NCT05579626

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

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

• Status: Enrolling By Invitation
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 4,000 (estimated)
• Sponsor: Seung-Whan Lee, M.D., Ph.D. · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

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.

Detailed 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)

Conditions

• Pre Diabetes
• ASCVD

Interventions

Type	Name	Description
DRUG	high-intensity statin arm	•high-intensity statin strategy (standard arm): rosuvastatin 20 mg 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

Timeline

• Start date: 2023-03-14
• Primary completion: 2030-12-31
• Completion: 2030-12-31
• First posted: 2022-10-14
• Last updated: 2026-01-07

Locations

31 sites across 1 country: South Korea