Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins

Kentaro Sakamoto; Mitsunobu Kawamura; Takahide Kohro; Masao Omura; Takayuki Watanabe; Keiko Ashidate; Toshiyuki Horiuchi; Hidehiko Hara; Nobuo Sekine; Rina Chin; Motoyoshi Tsujino; Toru Hiyoshi; Motoki Tagami; Akira Tanaka; Yasumichi Mori; Takeshi Inazawa; Tsutomu Hirano; Tsutomu Yamazaki; Teruo Shiba; RESEARCH Study Group

doi:10.1371/journal.pone.0138332

Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins

PLoS One. 2015 Sep 23;10(9):e0138332. doi: 10.1371/journal.pone.0138332. eCollection 2015.

Authors

Kentaro Sakamoto¹, Mitsunobu Kawamura², Takahide Kohro³, Masao Omura⁴, Takayuki Watanabe⁵, Keiko Ashidate⁶, Toshiyuki Horiuchi⁷, Hidehiko Hara⁸, Nobuo Sekine⁹, Rina Chin¹⁰, Motoyoshi Tsujino¹¹, Toru Hiyoshi¹², Motoki Tagami¹³, Akira Tanaka¹⁴, Yasumichi Mori¹⁵, Takeshi Inazawa¹⁶, Tsutomu Hirano¹⁷, Tsutomu Yamazaki¹⁸, Teruo Shiba¹⁹; RESEARCH Study Group

Affiliations

¹ Toho University Ohashi Medical Center, Department of Diabetes and Metabolism, Tokyo, Japan.
² Tokyo Teishin Hospital, Division of Endocrinology and Metabolism Department of Internal Medicine, Tokyo, Japan.
³ Jichi Medical University, Department of Medical Informatics / Cardiology, Tochigi, Japan.
⁴ Yokohama Rosai Hospital, Department of Endocrinology and Metabolism, Kanagawa, Japan.
⁵ Yokohama City Minato Red Cross Hospital, Department of Internal Medicine, Kanagawa, Japan.
⁶ Kudanzaka Hospital, Department of Internal Medicine, Tokyo, Japan.
⁷ Tokyo Metropolitan Health Medical Treatment Corporation Toshima Hospital, Department of Endocrinology and Metabolism, Tokyo, Japan.
⁸ Toho University Ohashi Medical Center, Department of Cardiology, Tokyo, Japan.
⁹ Tokyo Koseinenkin Hospital, Department of Internal Medicine, Tokyo, Japan.
¹⁰ Tokyo Kyosai Hospital, Department of Internal Medicine, Tokyo, Japan.
¹¹ Tokyo Metropolitan Tama Medical Center, Department of Internal Medicine, Tokyo, Japan.
¹² Japanese Red Cross Medical Center, Tokyo, Japan.
¹³ Sanraku Hospital, Life-style related Disease Clinic, Tokyo, Japan.
¹⁴ Kagawa Nutrition University, Nutrition Clinic, Tokyo, Japan.
¹⁵ Toranomon Hospital, Department of Endocrinology and Metabolism, Tokyo, Japan.
¹⁶ Kashiwa City Hospital, Internal Medicine, Chiba, Japan.
¹⁷ Showa University School of Medicine, Department of Medicine Division of Diabetes Metabolism and Endocrinology, Tokyo, Japan.
¹⁸ The University of Tokyo Hospital, Clinical Research Support Center, Tokyo, Japan.
¹⁹ Toho University Ohashi Medical Center, Department of Diabetes and Metabolism, Tokyo, Japan; Mitsui Memorial Hospital, Division of Diabetes and Metabolism, Tokyo Japan.

Abstract

Background: There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks.

Methods: Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM.

Results: The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups.

Conclusion: Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response.

Trial registration: The UMIN Clinical Trials Registry UMIN000002593.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Anticholesteremic Agents / pharmacology*
Cholesterol, LDL / antagonists & inhibitors*
Cholesterol, LDL / blood
Diabetes Mellitus, Type 2 / blood*
Diabetes Mellitus, Type 2 / drug therapy*
Ezetimibe / pharmacology*
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
Male
Middle Aged
Prospective Studies

Substances

Anticholesteremic Agents
Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Ezetimibe

Grants and funding

This study was supported by research grants from Japan Vascular Disease Research Foundation [http://www.disclo-koeki.org/02b/00412/index.html]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.