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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 ,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, , RESEARCH DESIGN AND METHODS 2Department of Cardiovascular Medicine, The ADOACLRADMTBLCRISK METABOLIC AND CARDIOVASCULAR 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, , 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, , Japan group patients (hazard ratio [HR] 0.84 [95% CI 0.67–1.07]; P = 0.15). The relationship 7Department of Cardiology, 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, 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, , 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, , 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, , Japan Medical University School of Medicine, Tokyo, 29Department of Cardiology, Jinnouchi Hospital, 41Medical Innovation Center, 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, , Japan lism, 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 , 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 Data online 33 Medicine Juntendo University, Tokyo, Japan Division of Diabetes, Metabolism and Endo- at http://care.diabetesjournals.org/lookup/suppl/ 20 Department of Ophthalmology, Kyoto Univer- crinology, Department of Internal Medicine, The doi:10.2337/dc17-2224/-/DC1. sity Graduate School of Medicine, Kyoto, Japan Jikei University School of Medicine, Tokyo, Japan 21Department of Cardiology, University 34Department of Cardiovascular and Internal Med- © 2018 by the American Diabetes Association. Graduate School of Medicine, Nagoya, Japan icine, University Graduate School of Readers may use this article as long as the work 22Department of Cardiovascular Medicine, Medicine, Kanazawa, Japan is properly cited, the use is educational and not fi University, Saga, Japan 35Clinical Research Support Center, The Univer- for pro t, and the work is not altered. More infor- 23Division of Nephrology, Endocrinology and Vas- sity of Tokyo Hospital, Tokyo, Japan mation is available at http://www.diabetesjournals cular Medicine, Tohoku University Hospital, Sendai, 36Yo Clinic, Kyoto, Japan .org/content/license. Japan 37Department of Clinical Cell Biology and Med- 24First Department of Internal Medicine, icine, University Graduate School of Med- Medical University, Kashihara, Japan icine, Chiba, Japan 25Department of Cardiology, Nippon Medical School 38Sakakibara Heart Institute of , Okayama, Chiba Hokuso Hospital, Inzai, Japan Japan care.diabetesjournals.org Itoh and Associates 1277

This study was designed to evaluate the patient’s answers. No situations The full analysis set (FAS) was selected the treat-to-target approach, so investiga- arose during the study that required as the main analysis set for efficacy. The tors could not be blinded to statin types consideration of study discontinuation primary and secondary end points were and doses. We thus selected a PROBE or suspension. analyzed in the same way in the FAS and design rather than a double-blind design. the per protocol set, and results for the To eliminate bias, defined end points Outcomes two sets were examined for consistency. were evaluated by a blinded end point The primary and secondary outcomes The FAS comprised all randomly allocated committee. of the EMPATHY study were previously subjects for whom efficacy data were described (9) (Supplementary Data). The available. The per protocol set comprised Procedures primary outcome was the composite in- all members of the FAS, except for sub- As previously described (9), this PROBE cidence of CV events, including cardiac, jects who did not qualify or were not study constituted a run-in period (4–8 cerebral, renal, and vascular events, or treated and cases of protocol violation or weeks) and a treatment period (2–5.5 CV-associated death. The secondary out- noncompliance. All subjects who received years). During run-in, patients received comes included death from any cause, the study treatment at least once and for oral statin monotherapy targeting LDL-C individual incidence of study-defined CV whom safety information was available between 100 and 120 mg/dL. Patients events for the primary end point, inci- were included in the safety analysis set. were then assessed for eligibility and dence of stroke, change in laboratory In all analyses, each subject was included randomly assigned (1:1) to oral intensive variables related to chronic kidney dis- in the allocation group. therapy (targeting LDL-C ,70 mg/dL) or ease (CKD), and safety. Items assessed for We compared the primary end point standard therapy (targeting LDL-C be- safety are listed in the Supplementary between the treatment groups by log-rank tween 100 and 120 mg/dL). LDL-C levels Data. Primary and secondary end points test, stratified by sex, age, and baseline were calculated from the Friedewald for- were adjudicated by an event evaluation HbA1c, and used a stratified Cox propor- mula. LDL-C targets were based on guide- committee whose members were un- tional hazards model to estimate the HR lines in the U.S. and Japan when the aware of the treatment allocation. and 95% CI. study was designed (10,11). Each inves- In the previous century, coronary artery Interim analysis was performed during tigator independently selected a statin disease and stroke were the primary end the study at a prespecified time point, for the run-in and treatment periods points in most large-scale clinical studies of adjusted by the Lan-DeMets a spending for each patient. Statin dose escalation statins. However, the relationship between function with O’Brien-Fleming boundaries. and switching to another statin were CKD and arteriosclerosis began to be more An independent data monitoring commit- permittedinbothgroups.Theinvesti- widely accepted from about 2000. Today tee assessed the analysis results. gators generally measured LDL-C once ischemic heart disease, cerebrovascular The software used was SAS version 9.2 monthly for 6 months after study start to disease, peripheral vascular disease, and (SAS Institute). confirm that the treatment target had renal impairment are widely understood been reached. After that point, LDL-C to be ischemic conditions, and a meta- RESULTS was measured every 6 months if values analysis of randomized control and cross- Study Patients remained within the treatment target, or over studies has shown that statins inhibit A total of 5,995 patients were enrolled more frequently at the discretion of the proteinuria and progression of nephropa- between May 2010 and October 2013 physician (for example, after LDL-C ex- thy (12). We thus selected a range of (Supplementary Fig. 1) at 772 primary ceeded the target treatment range, to primary end points based on arterioscle- prevention sites (323 hospitals and confirm that the treatment target had rosis, including renal events. 449 clinics) in Japan. Of these patients, been reacquired) (9). 5,144 were randomized to intensive Concomitant lipid-lowering therapy was Statistical Analysis (2,571) or standard (2,573) statin ther- prohibited with fibrates, ezetimibe, ethyl Statistical methods for the EMPATHY study apy; 53 in intensive therapy and 49 in icosapentate, anion exchange resins, pro- were previously described (9). The planned standard therapy were subsequently ex- bucol, nicotinic acid derivatives, phytoster- sample size was 5,000 patients, with cluded from data analysis. Data were an- ols, elastase, dextran sulfate sodium sulfur, 2,500 in each treatment group. This alyzed from 5,042 patients (2,518 in the pantethine, or polyenephosphatidylcholine. was considered sufficient to detect a haz- intensive therapy group and 2,524 in the Details of treatment for diabetes and ard ratio (HR) of 0.65 for the superiority of standard therapy group). Mean follow-up hypertension were provided previously, intensive therapy with a power of 80% was 37 6 13 months. along with medical histories, baseline and a two-sided significance level of 5%. findings, and changes during the treat- The incidence of CV events during the Baseline Characteristics ment period in parameters such as body 3-year treatment period was estimated Patients randomized to the two treatment weight, blood pressure, blood chemistry, at 2.7% for intensive therapy and 4.1% groups had similar baseline characteristics and electrocardiogram (9). Statin treat- for standard therapy, based on earlier (Table 1). Atorvastatin, rosuvastatin, and ment adherence, concomitant use of other reports in the literature (13–16). We pitavastatin users accounted for 54.8% of drugs, and adverse events (AEs) were in- usedtheseestimatestocalculatethesam- all patients in the intensive group and vestigated periodically throughout the ple size, assuming a withdrawal rate of 54.4% in the standard group at baseline. study. The physician determined adher- 15% and a study period of 4.5 years. We The other patients used pravastatin, flu- ence by questioning each patient during estimated 179 occurrences of the pri- vastatin, or simvastatin. At the end of the each visit to the hospital and recording mary end point by the end of the study. study, the proportion of patients using 1278 Intensive Statin Therapy in High-Risk Patients Diabetes Care Volume 41, June 2018

“ Table 1—Demographic characteristics (FAS) would be considered moderate to low- ” Intensive therapy Standard therapy intensity statin therapy under ACC/AHA Characteristics (n = 2,518) (n = 2,524) guidelines. Male 1,200 (47.7) 1,203 (47.7) Laboratory Values 6 6 Age (years)* 63.0 10.8 63.2 10.4 The mean level of LDL-C for the patients 6 6 Height (cm) 158.9 9.6 159.0 9.5 in the intensive group was 106.2 6 6 6 Weight (kg) 65.2 13.9 64.9 13.7 26.7 mg/dL (median 105.0 mg/dL) at the BMI† 25.7 6 4.3 25.6 6 4.4 start of treatment. That level decreased Abdominal circumference (cm) 90.4 6 10.6 90.4 6 11.1 to 85.6 6 24.3 mg/dL (83.0 mg/dL) after Lipid-lowering agents‡ 6 months of treatment and continued None 1,105 (43.9) 1,040 (41.2) to gradually decline over time, reaching 1 drug 1,406 (55.8) 1,481 (58.7) 76.5 6 21.6 mg/dL (73.0 mg/dL) at $2 drugs 7 (0.3) 3 (0.1) 36 months of treatment. For patients Statin‡ No 1,201 (47.7) 1,155 (45.8) treated with standard statin therapy, Yes 1,317 (52.3) 1,369 (54.2) mean LDL-C was 106.1 6 25.9 mg/dL Smoking§ 462 (18.3) 480 (19.0) (105.0 mg/dL) at the start of treat- Family history ment and remained at or near that level Diabetes 1,334 (53.0) 1,308 (51.8) throughout the treatment period. The Coronary artery disease 325 (12.9) 318 (12.6) difference between the two groups was Cerebrovascular disease 494 (19.6) 530 (21.0) 23.6 mg/dL at 1 year and 27.7 mg/dL at Duration of diabetes (years) 12.8 6 8.6 13.0 6 9.0 3 years. The difference was significant Diabetic complications from 6 to 60 months after the start of Neuropathy 777 (30.9) 781 (30.9) treatment (Supplementary Fig. 2). Nephropathy 1,358 (53.9) 1,290 (51.1) Changes in other lipid parameters are Hypertension 1,777 (70.6) 1,797 (71.2) shown in Supplementary Table 2. Total Peripheral artery disease (Fontaine class I) 125 (5.0) 110 (4.4) cholesterol and triglycerides were lower Other complications and medical history 1,971 (78.3) 2,021 (80.1) in the intensive than the standard group. Compliance with statin use from provisional HDL-C values differed very little between enrollment to full enrollment the two groups. None 13 (0.5) 5 (0.2) Blood pressure, HbA , serum creati- ,50 11 (0.4) 6 (0.2) 1c 50–75 36 (1.4) 28 (1.1) nine, creatinekinase, and hs-CRPare sum- $75 2,448 (97.2) 2,477 (98.1) marized in Supplementary Fig. 3. Overall fi Funduscopy| ndings for each treatment group dif- Simple retinopathy 1,683 (66.8) 1,669 (66.1) feredlittleovertime,includingthesepara- Preproliferative retinopathy 423 (16.8) 485 (19.2) meters or hematological results, or liver Proliferative retinopathy 390 (15.5) 355 (14.1) and renalfunction test results. After treat- Other¶ 16 (0.6) 10 (0.4) ment for 1 year and thereafter, mean hs- 6 6 HbA1c (%)* 7.8 1.3 7.8 1.3 CRP was significantly lower in the intensive LDL-C (mg/dL)# 106.2 6 26.7 106.1 6 25.9 group than the standard group. Blood pressure (mmHg) 6 6 Systolic 134.6 16.8 134.6 16.3 Efficacy End Points 6 6 Diastolic 74.9 11.5 74.8 11.1 The primary outcome, combined incidence fi Estimated glomerular ltration rate of CV events or deaths associated with CV (mL/min/1.73 m2) 74.0 6 20.6 74.6 6 20.3 events, was lower in the intensive group Data are mean 6 SD or n (%). *Values were obtained at the time of consent. †BMI is the weight in (LDL-C target ,70 mg/dL, 129 patients) kilograms divided by the square of the height in meters. ‡Values were obtained at provisional enrollment. §Not including past smokers. |Diagnosed by ophthalmologists based on the than the standard group (LDL-C target modified Davis classification. ¶Includes 17 patients who had a history of laser therapy but no $100 and ,120 mg/dL, 153 patients), funduscopic findings at enrollment. The remaining nine patients were found to be retinopathy but that difference was not statistically negative after enrollment. #Values were calculated using the Friedewald equation; LDL-C = total significant (HR 0.84 [95% CI 0.67–1.07]; cholesterol 2 (HDL-C 1 triglyceride/5). P = 0.15) (Fig. 1). Calculated values for the primary and secondary outcomes are listed atorvastatin, rosuvastatin, and pitavasta- intensive group; the mean doses for the in Supplementary Table 3. tin increased (95.6%) in the intensive standard group remained essentially un- The incidence of deaths from any group but remained nearly unchanged changed over the course of the study cause did not differ significantly between (53.4%) in the standard group. For all (Supplementary Table 1). It should be the two groups (HR 1.21 [95% CI 0.77– statin types, dose at baseline was nearly noted that the statin dose for “intensive” 1.91]) (Fig. 2). The incidence of cerebral identical between the intensive and stan- therapyinJapanislowerthaninthe events (cerebral infarction or cerebral dard groups. By the last visit, statin dose U.S. and Europe; at the last visit in this revascularization) decreased significantly had increased for all statin types in the study, the dose in the intensive group in the intensive group (HR 0.52 [95% CI care.diabetesjournals.org Itoh and Associates 1279

Figure 1—Cumulative event curve for the primary end point (A) and HR of the primary and secondary end points (each component of primary end points) in the intensive and standard therapy groups (B). Cardiac events included myocardial infarction, unstable angina requiring unscheduled hospitalization, or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting). Cerebral events included cerebral infarction or cerebral revascularization. Renal events included initiation of chronic dialysis or increase in serum creatinine level by at least twofold (and .1.5 mg/dL). Vascular events included aortic disease or peripheral arterial disease (aortic dissection, mesenteric artery thrombosis, severe lower-limb ischemia [ulceration], revascularization, or finger/lower-limb amputation caused by arteriosclerosis obliterans). P value was calculated using a stratified log-rank test with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP%]) as stratification factors. HR (95% CI) was estimated using a stratified Cox proportional hazards model with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP%]) as stratification factors; P values for secondary end points are nominal.

0.31–0.88]) (Fig. 1), as did the incidence creatinine (343.2%) and 86.5 mg/g creat- of patients experienced adverse drug re- of cerebral infarction (HR 0.54 [95% inine (300.8%), and urine protein in- actions (ADRs) in the intensive group CI 0.32–0.90]) (Fig. 2). The incidence of creased 10.7 mg/dL (1,503.1%) and (10.1%) than the standard group (6.7%) stroke (cerebral infarction, cerebral hem- 11.0 mg/dL (236.1%) in the intensive (P , 0.001), but most of those ADRs were orrhage, and subarachnoid hemorrhage), and standard groups, respectively. None mild. The proportion of serious ADRs was cerebral hemorrhage, and subarachnoid of these parameters differed significantly similar between groups (1.3% vs. 0.9%; hemorrhage did not differ between the between the intensive and standard groups P =0.22). groups (HR 0.64 [95% CI 0.40–1.01], HR (Supplementary Table 4). 1.34 [95% CI 0.46–3.86], and HR NA [not As part of an exploratory analysis, we applicable], respectively). No other sig- performed subgroup analysis of the pri- CONCLUSIONS nificant differences were noted. The HR mary end point for both treatment The EMPATHY study assessed the bene- for cardiac events was 0.93 (95% CI 0.65– groups based on various demographic fits of intensive statin monotherapy for 1.33), for renal events 1.07 (95% CI 0.72– factors (Supplementary Fig. 4). No sig- lipid management in patients with hyper- 1.58), and for vascular events 1.00 (95% nificant heterogeneity of treatment ef- cholesterolemia and diabetic retinopathy CI 0.38–2.67) (Supplementary Table 3). fects was seen in any of the factors in a primary prevention setting. The study Change and percent change from examined. also evaluated the appropriateness of the baseline to 36 months in the parameters treat-to-target approach in this patient for CKD were evaluated as a secondary Safety population. Results indicated that lipid- end point. Estimated glomerular filtration Overall, a similar percentage of patients lowering therapy targeting LDL-C ,70 mg/dL rate decreased by 5.9 mL/min/1.73 m2 in both groups experienced AEs (inten- had no more beneficial effect on the primary (7.8%) in the intensive group and 6.5 sive 75.3%; standard 75.2%) and serious end point than therapy targeting LDL-C of mL/min/1.73 m2 (8.3%) in the standard AEs (intensive 21.3%; standard 22.0%) 100–120 mg/dL. In exploratory findings, the group. Urine albumin increased by 85.3 mg/g (Table 2). A significantly higher proportion secondary end points of cerebral events and 1280 Intensive Statin Therapy in High-Risk Patients Diabetes Care Volume 41, June 2018

Figure 2—Cumulative event curve for secondary end points in the intensive and standard therapy groups: death from any cause (A), stroke (B), cerebral infarction (C), cerebral hemorrhage (D), and subarachnoid hemorrhage (E). P value was calculated using a stratified log-rank test with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP %]) as stratification factors. HR (95% CI) was estimated using a stratified Cox proportional hazards model with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP %]) as stratification factors; P values for secondary end points are nominal.

cerebral infarction were reduced significantly (IMPROVE-IT) (17) demonstrated the use- on primary prevention to expand the in the intensive group. No major safety fulness of intensive lipid therapy for the evidence regarding intensive lipid man- concerns were noted. secondary prevention of CV events, using agement using statin monotherapy. How- The Improved Reduction of Out- statin and ezetimibe to achieve LDL-C ever, our results differed from those comes: Vytorin Efficacy International Trial as low as 50 mg/dL. Our study focused previous studies using statins. care.diabetesjournals.org Itoh and Associates 1281

Table 2—Safety issues: AEs and ADRs Intensive therapy (n = 2,511) Standard therapy (n = 2,518) Events (n)Patients(n [%]) Events (n)Patients(n [%]) P value AEs Total 7,832 1,890 (75.3) 8,189 1,894 (75.2) 0.97 Serious 815 535 (21.3) 901 554 (22.0) 0.55 ADRs Total 368 253 (10.1) 218 168 (6.7) ,0.001 Serious 41 32 (1.3) 28 23 (0.9) 0.22 Main AEs Hepatobiliary disorders Total 82 71 (2.8) 52 48 (1.9) 0.03 Serious 29 22 (0.9) 14 13 (0.5) 0.13 Renal and urinary disorders Total 200 166 (6.6) 250 215 (8.5) 0.01 Serious 26 21 (0.8) 28 28 (1.1) 0.39 Rhabdomyolysis Total 3 3 (0.1) 4 4 (0.2) 1.00 Serious 1 1 (0.0) 1 1 (0.0) 1.00 Myopathy Total 1 1 (0.0) 0 0 0.50 Serious 1 1 (0.0) 0 0 0.50 Cancer* Total 132 114 (4.5) 107 120 (4.2) 0.63 Serious 94 81 (3.2) 91 80 (3.2) 0.94 P values were calculated using the Fisher exact test. *Including neoplasms benign, malignant, and unspecified, including cysts and polyps.

Why did our study fail to show superior between-group difference in LDL-C was would be predicted by Supplementary results for intensive therapy? EMPATHY ;40 mg/dL (,70 mg/dL for the intensive Fig. 6, given the observed 23.6 mg/dL included some soft end points that re- group vs. ;110 mg/dL for the standard reduction in LDL-C (after 1 year). In other quired subjective assessment, such as re- group), and the HR was predicted to be words, the primary results of the EMPATHY vascularization, and renal events that 0.65. However, after 3 years of treatment, study, despite not being significant, are were attributable to arteriosclerosis. To the actual LDL-C difference was 27.7 mg/dL consistent with previous findings. We hy- evaluate these effects on the study results, (76.5 vs. 104.1 mg/dL). pothesize that if we had achieved the we compared the groups using three- In exploratory findings, we compared predicted difference of 40 mg/dL LDL-C point major CV events (CV death, nonfatal our results to the Cholesterol Treatment between two treatment groups, the pri- myocardial infarction, and nonfatal stroke) Trialists’ (CTT) meta-analysis (18) and mary end point would have reached sta- and the primary end point after excluding three primary prevention studies in pa- tistical significance. This suggests that renal events. We found no significant tients with diabetes (13–15). We graphed aggressive LDL-C management may further differences (HR 0.82 [95% CI 0.58–1.14] the relationship between changes in reduce risk in patients with conditions such and HR 0.76 [95% CI 0.57–1.01], respec- LDL-C and proportional reduction in event as hyperlipidemia and diabetic retinopathy. tively) (Supplementary Fig. 5), suggesting rate (major CV events including major To further clarify the reasons for the that our study findings were unaffected coronary events [coronary death or non- failure to demonstrate the efficacy of in- by either soft end points or renal events. fatalmyocardialinfarction],strokeof tensive therapy, we performed post hoc Primary end point incidence was 20.41/ any type, and coronary revascularization analysis, classifying patient data into four 1,000 person-years in the standard group [angioplasty or bypass grafting]). Inter- subcategories (mean LDL-C ,70, 70 to and 17.27/1,000 person-years in the in- estingly, the slope of the line for the di- ,100, 100 to ,120, and $120 mg/dL tensive group. The cumulative incidence abetes studies seems to be steeper than during the study). Our exploratory find- at 3 years was 5.8% and 5.4%, respec- the original CTT line (Supplementary Fig. ings tended to show event prevention at tively, exceeding our earlier estimates of 6). Next, we plotted the findings of the lower LDL-C values in both the intensive 4.1% and 2.7%. The statistical power of EMPATHY study. In our study, the predic- and standard groups (Supplementary the study was thus sufficient to detect ted between-group difference in LDL-C of Fig. 7). We plan additional exploratory significant differences in CV events be- ;40 mg/dL should have provided a re- analysis of between-group comparison, tween the two groups. duction of ;30% in major CV events, limited to patients in each group with We believe that this study failed to close to this data line and to the originally LDL-C levels within the targeted range. find a significant reduction in the primary predicted primary event reduction rate We obtained preliminary results show- end point because of the smaller-than- (HR 0.65). The observed 20% reduction in ing that the event rate for the primary predicted difference in LDL-C between major CV events (HR 0.80 [95% CI 0.59– end point was significantly lower in the the two treatment groups. Our planned 1.07]) is quite similar to the reduction that intensive group than in the standard group. 1282 Intensive Statin Therapy in High-Risk Patients Diabetes Care Volume 41, June 2018

Our findings from that subanalysis will be groups. This suggested low potential risk more significantly than the standard therapy published separately. for excessive LDL-C reduction by statin targeting LDL-C $100 and ,120 mg/dL. In an intervention study where the monotherapy. Aggressive LDL-C lowering However, based on previous studies in control group also receives statin ther- might be associated with increased levels patients with diabetes in a primary pre- apy, the duration of follow-up is of of cerebral hemorrhage, since cerebral vention setting, the event reduction rate considerable importance. Non-Japanese hemorrhage increased with intensive ther- in this study is consistent with expect- studies with a relative difference in LDL-C of apy in the SPARCL study (21). However, ations regarding the LDL-C difference that 40–50% between two groups required subsequent investigation of SPARCL was achieved and might be clinically mean- 2 years to show significance in incidence showed that on-treatment LDL-C did ingful. Exploratory results suggest that in- between groups (19,20). EMPATHY follow- not predict cerebral hemorrhage (23). tensive therapy reduces cerebral events, up time was 3 years, but the between- EMPATHY findings showed no intergroup especially cerebral infarction, with no in- group difference in LDL-C was lower than differences in cerebral hemorrhage, po- crease in AEs in this population. anticipated; longer follow-up might have tentially eliminating concerns of in- shown greater between-group difference. creased cerebral hemorrhage risk due to Our study data indicated that intensive intensive statin therapy. Although con- Acknowledgments. EDIT, Inc. (Tokyo, Japan) pro- therapy favorably affected cerebral events, cerns have been raised over worsening of vided medical writing and editing. Funding and Duality of Interest. This work was particularly cerebral infarction. An in- HbA1c due to statin therapy (24,25), no fi supported by Shionogi & Co., Ltd. H.I. reports ference of signi cant reduction cannot such effects were noted in this study. grants and personal fees from Shionogi & Co., Ltd. be supported given the lack of a statistically Key strengths of this study were imple- during the conducting of the study and grants and significant difference in the primary end mentation of the first-ever assessment of personal fees from Takeda Pharmaceutical Co., point. However, we note that in the Stroke benefits of intensive statin therapy in pa- Ltd., Nippon Boehringer Ingelheim Co., Ltd., Prevention by Aggressive Reduction in tients with hypercholesterolemia and dia- Daiichi Sankyo Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corp., Shionogi & Co., Ltd., and Cholesterol Levels (SPARCL) study (21), betic retinopathy in primary prevention; Taisho Pharmaceutical Co., Ltd., grants statin therapy effectively reduced cere- suitability assessment of a treat-to-target from Sumitomo Dainippon Pharma Co., Ltd., brovascular events when LDL-C was low- approach for LDL-C management by titrating Astellas Pharma Inc., Kyowa Hakko Kirin Co., ered to 70 mg/dL, whereas in the Japan statin therapy; and inclusion of clinics as over Ltd., Teijin Pharma Ltd., Mochida Pharmaceutical Statin Treatment Against Recurrent half the participating sites so that patient Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Eli Lilly and Com- Stroke (J-STARS) study (22), where management was closer to routine clinical pany Japan K.K., and personal fees from Nipro LDL-C levels were reduced only to 100 practice, which is advantageous for assessing Corp. and SBI Pharmaceuticals Co., Ltd. outside mg/dL, no such efficacy was detected. real-world effects of lipid-lowering therapy. the submitted work. I.K. reports personal fees Exploratory results from EMPATHY were Limitations of this study were the use from Shionogi & Co., Ltd. during the conducting similar to those from SPARCL in that LDL- of PROBE rather than double-blind com- of the study and grants and personal fees fi from Takeda Pharmaceutical Co., Ltd., Nippon C reached 70 mg/dL and may con rm that parison of the two treatment methods; Boehringer Ingelheim Co., Ltd., Astellas Pharma a decrease in LDL-C contributes to reduc- inclusion of soft end points (although those Inc., Daiichi Sankyo Co., Ltd., and Otsuka Pharma- ing the event risk for cerebral infarction. end points were assessed by a blinded ceutical Co., Ltd. and grants from MSD K.K., Shionogi Of further interest, the Japan Diabetes independent committee to ensure objec- & Co., Ltd., GlaxoSmithKline K.K., Sanofi K.K., Complications Study (JDCS) (2) reported tivity); unexpectedly high patient discon- Genzyme Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma that the incidences of coronary heart tinuation from data loss during a major Corp., and Bristol-Myers Squibb outside the sub- disease and stroke were 9.59/1,000 and earthquake, which may have reduced study mitted work. M.T. reports personal fees from 7.45/1,000 person-years, respectively, in power even though discontinuations were Shionogi & Co., Ltd. during the conducting of Japanese patients with type 2 diabetes. well balanced between the two groups; the study. T.A. reports personal fees from Shionogi In EMPATHY, the incidences of cardiac and failure to control LDL-C within the & Co., Ltd. during the conducting of the study and grants and personal fees from St. Jude events and stroke were 8.13/1,000 and target range in some patients in both Medical Japan Co., Ltd., Terumo Corp., Daiichi 6.14/1,000 person-years, respectively, in groups, resulting in a smaller-than-planned Sankyo Co., Ltd., and Abbott Vascular Japan Co., the standard group. The incidences of intergroup difference in LDL-C that possibly Ltd., grants from Goodman Co., Ltd., Otsuka cardiac events and ischemic stroke were affected study power. Median LDL-C level Pharmaceutical Co., Ltd., Pfizer Japan Inc., Bayer fi surprisingly similar between the JDCS and at 6 months in the intensive group was Yakuhin, Ltd., and Boston Scienti cCorp.,and personal fees from Nippon Boehringer Ingelheim EMPATHY. This is noteworthy because the 83.0 mg/dL, indicating failure to reach the Co., Ltd. outside the submitted work. H.D. re- EMPATHY study targeted patients who protocol-stipulated target LDL-C level ports grants and personal fees from Shionogi & were already under statin therapy, and of ,70 mg/dL. In real-world clinical prac- Co., Ltd. during the conducting of the study, and the LDL-C baseline in the standard group tice, many Japanese physicians who are grants and personal fees from AstraZeneca K.K., (106 mg/dL) was substantially lower than not lipid management experts worry about Astellas Pharma Inc., Abbott Vascular Japan Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kaken Phar- in the JDCS patients (120 vs. 135 mg/dL). adverse effects such as intracranial hemor- maceutical Co., Ltd., Kissei Pharmaceutical Co., These findings suggest that Japanese pa- rhage from intensive LDL-C lowering, and Ltd., Kyowa Hakko Kirin Co., Ltd., Kowa Phar- tients with diabetic retinopathy may be at may have been somehow affected by these maceutical Company Ltd., Sanofi K.K., Daiichi particularly high risk for CV events. concerns even when the protocol stipu- Sankyo Co., Ltd., Sumitomo Dainippon Pharma No major AE or severe ADR increases lated the aggressive target of ,70 mg/dL. Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ter- umo Corp., Nippon Boehringer Ingelheim Co., were associated with statin monotherapy In conclusion, the intensive therapy tar- Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., targeting LDL-C ,70 mg/dL, and rhabdo- geting LDL-C ,70 mg/dL did not reduce Philips Respironics GK, Bristol-Myers Squibb, myolysis occurred at a similar rate in both the incidence of composite CV events Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi care.diabetesjournals.org Itoh and Associates 1283

Tanabe Pharma Corp., MSD K.K., and GlaxoS- Pharma Inc., Sunstar Group Ltd., Eli Lilly and Shionogi & Co., Ltd. during the conducting of the mithKline K.K., grants from Eisai Co., Ltd., Teijin Company Japan K.K., Sanofi K.K., AstraZeneca study and grants and personal fees from Otsuka Pharma Ltd., Nippon Shinyaku Co., Ltd., VitalAire K.K., Takeda Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. and Nippon Boehringer Japan K.K., Fujifilm RI Pharma Co., Ltd., Boston Toyama Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. and grants from Mitsubishi Scientific Corp., Fuji Chemical Industries Co., Ingelheim Co., Ltd., Kowa Pharmaceutical Co., Tanabe Pharma Corp., Fujifilm RI Pharma Co., Ltd., Fukuda Denshi Co., Ltd., and Actelion Phar- Ltd., and Sanwa Kagaku Kenkyusho Co., Ltd. out- Ltd., Roche Diagnostics K.K., MSD K.K., Pfizer maceuticals Japan Ltd., and personal fees from side the submitted work. S.K. reports grants from Japan Inc., Bayer Yakuhin, Ltd., and Shionogi & ASKA Pharmaceutical Co., Ltd., Chugai Pharma- Shionogi & Co., Ltd. during the conducting of the Co., Ltd. outside the submitted work. T.S. reports ceutical Co., Ltd., Taisho Toyama Pharmaceutical study. K.K. reports grants and personal fees from personal fees and nonfinancial support from Co., Ltd., Toa Eiyo Ltd., Ono Pharmaceutical Co., Shionogi & Co., Ltd. during the conducting of the Shionogi & Co., Ltd. during the conducting of Ltd., Medtronic Japan Co., Ltd., and Mochida study. M.Ki. reports grants and personal fees the study. S.Sh. reports personal fees and non- Pharmaceutical Co., Ltd. outside the submitted from Shionogi & Co., Ltd. during the conducting financial support from Shionogi & Co., Ltd. during work. Y.E. reports nonfinancial support from of the study and grants and personal fees from the conducting of the study. M.S. reports per- fi fi Shionogi & Co., Ltd. during the conducting of Astellas Pharma Inc., Sano K.K., P zer Japan Inc., sonal fees and nonfinancial support from the study. H.F. reports other fees (consultant) Ono Pharmaceutical Co., Ltd., Novartis Pharma Shionogi & Co., Ltd. during the conducting of from Mehergen Group Holdings, Inc. outside the K.K., Mitsubishi Tanabe Pharma Corp., Kyowa the study. S.Su. reports personal fees from Shio- submitted work. J.H. reports grants and personal Hakko Kirin Co., Ltd., Abbott Japan Co., Ltd., nogi & Co., Ltd. during the conducting of the fees from Shionogi & Co., Ltd. during the con- and Otsuka Pharmaceutical Co., Ltd., grants study and grants from the Ministry of Education, ducting of the study and grants and personal fees from the Japanese government, Japan Heart Culture, Sports, Science and Technology in Japan from Astellas Pharma Inc., Nippon Boehringer Foundation, Japan Cardiovascular Research Foun- outside the submitted work. Y.T. reports personal Ingelheim Co., Ltd., Mochida Pharmaceutical dation, Calpis Co., Ltd., and Nihon Kohden Corp., fees from Shionogi & Co., Ltd. during the con- Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Phar- and personal fees from Daiichi Sankyo Co., Ltd., ducting of the study and grants and personal fees maceutical Co., Ltd., Sumitomo Dainippon Bayer Yakuhin Ltd., Nippon Boehringer Ingelheim from Astellas Pharma Inc., AstraZeneca K.K., Bayer Pharma Co., Ltd., MSD K.K., Teijin Pharma Ltd., Co., Ltd., Kowa Pharmaceutical Co., Ltd., Sumitomo Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Sumitomo Actelion Pharmaceuticals Japan Ltd., Otsuka Phar- Dainippon Pharma Co., Ltd., Sawai Pharma- Dainippon Pharma Co., Ltd., Eli Lilly and Company maceutical Co., Ltd., Novartis Pharma K.K., and ceutical Co., Ltd., MSD K.K., Shionogi & Co., Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Sanwa Kagaku Kenkyusho Co., Ltd. outside the Ltd., AstraZeneca K.K., Asahi Kasei Medical Co., Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., fi submitted work. K.-i.H. reports personal fees and Ltd., Novo Nordisk Pharma Ltd., Fuji lm RI Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corp., fi non nancial support from Shionogi & Co., Ltd. Pharma Co., Ltd., and Japan Medical Data outside Nippon Boehringer Ingelheim Co., Ltd., Novo during the conducting of the study and grants and the submitted work. T.K. reports grants and Nordisk Pharma Ltd., Ono Pharmaceutical Co., personal fees from Daiichi Sankyo Co., Ltd. and personal fees from Shionogi & Co., Ltd. during Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi Mochida Pharmaceutical Co., Ltd., grants from the conducting of the study and grants and K.K., Shionogi & Co., Ltd., Taisho Toyama Phar- Actelion Pharmaceuticals Japan Ltd., Eisai Co., personal fees from Daiichi Sankyo Co., Ltd. and maceutical Co., Ltd., and Takeda Pharmaceutical Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Bayer Yakuhin Ltd. and grants from MSD K.K., Co., Ltd. and personal fees from Novartis Pharma Dainippon Pharma Co., Ltd., Takeda Pharmaceu- Novartis Pharma K.K., Astellas Pharma Inc., and K.K. outside the submitted work. H.T. reports fi tical Co. Ltd., Nippon Boehringer Ingelheim Co., P zer Japan Inc. outside the submitted work. M. personal fees and nonfinancial support from Ltd., Bayer Yakuhin, Ltd., Sysmex Corp., Med- Ku. reports personal fees from Shionogi & Co., Shionogi & Co., Ltd. during the conducting of tronic Japan Co., Ltd., and St. Jude Medical Japan Ltd. during the conducting of the study and grants the study and grants and personal fees from Co., Ltd., and personal fees from Kowa Pharma- and personal fees from Shionogi & Co., Ltd. Daiichi Sankyo Co., Ltd. and Takeda Pharmaceu- ceutical Co., Ltd. outside the submitted work. S.Is. outside the submitted work. K.M. reports other tical Co., Ltd., grants from Novartis Pharma K.K. reports grants and personal fees from Shionogi & (meeting attendance fee) from Shionogi & Co., and Astellas Pharma Inc., and personal fees from Co., Ltd. during the conducting of the study and Ltd. during the conducting of the study. T.Mura. MSD K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer grants and personal fees from Amgen Astellas reports personal fees from Shionogi & Co., Ltd. Japan Inc., Mitsubishi Tanabe Pharma Corp., BioPharma K.K., Astellas Pharma Inc., Daiichi during the conducting of the study. T.Muro. Teijin Pharma Ltd., Nippon Boehringer Ingelheim Sankyo Co., Ltd., Eli Lilly and Company Japan reports personal fees from Shionogi & Co., Ltd. Co., Ltd., Bayer Yakuhin, Ltd., and Bristol-Myers K.K., Kowa Pharmaceutical Co., Ltd., Nippon during the conducting of the study and grants and Squibb outside the submitted work. K.Ue. reports Boehringer Ingelheim Co., Ltd., Kissei Pharmaceu- personal fees from Daiichi Sankyo Co., Ltd., Pfizer other (contracted work) from Shionogi & Co., Ltd. tical Co., Ltd., MSD K.K., Novartis Pharma K.K., Japan Inc., Kowa Pharmaceutical Co., Ltd., MSD during the conducting of the study and personal Mitsubishi Tanabe Pharma Corp., Ono Pharma- K.K., and Mitsubishi Tanabe Pharma Corp. and fees from Shionogi & Co., Ltd. outside the sub- ceutical Co. Ltd., Sanofi K.K., Takeda Pharmaceu- personal fees from AstraZeneca K.K. outside the mitted work. K.Ut. reports personal fees and tical Co., Ltd., Taisho Toyama Pharmaceutical Co., submitted work. K.No. reports nonfinancial sup- nonfinancial support from Shionogi & Co., Ltd. Ltd., and Teijin Pharma Ltd., grants from Fujifilm port from Shionogi & Co., Ltd. during the con- during the conducting of the study and grants Pharma Co., Ltd., Sumitomo Dainippon Pharma ducting of the study. S.O. reports personal fees from Sanofi K.K., MSD K.K., Taisho Toyama Phar- Co., Ltd., and Kyowa Hakko Kirin Co., Ltd., and and nonfinancial support from Shionogi & Co., maceutical Co., Ltd., Nippon Boehringer lngel- personal fees from AstraZeneca K.K., Bayer Ltd. during the conducting of the study. Y.Sa. heim Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yakuhin, Ltd., Novo Nordisk Pharma Ltd., Pfizer reports grants, personal fees, and nonfinancial Eli Lilly and Company Japan K.K., and Novo Japan Inc., and Sanwa Kagaku Kenkyusho Co., Ltd. support from Shionogi & Co., Ltd. during the Nordisk Pharma Ltd. outside the submitted outside the submitted work. T.I. reports personal conducting of the study and grants, personal work. M.Ya. reports personal fees from Shionogi fees and nonfinancial support from Shionogi & fees, and other (advisory boards) from MSD & Co., Ltd. during the conducting of the study and Co., Ltd. during the conducting of the study K.K., Ono Pharmaceutical Co., Ltd., Mitsubishi other (donation) from Shionogi & Co., Ltd. out- and grants and personal fees from Sanofi K.K., Tanabe Pharma Corp., Pfizer Japan Inc., and side the submitted work. T.Y. reports other (lec- Sumitomo Dainippon Pharma Co., Ltd., and Daiichi Novartis Pharma K.K., grants and personal fees ture fee) from Shionogi & Co., Ltd. during the Sankyo Co., Ltd., grants from Takeda Pharmaceu- from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, conducting of the study. S.Y. reports other (con- tical Co., Ltd. and Mitsubishi Tanabe Pharma Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo tracted work) from Shionogi & Co., Ltd. during the Corp., and personal fees from Astellas Pharma Dainippon Pharma Co., Ltd., Astellas Pharma Inc., conducting of the study. K.Yok. reports personal Inc., AstraZeneca K.K., and MSD K.K. outside the and Takeda Pharmaceutical Co., Ltd., and grants fees from Shionogi & Co., Ltd. during the con- submitted work. S.It. reports grants, personal from Baxter Ltd., Kyowa Hakko Kirin Co., Ltd., ducting of the study and grants, personal fees, fees, and nonfinancial support from Shionogi & Teijin Pharma Ltd., Eisai Co., Ltd., Zeria Pharma- and nonfinancial support from MSD K.K., grants Co., Ltd. during the conducting of the study. A.K. ceutical Co., Ltd., Nihon Medi-Physics Co., Ltd., and personal fees from Astellas Pharma Inc., reports personal fees and nonfinancial support Chugai Pharmaceutical Co., Ltd., Genzyme Japan Daiichi Sankyo Co., Ltd., Sumitomo Dainippon from Shionogi & Co., Ltd. during the conducting K.K., and Medtronic Japan Co., Ltd. outside the Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., of the study and personal fees from Astellas submitted work. Y.Se. reports personal fees from Mochida Pharmaceutical Co., Ltd., Nippon 1284 Intensive Statin Therapy in High-Risk Patients Diabetes Care Volume 41, June 2018

Boehringer lngelheim Co., Ltd., Ono Pharmaceu- 2. Sone H, Tanaka S, Tanaka S, et al.; Japan 13. Colhoun HM, Betteridge DJ, Durrington PN, tical Co., Ltd., Pfizer Japan Inc., Shionogi & Co., Diabetes Complications Study Group. Serum level et al.; CARDS investigators. Primary prevention Ltd., Taisho Toyama Pharmaceutical Co., Ltd., of triglycerides is a potent risk factor comparable of cardiovascular disease with atorvastatin in Takeda Pharmaceutical Company Ltd., and Mitsubishi to LDL cholesterol for coronary heart disease in type 2 diabetes in the Collaborative Atorvastatin Tanabe Pharma Corp., grants from Bristol-Myers Japanese patients with type 2 diabetes: subanal- Diabetes Study (CARDS): multicentre randomised Squibb, Eli Lilly and Company Japan K.K., Teijin ysis of the Japan Diabetes Complications Study placebo-controlled trial. Lancet 2004;364:685–696 Pharma Ltd., and Toyama Chemical Co., Ltd., and (JDCS). J Clin Endocrinol Metab 2011;96:3448– 14. Sever PS, Poulter NR, Dahlof¨ B, et al. Re- personal fees from AstraZeneca K.K., Eisai Co., 3456 duction in cardiovascular events with atorvas- Ltd., Kowa Company, Ltd., Kowa Pharmaceutical 3. Gaede P, Pedersen O. Intensive integrated ther- tatin in 2,532 patients with type 2 diabetes: Co., Ltd., Sanofi K.K., and Sanwa Kagaku Ken- apy of type 2 diabetes: implications for long-term Anglo-Scandinavian Cardiac Outcomes Trial– – kyusho Co., Ltd. outside the submitted work. K. prognosis. Diabetes 2004;53(Suppl. 3):S39 S47 lipid-lowering arm (ASCOT-LLA). Diabetes Care fi Yos. reports personal fees and non nancial sup- 4. Kearney PM, Blackwell L, Collins R, et al.; 2005;28:1151–1157 ’ port from Shionogi & Co., Ltd. during the con- Cholesterol Treatment Trialists (CTT) Collaborators. 15.CollinsR,ArmitageJ,ParishS,SleighP,Peto fi ducting of the study. M.Yo. reports grants and Ef cacy of cholesterol-lowering therapy in 18,686 R; Heart Protection Study Collaborative Group. people with diabetes in 14 randomised trials of personal fees from Shionogi & Co., Ltd. outside MRC/BHF Heart Protection Study of cholesterol- statins: a meta-analysis. Lancet 2008;371:117–125 the submitted work. N.Y. reports personal fees lowering with simvastatin in 5963 people with 5. Kramer CK, Rodrigues TC, Canani LH, Gross JL, from Shionogi & Co., Ltd. during the conducting diabetes: a randomised placebo-controlled trial. Azevedo MJ. Diabetic retinopathy predicts all- of the study and personal fees from Shionogi & Lancet 2003;361:2005–2016 cause mortality and cardiovascular events in Co., Ltd. outside the submitted work. K.Na. re- 16. Ogawa H, Nakayama M, Morimoto T, et al.; both type 1 and 2 diabetes: meta-analysis of ports other (contracted) work from Shionogi & Japanese Primary Prevention of Atherosclerosis Co., Ltd. during the conducting of the study and observational studies. Diabetes Care 2011;34: 1238–1244 With Aspirin for Diabetes (JPAD) Trial Investiga- grants from Takeda Pharmaceutical Co., Ltd. and tors. Low-dose aspirin for primary prevention Fujifilm Pharma Co., Ltd. outside the submitted 6. Ohno T, Kinoshita O, Fujita H, et al. Detecting occult coronary artery disease followed by early of atherosclerotic events in patients with type 2 work. R.N. reports personal fees from Shionogi & diabetes: a randomized controlled trial. JAMA Co., Ltd. during the conducting of the study and coronary artery bypass surgery in patients with diabetic retinopathy: report from a diabetic ret- 2008;300:2134–2141 personal fees from Astellas Pharma Inc., Sumi- 17. Cannon CP, Blazing MA, Giugliano RP, et al.; tomo Dainippon Pharma Co., Ltd., MSD K.K., Ono inocoronary clinic. J Thorac Cardiovasc Surg 2010; 139:92–97 IMPROVE-IT Investigators. Ezetimibe added to Pharmaceutical Co. Ltd., Kowa Pharmaceutical Co., 7. Baigent C, Blackwell L, Emberson J, et al.; statin therapy after acute coronary syndromes. Ltd., Mitsubishi Tanabe Pharma Corp., Nippon Cholesterol Treatment Trialists’ (CTT) Collabora- N Engl J Med 2015;372:2387–2397 Boehringer Ingelheim Co., Ltd., Toa Eiyo Ltd., Eisai tion. Efficacy and safety of more intensive low- 18. Baigent C, Keech A, Kearney PM, et al.; Co., Ltd., and Nippon Chemiphar Co., Ltd. outside ering of LDL cholesterol: a meta-analysis of data Cholesterol Treatment Trialists’ (CTT) Collabora- the submitted work. No other potential conflicts of from 170,000 participants in 26 randomised trials. tors. Efficacy and safety of cholesterol-lowering interest relevant to this article were reported. Lancet 2010;376:1670–1681 treatment: prospective meta-analysis of data Author Contributions. H.I., I.K., H.F., T.Muro., 8. Stone NJ, Robinson JG, Lichtenstein AH, et al.; from 90,056 participants in 14 randomised and T.Y. designed the study, collected and inter- American College of Cardiology/American Heart trials of statins. Lancet 2005;366:1267–1278 preted data, and contributed to the writing. M.T. Association Task Force on Practice Guidelines. 19. Sabatine MS, Giugliano RP, Keech AC, et al.; collected and analyzed data and contributed to 2013 ACC/AHA guideline on the treatment of the writing. T.A., J.H., T.I., A.K., M.Ki., T.K., M.Ku., FOURIER Steering Committee and Investigators. blood cholesterol to reduce atherosclerotic car- K.No., S.O., Y.Sa., Y.Se., T.S., S.Sh., and S.Y. in- Evolocumab and clinical outcomes in patients diovascular risk in adults: a report of the American terpreted data. H.D. and K.Ut. designed the study with cardiovascular disease. N Engl J Med 2017; College of Cardiology/American Heart Association – and collected and interpreted data. Y.E. collected 376:1713 1722 Task Force on Practice Guidelines [published cor- data. K.-i.H., S.It., S.Su., K.Yok., and K.Na. designed 20. Bowman L, Hopewell JC, Chen F, et al.; HPS3/ rection appears in J Am Coll Cardiol 2014;63:3024– the study and interpreted data. S.Is., K.K., Y.T., and TIMI55–REVEAL Collaborative Group. Effects of 3025, 2015;66:2812]. J Am Coll Cardiol 2014;63 M.Ya. collected and interpreted data and contrib- anacetrapib in patients with atherosclerotic vas- (25 Pt. B):2889–2934 uted to the writing. S.K. designed the study, col- cular disease. N Engl J Med 2017;377:1217–1227 9. Ueshima K, Itoh H, Kanazawa N, et al.; lected data, and contributed to the writing. K.M. 21. Amarenco P, Bogousslavsky J, Callahan A 3rd, EMPATHY study group. Rationale and design of designed the study and collected data. T.Mura. et al.; Stroke Prevention by Aggressive Reduction the standard versus intEnsive statin therapy for designed the study. M.S. collected data and con- in Cholesterol Levels (SPARCL) Investigators. hypercholesteroleMic Patients with DiAbetic tributed to the writing. H.T. and N.Y. interpreted High-dose atorvastatin after stroke or transient RetinopaTHY (EMPATHY) study: a randomized data and contributed to the writing. K.Ue. and R.N. ischemic attack. N Engl J Med 2006;355:549–559 controlled trial. J Atheroscler Thromb 2016;23: designed the study, interpreted data, and contrib- 22. Hosomi N, Nagai Y, Kohriyama T, et al.; J-STARS 976–990 uted to the writing. K.Yos. and M.Yo. collected and Collaborators. The Japan Statin Treatment Against 10. Brunzell JD, Davidson M, Furberg CD, et al.; interpreted data. All authors read the drafted man- American Diabetes Association; American College Recurrent Stroke (J-STARS): a multicenter, ran- uscript, provided feedback, and approved the final of Cardiology Foundation. Lipoprotein manage- domized, open-label, parallel-group study. EBio- version of the manuscript. H.I. is the guarantor of – ment in patients with cardiometabolic risk: con- Medicine 2015;2:1071 1078 this work and, as such, had full access to all the data sensus statement from the American Diabetes 23. Goldstein LB, Amarenco P, Szarek M, et al.; in the study and takes responsibility for the integrity Association and the American College of Cardi- SPARCL Investigators. Hemorrhagic stroke in the of the data and the accuracy of the data analysis. ology Foundation. Diabetes Care 2008;31:811– Stroke Prevention by Aggressive Reduction in Choles- This study was presented at Prior Presentation. 822 terol Levels study. Neurology 2008;70:2364–2370 the European Society of Cardiology Congress 2017 11. Teramoto T, Sasaki J, Ueshima H, et al. Ex- 24. Rajpathak SN, Kumbhani DJ, Crandall J, Hot Line session, , Spain, 29 August 2017. ecutive summary of Japan Atherosclerosis Society Barzilai N, Alderman M, Ridker PM. Statin therapy (JAS) guideline for diagnosis and prevention of and risk of developing type 2 diabetes: a meta- References atherosclerotic cardiovascular diseases for Japa- analysis. Diabetes Care 2009;32:1924–1929 1. Turner RC, Millns H, Neil HA, et al. Risk factors nese. J Atheroscler Thromb 2007;14:45–50 25. Sattar N, Preiss D, Murray HM, et al. Statins for coronary artery disease in non-insulin dependent 12. Sandhu S, Wiebe N, Fried LF, Tonelli M. and risk of incident diabetes: a collaborative meta- diabetes mellitus: United Kingdom Prospective Di- Statins for improving renal outcomes: a meta- analysis of randomised statin trials. Lancet 2010; abetes Study (UKPDS: 23). 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