Endocrinol Metab.  2024 Oct;39(5):722-731. 10.3803/EnM.2024.1995.

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE)

• Kim NH
• Lee J
• Chon S
• Yu JM
• Jeong IK
• Lim S
• Kim WJ
• Song K
• Cho HC
• Yu HM
• Kim KA
• Kim SS
• Lee SH
• Kim CH
• Kwak SH
• Lee Y
• Chung CH
• Lee S
• Jin HY
• Lee JH
• Koh G
• Kim SY
• Kim J
• Lee JH
• Kim TN
• Jeon HJ
• Lee JH
• Jeon JH
• Yoo HJ
• Kim HK
• Park HK
• Nam-Goong IS
• Hong S
• Ahn CW
• Yu JH
• Park JH
• Park KG
• Park CH
• Joung KH
• Ryu OH
• Park KY
• Hong EG
• Cha BS
• Won KC
• Chung YS
• Kim SG

• KMID: 2560281
• DOI: http://doi.org/10.3803/EnM.2024.1995

Abstract

Background
Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined.
Methods
This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months.
Conclusion
This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Keyword

Diabetes mellitus, type 2; Statin; Ezetimibe; Fibric acids; Dyslipidemias; Cardiovascular diseases

Figure

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  Fig. 1. Overall study design. HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; AE, adverse event.

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