. 2024 Oct;39(5):722-731.

doi: 10.3803/EnM.2024.1995. Epub 2024 Aug 22.

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 Kim¹, Juneyoung Lee², Suk Chon³, Jae Myung Yu⁴, In-Kyung Jeong⁵, Soo Lim⁶, Won Jun Kim⁷, Keeho Song⁸, Ho Chan Cho⁹, Hea Min Yu¹⁰, Kyoung-Ah Kim¹¹, Sang Soo Kim¹², Soon Hee Lee¹³, Chong Hwa Kim¹⁴, Soo Heon Kwak¹⁵, Yong-Ho Lee¹⁶, Choon Hee Chung¹⁷, Sihoon Lee¹⁸, Heung Yong Jin¹⁹, Jae Hyuk Lee²⁰, Gwanpyo Koh²¹, Sang-Yong Kim²², Jaetaek Kim²³, Ju Hee Lee²⁴, Tae Nyun Kim²⁵, Hyun Jeong Jeon²⁶, Ji Hyun Lee²⁷, Jae-Han Jeon²⁸, Hye Jin Yoo²⁹, Hee Kyung Kim³⁰, Hyeong-Kyu Park³¹, Il Seong Nam-Goong³², Seongbin Hong³³, Chul Woo Ahn³⁴, Ji Hee Yu³⁵, Jong Heon Park³⁶, Keun-Gyu Park³⁷, Chan Ho Park³⁸, Kyong Hye Joung³⁹, Ohk-Hyun Ryu⁴⁰, Keun Yong Park⁴¹, Eun-Gyoung Hong⁴², Bong-Soo Cha¹⁶, Kyu Chang Won⁴³, Yoon-Sok Chung⁴⁴, Sin Gon Kim¹

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
² Department of Biostatistics, Korea University College of Medicine, Seoul, Korea.
³ Department of Endocrinology and Metabolism, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Korea.
⁴ Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.
⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea.
⁶ Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
⁷ Division of Endocrinology, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.
⁸ Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.
⁹ Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
¹⁰ Department of Internal Medicine, Daejeon Eulji Medical Center, Eulji University, Daejeon, Korea.
¹¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea.
¹² Department of Internal Medicine, Pusan National University Hospital, Busan, Korea.
¹³ Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.
¹⁴ Department of Internal Medicine, Bucheon Sejong Hospital, Bucheon, Korea.
¹⁵ Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
¹⁶ Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
¹⁷ Department of Internal Medicine, Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea.
¹⁸ Department of Internal Medicine, Gachon University College of Medicine, Incheon, Korea.
¹⁹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University Medical School-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.
²⁰ Division of Endocrinology, Department of Internal Medicine, Myongji Hospital, Goyang, Korea.
²¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeju National University College of Medicine, Jeju, Korea.
²² Division of Endocrinology and Metabolism, Chosun University College of Medicine, Gwangju, Korea.
²³ Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.
²⁴ Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.
²⁵ Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
²⁶ Department of Endocrinology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.
²⁷ Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea.
²⁸ Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.
²⁹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea.
³⁰ Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
³¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea.
³² Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
³³ Department of Endocrinology and Metabolism, Inha University College of Medicine, Incheon, Korea.
³⁴ Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
³⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.
³⁶ Big Data Steering Department, National Health Insurance Service, Wonju, Korea.
³⁷ Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.
³⁸ Division of Endocrinology and Metabolism, Department of Internal Medicine, Dong-A University Medical Center, Dong-A University College of Medicine, Busan, Korea.
³⁹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.
⁴⁰ Division of Endocrinology and Metabolism, College of Medicine, Hallym University, Chuncheon, Korea.
⁴¹ Department of Endocrinology and Metabolism, Konyang University Hospital, Konyang University College of Medicine, Daejeon, Korea.
⁴² Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea.
⁴³ Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.
⁴⁴ Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea.

PMID: 39174014
PMCID: PMC11525705
DOI: 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)

Nam Hoon Kim et al. Endocrinol Metab (Seoul). 2024 Oct.

. 2024 Oct;39(5):722-731.

doi: 10.3803/EnM.2024.1995. Epub 2024 Aug 22.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
² Department of Biostatistics, Korea University College of Medicine, Seoul, Korea.
³ Department of Endocrinology and Metabolism, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Korea.
⁴ Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.
⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea.
⁶ Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
⁷ Division of Endocrinology, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.
⁸ Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.
⁹ Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
¹⁰ Department of Internal Medicine, Daejeon Eulji Medical Center, Eulji University, Daejeon, Korea.
¹¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea.
¹² Department of Internal Medicine, Pusan National University Hospital, Busan, Korea.
¹³ Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.
¹⁴ Department of Internal Medicine, Bucheon Sejong Hospital, Bucheon, Korea.
¹⁵ Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
¹⁶ Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
¹⁷ Department of Internal Medicine, Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea.
¹⁸ Department of Internal Medicine, Gachon University College of Medicine, Incheon, Korea.
¹⁹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University Medical School-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.
²⁰ Division of Endocrinology, Department of Internal Medicine, Myongji Hospital, Goyang, Korea.
²¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeju National University College of Medicine, Jeju, Korea.
²² Division of Endocrinology and Metabolism, Chosun University College of Medicine, Gwangju, Korea.
²³ Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.
²⁴ Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.
²⁵ Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
²⁶ Department of Endocrinology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.
²⁷ Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea.
²⁸ Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.
²⁹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea.
³⁰ Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
³¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea.
³² Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
³³ Department of Endocrinology and Metabolism, Inha University College of Medicine, Incheon, Korea.
³⁴ Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
³⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.
³⁶ Big Data Steering Department, National Health Insurance Service, Wonju, Korea.
³⁷ Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.
³⁸ Division of Endocrinology and Metabolism, Department of Internal Medicine, Dong-A University Medical Center, Dong-A University College of Medicine, Busan, Korea.
³⁹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.
⁴⁰ Division of Endocrinology and Metabolism, College of Medicine, Hallym University, Chuncheon, Korea.
⁴¹ Department of Endocrinology and Metabolism, Konyang University Hospital, Konyang University College of Medicine, Daejeon, Korea.
⁴² Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea.
⁴³ Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.
⁴⁴ Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea.

PMID: 39174014
PMCID: PMC11525705
DOI: 10.3803/EnM.2024.1995

Abstract

Backgruound: 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.

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

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST

This study is supported by Hyundai Pharm.

Figures

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

See this image and copyright information in PMC

Cited by

Current and Emerging Treatment Options for Hypertriglyceridemia: State-of-the-Art Review.
Zimodro JM, Rizzo M, Gouni-Berthold I. Zimodro JM, et al. Pharmaceuticals (Basel). 2025 Jan 23;18(2):147. doi: 10.3390/ph18020147. Pharmaceuticals (Basel). 2025. PMID: 40005962 Free PMC article. Review.

References

1. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1:15019. - PubMed
1. Goldberg IJ. Clinical review 124: diabetic dyslipidemia: causes and consequences. J Clin Endocrinol Metab. 2001;86:965–71. - PubMed
1. Eid S, Sas KM, Abcouwer SF, Feldman EL, Gardner TW, Pennathur S, et al. New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia. 2019;62:1539–49. - PMC - PubMed
1. Verbeek R, Hovingh GK, Boekholdt SM. Non-high-density lipoprotein cholesterol: current status as cardiovascular marker. Curr Opin Lipidol. 2015;26:502–10. - PubMed
1. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337–45. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

Grants and funding

Hyundai Pharm

LinkOut - more resources

Full Text Sources
- M2PI
- PubMed Central
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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)

Affiliations

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)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical