within 6months after randomization

  12. A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) inthe past 3 years or current treatment for the active cancer.

  13. Any clinically significant abnormality identified at the screening visit, physicalexamination, laboratory tests, or electrocardiogram which, in the judgment of theInvestigator, would preclude safe completion of the study.

  14. Hepatic disease or biliary tract obstruction, or significant hepatic enzymeelevation (ALT or AST > 3 times upper limit of normal) or (Total bilirubin> 2 timesupper 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. People who have previously been diagnosed with diabetes and are taking lifestylemodification and oral hypoglycemic agent (OHA) or insulin (In woman, gestationaldiabetes is included)

Study Design

Total Participants: 4000
Treatment Group(s): 2
Primary Treatment: high-intensity statin arm
Phase:
Study Start date:
March 14, 2023
Estimated Completion Date:
December 30, 2027

Study Description

Statins [3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA) inhibitors] decreases the risk of death and cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). The cardiovascular benefits of high-intensity compared to low-intensity statin therapy are well demonstrated, and current guidelines recommend high-intensity statin therapy for high-risk patients with ASCVD . However, statin-related side effects are usually dose-dependent, and more frequent in patients receiving high-intensity statin therapy. A meta-analysis of 13 statin trials with 91,140 individuals reported that statin therapy is associated with an increased risk of developing diabetes mellitus (DM) over a 4-year period compared to patients randomized to placebo (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02-1.17). The high-intensity statin was associated with an increased risk of new onset DM compared with low doses of statins (HR 1.22, 95% CI 1.15 to 1.29). In addition, meta-analysis of five intensive-dose statin trials suggested the likelihood of developing DM is also higher with high-intensity statins compared to moderate-intensity statins in 32,752 subjects over a mean follow-up of 4.9 years (OR 1.12; 95% CI 1.04-1.22).

Prediabetes is a risk factor for ASCVD with a rapidly increasing prevalence worldwide (7.5% in 2019 and projected to reach 8.0% by 2030). Every year about 6.4-12.1% of these people develop diabetes and the risk increase further in the elderly, obese patients, and patients with metabolic syndrome. Considering that the risk of ASCVD increases even before the onset of DM, prediabetes patients need aggressive statin therapy for primary and secondary prevention. However, high-intensity therapy may increase the risk of new-onset DM, especially in patients with pre-diabetes. For this reason, caution is required in determining statin treatment strategies. An effectiveness of statins in reducing cardiovascular events depends on an absolute reduction in low-density lipoprotein (LDL) cholesterol levels and the duration of statin administration A combination therapy of low-dose statin and ezetimibe is an equivalent approach to high-dose statin therapy for decreasing LDL cholesterol level by 50% and achieving LDL cholesterol target level. This strategy is therefore considered attractive to reduce the risk of new-onset DM, and often used because of concerns regarding statin-induced diabetes in pre-diabetic patients. However, there are no data to compare the incidence of new onset DM as a pre-specified primary outcome between two lipid lowering strategies among prediabetic patients with ASCVD. Herein, we designed the study of comparison of low-intensity statin plus ezetimibe versus high-intensity statin therapy on risk of new-onset DM (PROVE-DM), a phase 4 trial involving patients with established atherosclerosis requiring lipid lowering (statin or ezetimibe) agents, comparing a regimen of high-intensity statin (rosuvastatin 20 mg) with the low intensity statin and ezetimibe (rosuvastatin 5 mg plus ezetimibe 10 mg)

Connect with a study center

  • Bycheon Sejong Hospital

    Bucheon,
    Korea, Republic of

    Active - Recruiting

  • Gyeongsang National University Changwon Hospital

    Changwon,
    Korea, Republic of

    Active - Recruiting

  • Chungbuk National University Hospital

    Cheonju,
    Korea, Republic of

    Active - Recruiting

  • Gangwon National University Hospital

    Chuncheon,
    Korea, Republic of

    Active - Recruiting

  • Daegu Catholic University Medical Center

    Daegu,
    Korea, Republic of

    Active - Recruiting

  • Keimyung University Dongsan Medical Center

    Daegu,
    Korea, Republic of

    Active - Recruiting

  • Yungnam universury Hospital

    Daegu,
    Korea, Republic of

    Site Not Available

  • Chungnam National University Sejong Hospital

    Daejeon,
    Korea, Republic of

    Active - Recruiting

  • Konyang University Hospital

    Daejeon,
    Korea, Republic of

    Active - Recruiting

  • Gangneung Asan Hospital

    Gangneung,
    Korea, Republic of

    Active - Recruiting

  • Gachon University Gil Medical Center

    Incheon,
    Korea, Republic of

    Site Not Available

  • Jeju National University Hospital

    Jeju,
    Korea, Republic of

    Site Not Available

  • Gyeongsang National University Hospital

    Jinju,
    Korea, Republic of

    Active - Recruiting

  • Dong-A Medical Center

    Pusan,
    Korea, Republic of

    Active - Recruiting

  • Inje University Busan Paik Hospital

    Pusan,
    Korea, Republic of

    Active - Recruiting

  • Kosin University Gospel Hospital

    Pusan,
    Korea, Republic of

    Site Not Available

  • Pusan National University Yangsan Hospital

    Pusan,
    Korea, Republic of

    Site Not Available

  • Asan Medical Center

    Seoul,
    Korea, Republic of

    Active - Recruiting

  • Ewha womans university seoul hospital

    Seoul,
    Korea, Republic of

    Site Not Available

  • Hallym University Medical Center-Kangdong

    Seoul,
    Korea, Republic of

    Site Not Available

  • Kangdong Sacred Heart Hospital

    Seoul,
    Korea, Republic of

    Site Not Available

  • Korea University Anam Hospital

    Seoul,
    Korea, Republic of

    Active - Recruiting

  • The Catholic Univ. of Korea Eunpyeong St. Mary's hospital

    Seoul,
    Korea, Republic of

    Active - Recruiting

  • Ajou University Hospital

    Suwon,
    Korea, Republic of

    Site Not Available

  • The Catholic University of Korea, St. Vincent's Hospital

    Suwon,
    Korea, Republic of

    Site Not Available

  • Ulsan University Hospital

    Ulsan,
    Korea, Republic of

    Site Not Available

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