Endocrinology and Metabolism

Original Articles

Diabetes, obesity and metabolism
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): Nam Hoon Kim, Juneyoung Lee, Suk Chon, Jae Myung Yu, In-Kyung Jeong, Soo Lim, Won Jun Kim, Keeho Song, Ho Chan Cho, Hea Min Yu, Kyoung-Ah Kim, Sang Soo Kim, Soon Hee Lee, Chong Hwa Kim, Soo Heon Kwak, Yong‐ho Lee, Choon Hee Chung, Sihoon Lee, Heung Yong Jin, Jae Hyuk Lee, Gwanpyo Koh, Sang-Yong Kim, Jaetaek Kim, Ju Hee Lee, Tae Nyun Kim, Hyun Jeong Jeon, Ji Hyun Lee, Jae-Han Jeon, Hye Jin Yoo, Hee Kyung Kim, Hyeong-Kyu Park, Il Seong Nam-Goong, Seongbin Hong, Chul Woo Ahn, Ji Hee Yu, Jong Heon Park, Keun-Gyu Park, Chan Ho Park, Kyong Hye Joung, Ohk-Hyun Ryu, Keun Yong Park, Eun-Gyoung Hong, Bong-Soo Cha, Kyu Chang Won, Yoon-Sok Chung, Sin Gon Kim; Endocrinol Metab. 2024;39(5):722-731. Published online August 22, 2024; DOI: https://doi.org/10.3803/EnM.2024.1995

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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.

Citations

Citations to this article as recorded by

Ezetimibe attenuates diabetic retinopathy via NRF2-mediated suppression of inflammation and oxidative stress
Lei Cheng, Shan Cheng, Ran Zhu, Guoxu Xu
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Jakub Michal Zimodro, Manfredi Rizzo, Ioanna Gouni-Berthold
Pharmaceuticals.2025; 18(2): 147. CrossRef
Fenofibrate therapy and risk of heart failure outcomes in patients with Type 2 diabetes: a propensity-matched cohort study
Ji Yoon Kim, Nam Hoon Kim, Jiyoon Lee, Dong-Hoon Kim, Sin Gon Kim
European Heart Journal - Cardiovascular Pharmacotherapy.2025; 11(7): 620. CrossRef
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Mengying Liu, Seok Ting Lim, Weihua Song, Thomas M. Coffman, Xiaomeng Wang
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Obesity and Metabolism
Comparison of the Effects of Ezetimibe-Statin Combination Therapy on Major Adverse Cardiovascular Events in Patients with and without Diabetes: A Meta-Analysis: Namki Hong, Yong-ho Lee, Kenichi Tsujita, Jorge A. Gonzalez, Christopher M. Kramer, Tomas Kovarnik, George N. Kouvelos, Hiromichi Suzuki, Kyungdo Han, Chan Joo Lee, Sung Ha Park, Byung-Wan Lee, Bong-Soo Cha, Eun Seok Kang; Endocrinol Metab. 2018;33(2):219-227. Published online May 4, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.2.219

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170 Download
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Abstract PDF Supplementary Material PubReader ePub

Background

Ezetimibe-statin combination therapy has been found to reduce low density lipoprotein cholesterol levels and the risk of major adverse cardiovascular events (MACEs) in large trials. We sought to examine the differential effect of ezetimibe on MACEs when added to statins according to the presence of diabetes.

Methods

Randomized clinical trials with a sample size of at least 50 participants and at least 24 weeks of follow-up that compared ezetimibe-statin combination therapy with a statin- or placebo-controlled arm and reported at least one MACE, stratified by diabetes status, were included in the meta-analysis and meta-regression.

Results

A total of seven trials with 28,191 enrolled patients (mean age, 63.6 years; 75.1% men; 7,298 with diabetes [25.9%]; mean follow-up, 5 years) were analysed. MACEs stratified by diabetes were obtained from the published data (two trials) or through direct contact (five trials). No significant heterogeneity was observed among studies (I²=14.7%, P=0.293). Ezetimibe was associated with a greater reduction of MACE risk in subjects with diabetes than in those without diabetes (pooled relative risk, 0.84 vs. 0.93; P_{heterogeneity}=0.012). In the meta-regression analysis, the presence of diabetes was associated with a greater reduction of MACE risk when ezetimibe was added to statins (β=0.87, P=0.038).

Conclusion

Ezetimibe-statin combination therapy was associated with greater cardiovascular benefits in patients with diabetes than in those without diabetes. Our findings suggest that ezetimibe-statin combination therapy might be a useful strategy in patients with diabetes at a residual risk of MACEs.

Citations

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