538 Diabetes Care Volume 41, March 2018 fi Eiichi Araki,1 Shizuya Yamashita,2,3 Effects of Pema brate, a Novel Hidenori Arai,4 Koutaro Yokote,5 Jo Satoh,6 Toyoshi Inoguchi,7 Jiro Nakamura,8 Selective PPARa Modulator, on Hiroshi Maegawa,9 Narihito Yoshioka,10 Yukio Tanizawa,11 Hirotaka Watada,12 Lipid and Glucose Metabolism in Hideki Suganami,13 and Shun Ishibashi14 Patients With Type 2 Diabetes and Hypertriglyceridemia: A Randomized, Double-Blind, 1Department of Metabolic Medicine, Faculty of Placebo-Controlled, Phase 3 Trial Life Sciences, Kumamoto University, Kumamoto, Japan – Diabetes Care 2018;41:538 546 | https://doi.org/10.2337/dc17-1589 2Department of Community Medicine and De- partment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan 3Rinku General Medical Center, Osaka, Japan 4National Center for Geriatrics and Gerontology, Aichi, Japan 5Department of Clinical Cell Biology and Medi- cine, Chiba University Graduate School of Medi- cine, Chiba, Japan 6Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Miyagi, Japan 7Fukuoka Health Promotion Support Center, OBJECTIVE Fukuoka, Japan Type 2 diabetes is frequently complicated with atherogenic dyslipidemia. This study 8Division of Diabetes, Department of Internal aimed to evaluate the efficacy and safety of pemafibrate (K-877) in patients with Medicine, Aichi Medical University, Aichi, Japan 9Department of Medicine, Shiga University of type 2 diabetes comorbid with hypertriglyceridemia. Medical Science, Shiga, Japan 10Division of Diabetes and Endocrinology, De- RESEARCH DESIGN AND METHODS partment of Medicine, Sapporo Medical Center, Patients were randomly assigned to three groups and received placebo (n =57), NTT East Corporation, Hokkaido, Japan 11 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks Division of Endocrinology, Metabolism, Hema- tological Science and Therapeutics, Yamaguchi (treatment period 1). Subsequently, the patients received follow-up treatment University Graduate School of Medicine, Yama- for another 28 weeks (treatment period 2), in which the placebo was switched to guchi, Japan 12 EMERGING TECHNOLOGIES AND THERAPEUTICS 0.2 mg/day pemafibrate. This article presents the results of treatment period 1, Department of Metabolism and Endocrinol- which were the primary objectives. ogy, Juntendo University Graduate School of Medicine, Tokyo, Japan 13 RESULTS Clinical Data Science Department, Kowa Com- pany, Ltd., Tokyo, Japan The pemafibrate groups showed significantly reduced fasting serum triglyceride 14Division of Endocrinology and Metabolism, levels by ∼45% compared with the placebo group (P < 0.001). Additionally, the Department of Medicine, Jichi Medical Univer- pemafibrate groups displayed significant decreases in non-HDL and remnant lipo- sity, Tochigi, Japan protein cholesterol, apolipoprotein (Apo) B100, ApoB48, and ApoCIII levels and sig- Corresponding author: Eiichi Araki, earaki@gpo .kumamoto-u.ac.jp. nificant increases in HDL cholesterol and ApoA-I levels. LDL cholesterol levels were fi Received 1 August 2017 and accepted 27 No- not considerably altered in the pema brate groups. Furthermore, the 0.2 mg/day vember 2017. fi fi – pema brate group showed a signi cantly reduced HOMA insulin resistance score Clinical trial reg. no. JapicCTI-142412, clinicaltrials compared with the placebo group; however, no significant changes compared with .jp. placebo were found in fasting plasma glucose, fasting insulin, glycoalbumin, or HbA1c This article contains Supplementary Data online levels. The pemafibrate groups also showed significantly increased fibroblast growth at http://care.diabetesjournals.org/lookup/ factor 21 levels compared with the placebo group. All groups displayed comparable suppl/doi:10.2337/dc17-1589/-/DC1. rates of adverse events and drug reactions. © 2018 by the American Diabetes Association. Readers may use this article as long as the work CONCLUSIONS is properly cited, the use is educational and not for profit, and the work is not altered. More infor- Pemafibrate significantly ameliorated lipid abnormalities and was well tolerated in mation is available at http://www.diabetesjournals patients with type 2 diabetes comorbid with hypertriglyceridemia. .org/content/license. care.diabetesjournals.org Araki and Associates 539 The leading cause of death in patients with Pemafibrate (K-877) is a novel selective patients provided written informed con- type 2 diabetes is atherosclerotic cardio- peroxisome proliferator–activated receptor sent prior to their participation. This study vascular disease (ASCVD) (1). Cardiovascu- a (PPARa) modulator approved for the is registered at Japan Pharmaceutical In- lar events are more common in patients treatment of dyslipidemia. A dose-finding formation Center Clinical Trials Informa- with diabetes than in those without (2,3). phase 2 trial on pemafibrate conducted in tion (JapicCTI-142412). The increased ASCVD risk in patients with patients with atherogenic dyslipidemia re- Patients diabetes is attributed to abnormalities in vealed that this drug exerted significant TG The inclusion criteria were as follows: 1) both glucose and lipid metabolism. Lipid reduction and HDL-C increase, with compa- type 2 diabetes comorbid with hypertri- abnormalities are often comorbid with rable rates of adverse events (AEs) to pla- glyceridemia ($6.2% [44.3 mmol/mol] type 2 diabetes and are unique in terms cebo, such as serum creatinine and liver HbA and $150 mg/dL [1.7 mmol/L] of quantitative and qualitative lipid ab- enzyme increases, which suggests that pe- 1c fasting serum TG levels for two consecu- normalities that are associated with insu- mafibrate may have a better benefit/ tive screening visits); 2)age$20 years; 3) lin resistance (IR) (4). The clinical features risk balance than fenofibrate (12) men and postmenopausal women; and of these abnormalities include elevated Given that type 2 diabetes is frequently 4) $12 weeks of dietary or exercise guid- triglyceride (TG) levels, reduced HDL cho- complicated with atherogenic dyslipi- ance before the first screening test. lesterol (HDL-C) levels, and delayed TG-rich demia, a considerable proportion of The exclusion criteria were as follows: 1) lipoprotein catabolism, leading to elevated patients treated with pemafibrate are fasting serum TG levels .1,000 mg/dL postprandial TG levels, remnant lipopro- anticipated to have type 2 diabetes. How- (11.3 mmol/L); 2) type 1 diabetes, in- tein accumulation, and increased small ever, to date, the efficacy and safety of adequately controlled diabetes ($8.0% dense LDL production. pemafibrate, specifically in patients with [63.9 mmol/mol] HbA ), diabetes requir- A number of large-scale clinical trials type 2 diabetes comorbid with hypertri- 1c ing treatment with insulin, thiazolidinedi- have demonstrated that the management glyceridemia, have not been investigated ones, biguanides, high-dose sulfonylureas of dyslipidemia resulted in significantly re- through a prospective randomized trial. ($4 mg/day glimepiride, $7.5 mg/day duced cardiovascular risk in patients with Therefore, we conducted this phase 3 clinical glibenclamide, and $120 mg/day gli- diabetes. The Collaborative Atorvastatin trial to evaluate them through placebo- clazide), sodium–glucose cotransporter 2 Diabetes Study (CARDS) (5) and Choles- controlled treatment for 24 weeks (treat- inhibitors, or combination therapy with terol Treatment Trialists (CTT) Collabora- ment period 1), followed by further three or more antidiabetic agents, and re- tion meta-analysis (6) reported that LDL long-term treatment for another 28 weeks, cent changes in the class and dosage of cholesterol (LDL-C)–lowering therapy in which placebo was switched to pemafi- antidiabetic agents within 12 weeks pri- with statins reduces cardiovascular risk brate (treatment period 2). This article is or to the first screening test; 3) inade- in patients with type 2 diabetes. Addition- based on the clinical study report for treat- quately controlled thyroid disorders; 4) ally, the Japan Diabetes Complications ment period 1, which was documented inadequately controlled hypertension Study (JDCS) identified both high LDL-C before the completion of a 52-week treat- ($180/$110 mmHg systolic/diastolic andTGlevelsasriskfactorsforthedevel- ment period. The overall results through- blood pressure); 5) $1.5 mg/dL serum opment of coronary artery disease (7). Fur- out the 52 weeks will be separately creatinine levels for patients receiving thermore, the UK Prospective Diabetes documented in another article based on statin treatment; 6) a creatine kinase Study (UKPDS) revealed that both high the other clinical study report that includes (CK) level that is more than five times LDL-C and low HDL-C levels were associ- the results of treatment period 2. the upper limit of normal (ULN) for pa- ated with elevated coronary artery dis- tients on statin treatment; 7) aspartate ease risk (8). Therefore, research in RESEARCH DESIGN AND METHODS aminotransferase (AST) and alanine ami- recent decades has focused on interven- Study Design notransferase (ALT) levels that are more tions targeting diabetic lipid abnormalities This multicenter, placebo-controlled, than three times the ULN, or serious he- other than high LDL-C levels. In particular, randomized, double-blind, parallel-group patic disorders; 8) gallstones or serious large-scale clinical trials have revealed that study was performed in 34 medical insti- biliary disorders; 9) occurrence of acute treatment with fibrates, which decrease