Intensive Treat-To-Target Statin Therapy in High
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Diabetes Care Volume 41, June 2018 1275 Hiroshi Itoh,1 Issei Komuro,2 Intensive Treat-to-Target Statin Masahiro Takeuchi,3 Takashi Akasaka,4 Hiroyuki Daida,5 Yoshiki Egashira,6 Therapy in High-Risk Japanese Hideo Fujita,7 Jitsuo Higaki,8 Ken-ichi Hirata,9 Shun Ishibashi,10 Takaaki Isshiki,11 Patients With Sadayoshi Ito,12 Atsunori Kashiwagi,13 Satoshi Kato,14 Kazuo Kitagawa,15 Hypercholesterolemia and Masafumi Kitakaze,16 Takanari Kitazono,17 Masahiko Kurabayashi,18 Diabetic Retinopathy: Report of Katsumi Miyauchi,19 Tomoaki Murakami,20 Toyoaki Murohara,21 Koichi Node,22 a Randomized Study Susumu Ogawa,23 Yoshihiko Saito,24 25 26 Diabetes Care 2018;41:1275–1284 | https://doi.org/10.2337/dc17-2224 Yoshihiko Seino, Takashi Shigeeda, Shunya Shindo,27 Masahiro Sugawara,28 Seigo Sugiyama,29 Yasuo Terauchi,30 Hiroyuki Tsutsui,31 Kenji Ueshima,32 Kazunori Utsunomiya,33 Masakazu Yamagishi,34 Tsutomu Yamazaki,35 Shoei Yo,36 Koutaro Yokote,37 Kiyoshi Yoshida,38 Michihiro Yoshimura,39 Nagahisa Yoshimura,40 Kazuwa Nakao,41 and Ryozo Nagai,42 for the EMPATHY Investigators OBJECTIVE Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the in- cidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery 1Department of Endocrinology, Metabolism and disease (treat-to-target approach). Nephrology, Keio University School of Medicine, Tokyo, Japan RESEARCH DESIGN AND METHODS 2Department of Cardiovascular Medicine, The CARDIOVASCULAR AND METABOLIC RISK In this multicenter, prospective, randomized, open-label, blinded end point study, University of Tokyo Graduate School of Medi- cine, Tokyo, Japan eligible patients were randomly assigned (1:1) to intensive statin therapy targeting 3 < n Department of Clinical Medicine (Biostatistics LDL cholesterol (LDL-C) 70 mg/dL ( = 2,518) or standard statin therapy targeting and Pharmaceutical Medicine), School of Phar- LDL-C 100–120 mg/dL (n = 2,524). macy, Kitasato University, Tokyo, Japan 4Department of Cardiovascular Medicine, Wa- RESULTS kayama Medical University, Wakayama, Japan 5 Mean follow-up was 37 6 13 months. LDL-C at 36 months was 76.5 6 21.6 mg/dL in Department of Cardiovascular Medicine, Grad- 6 P < uate School of Medicine Juntendo University, the intensive group and 104.1 22.1 mg/dL in the standard group ( 0.001). The Tokyo, Japan primary end point events occurred in 129 intensive group patients and 153 standard 6Sakura Hospital, Fukuoka, Japan group patients (hazard ratio [HR] 0.84 [95% CI 0.67–1.07]; P = 0.15). The relationship 7Department of Cardiology, Saitama Medical between the LDL-C difference in the two groups and the event reduction rate was Center, Jichi Medical University, Saitama, Japan 8Department of Integrated Medicine and Informat- consistent with primary prevention studies in patients with diabetes. Exploratory ics, Ehime University Graduate School of Medicine, findings showed significantly fewer cerebral events in the intensive group (HR 0.52 Toon, Japan [95% CI 0.31–0.88]; P = 0.01). Safety did not differ significantly between the two 9Division of Cardiovascular Medicine, Department groups. of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan 10 CONCLUSIONS Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical Wefoundnosignificant decrease in CV events or CV-associated deaths with intensive University, Shimotsuke, Japan therapy, possibly because our between-group difference of LDL-C was lower than 11Division of Cardiology, Cardiovascular Center, fi Ageo Central General Hospital, Ageo, Japan expected (27.7 mg/dL at 36 months of treatment). The potential bene tofachieving 12 < Division of Nephrology, Endocrinology and Vas- LDL-C 70 mg/dL in a treat-to-target strategy in high-risk patients deserves further cular Medicine, Tohoku University Graduate School investigation. of Medicine, Sendai, Japan 1276 Intensive Statin Therapy in High-Risk Patients Diabetes Care Volume 41, June 2018 Dyslipidemia and impaired glucose me- we conducted a large-scale clinical study to achieve specific LDL-C targets by titrat- tabolism in diseases such as diabetes are in patients with hypercholesterolemia and ing statin therapy. known risk factors for cardiovascular dis- diabetic retinopathy (type 2 diabetes). Few ease;patientswithbothconditionsareat prospective clinical studies have evaluated RESEARCH DESIGN AND METHODS even greater risk of cardiovascular (CV) the efficacy of intensive lipid-lowering ther- Study Design events (1–3). Meta-analysis (4) has asso- apy specifically in primary prevention pa- The study used a multicenter, prospec- ciated lower levels of LDL cholesterol tients with diabetes, particularly for reducing tive, randomized, open-label, blinded end (LDL-C) with reduced risk of CV events in risk through lipid-lowering intervention in point (PROBE) design (9) and enrolled pa- patients with type 2 diabetes, and the risk hypercholesterolemic patients with dia- tients at hospitals and family practice clin- of CV events increases further in patients betic retinopathy. ics across Japan. The study was conducted with diabetic retinopathy (5,6). However, The standard versus intEnsive statin under the Declaration of Helsinki and Jap- little evidence is currently available on therapy for hypercholesteroleMic Patients anese ethical guidelines for clinical studies. the efficacy of lipid therapy specifically in with diAbetic retinopaTHY (EMPATHY) The protocol was reviewed and approved these very high-risk patients. study examined whether intensive lipid- by the institutional review board of each The association of lower LDL-C and lowering therapy is superior to standard participating center. reduced risk of CV events has spurred therapy in reducing the incidence of CV interest in a treat-to-target approach, events in patients with hyperlipidemia Patients adjusting the drug dose to achieve a and diabetic retinopathy but no history Patients who had elevated LDL-C and specific LDL-C target. However, at the of coronary artery disease. Patients were diabetic retinopathy without a history time of this study, almost all large-scale divided into two groups targeting differ- of coronary artery disease were eligible lipid-lowering clinical studies with statins ent LDL-C levels (,70 or $100 and for participation (Supplementary Data). were either placebo controlled or com- ,120 mg/dL). Statin therapy, regardless All patients were enrolled by the inves- pared treatment results based on statin of statin type, was used to control LDL-C tigators and provided written informed type or dose (7). The authors of the 2013 at the targeted level in each group. Safety consent. American College of Cardiology (ACC)/ and efficacy were compared between Randomization and Masking American Heart Association (AHA) guide- groups. A data center provided the computer- line on lipid management (8) thus con- The EMPATHY study is the first to assess generated allocation sequence, stratified cluded that evidence was insufficient to the benefits of intensive versus standard by sex, age, and baseline hemoglobin A1c prove the benefits of treat-to-target and statin therapy for patients with hypercho- (HbA1c). After patient eligibility was con- did not include specific treat-to-target lesterolemia and diabetic retinopathy in a firmed, the investigator contacted the data levels. primary prevention setting. The study also center for the allocated treatment. Staff who To explore the potential benefits of evaluates the appropriateness of treat-to- generated the allocation sequence were not treat-to-target in very high-risk patients, target, because all patients were treated involved in patient enrollment. 13Kusatsu General Hospital, Kusatsu, Japan 26Ideta Eye Clinic, Kumamoto, Japan 39Division of Cardiology, Department of Internal 14Department of Ophthalmology, The University 27Department of Cardiovascular Surgery, Tokyo Medicine, The Jikei University School of Medi- of Tokyo Graduate School of Medicine, Tokyo, Medical University Hachioji Medical Center, cine, Tokyo, Japan Japan Hachioji, Japan 40Kitano Hospital, The Tazuke Kofukai Medical Re- 15Department of Neurology, Tokyo Women’s 28Sugawara Medical Clinic, Tokyo, Japan search Institute, Osaka, Japan Medical University School of Medicine, Tokyo, 29Department of Cardiology, Jinnouchi Hospital, 41Medical Innovation Center, Kyoto University Grad- Japan Kumamoto, Japan uate School of Medicine, Kyoto, Japan 16Division of Cardiology, National Cerebral and 30Department of Endocrinology and Metabo- 42Jichi Medical University, Shimotsuke, Japan Cardiovascular Center, Suita, Japan lism, Yokohama City University School of Med- 17 Corresponding author: Hiroshi Itoh, hiito@keio Department of Medicine and Clinical Science, icine, Yokohama, Japan .jp. Graduate School of Medical Sciences, Kyushu 31Department of Cardiovascular Medicine, Faculty University, Fukuoka, Japan of Medical Sciences, Kyushu University, Fukuoka, Received 24 October 2017 and accepted 12 18Department of Medicine and Biological Science, Japan March 2018. Gunma University Graduate School of Medicine, 32Department of EBM Research, Institute for Ad- Clinical trial reg. no. UMIN000003486, www Maebashi, Japan vancement of Clinical and Translational Science, .umin.ac.jp/ctr/. 19 Department of Cardiology, Graduate School of Kyoto University Hospital, Kyoto, Japan This article contains Supplementary