Diabetes Care Volume 41, November 2018 e145

RESPONSE TO COMMENT ON ITOH ET AL. Intensive Treat-to-Target Statin Therapy Hiroshi Itoh,1 Kenji Ueshima,2 and Issei Komuro3 in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. Diabetes Care 2018;41:1275–1284 Diabetes Care 2018;41:e145–e146 | https://doi.org/10.2337/dci18-0028

We thank Donzelli et al. (1) for their premature to discuss risks and benefits myocardial infarction. Among the soft interest in our article (2). The report of from our current data based on numer- end points, unstable angina was more the EMPATHY study (2) showed no sig- ical differences in the actual values be- common in the intensive group, coro- nificant difference between the intensive tween the two groups. nary angioplasty was more common in group and the standard group for the Donzelli et al. (1) pointed to a J-curve the standard group, and the incidence primary end point, but the difference was association between LDL-C and total of coronary artery bypass grafting was significant for cerebral events, which was mortality, citing the Lipid Interven- nearly the same in both groups. Based one of the secondary end points. Our tion Trial (J-LIT) study (4) as an example. on these findings, we discounted the study did not adjust for multiplicity of However, because J-LIT is a cohort study, it likelihood of overestimation of event in- secondary end points. We thus agree includes potential risks such as reversal of cidence due to overdiagnosis in the stan- with the authors of the letter (1) that cause and effect (5). We feel that direct dard group. these results do not provide substantial comparison of the J-LIT findings with We appreciate this opportunity to evidence that aggressive LDL cholesterol those from randomized controlled trials discuss the implications of our findings. (LDL-C)–lowering therapy prevents cere- such as the EMPATHY study may be prob- bral events. This is why we identified our lematic and would like to point out that investigation of cerebral events as an meta-analysis has shown no increase in Acknowledgments. EDIT, Inc. (Tokyo, Japan) exploratory analysis. mortality from statin intervention to ag- provided medical writing and editing. Our study focused particularly on the gressively lower LDL-C (6). Funding and Duality of Interest. The EMPATHY study was supported by Shionogi & Co., Ltd. H.I. assessment of effects of stains on ath- The EMPATHY study was designed to reports grants and personal fees from Shionogi & erosclerotic events. Thus, we established evaluate the effects of a treat-to-target Co., Ltd. during the conduct of the study and grants

the secondary end point of stroke (ce- approach to lipid management. As such, and personal fees from Takeda Pharmaceutical e-LETTERS rebral infarction, cerebral hemorrhage, the study was not blinded but instead Company Limited, Nippon Boehringer Ingelheim subarachnoid hemorrhage) and assessed used prospective randomized open-label Co., Ltd., Company, Limited, MSD K.K., Mitsubishi Tanabe Pharma Corporation, the data within that context. We believe blinded end point (PROBE) methodology. Shionogi & Co., Ltd., and Taisho Toyama Pharma- – that our findings support those of pre- This imposes a number of limitations on ceutical Co., Ltd.; grants from Sumitomo Dainippon RESPONSES AND COMMENTS vious studies (3) that statins do not the study, which of course means that Pharma Co., Ltd., Inc., Kyowa contribute to increases in hemorrhagic care must be taken when interpreting the Hakko Kirin Co., Ltd., Pharma Limited, Mo- stroke. results. For example, as the authors of chida Pharmaceutical Co., Ltd., Ono Pharmaceu- tical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Just as for the primary end point, we the letter point out, the unblinded nature Eli Lilly Japan K.K.; and personal fees from Nipro found no statistically significant differ- of the study raises the potential issue of Corporation and SBI Pharmaceuticals Co., Ltd. out- ence in deaths from any cause or in serious soft end points (7). However, in this study side the submitted work. K.U. reports other (con- adverse drug reactions between the in- if we look at the cardiac events that were tracted work) from Shionogi & Co., Ltd. during the conduct of the study and personal fees from tensive and standard treatment groups. included within the primary end point, Shionogi & Co., Ltd. outside the submitted work. Because we did not find statistical sig- the intergroup results were compara- I.K. reports personal fees from Shionogi & Co., Ltd. nificance, we feel that it is probably ble to those for the hard end point of during the conduct of the study and grants and

1Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine, Tokyo, Japan 2Department of EBM Research, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan 3Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan Corresponding author: Hiroshi Itoh, [email protected]. © 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. e146 Response Diabetes Care Volume 41, November 2018

personal fees from Takeda Pharmaceutical Com- study. Diabetes Care 2018;41:1275–1284 (Letter). hypercholesterolemia. Circ J 2002;66:1087– pany Limited, Nippon Boehringer Ingelheim Co., Diabetes Care 2018;41:e143–e144. DOI: 10.2337/ 1095 Ltd., Astellas Pharma Inc., Daiichi Sankyo Com- dc18-1358 5. Okamura T, Kadowaki T, Hayakawa T, Kita Y, pany, Limited, and Co., Ltd. 2. Itoh H, Komuro I, Takeuchi M, et al.; EMPATHY Okayama A, Ueshima H; Nippon Data80 Re- and grants from MSD K.K., Shionogi & Co., Ltd., Investigators. Intensive treat-to-target statin search Group. What cause of mortality can GlaxoSmithKline K.K., Sanofi K.K., Genzyme Japan K.K., therapy in high-risk Japanese patients with hyper- we predict by cholesterol screening in the Jap- SumitomoDainippon Pharma Co., Ltd., Mitsubishi cholesterolemia and diabetic retinopathy: report anese general population? J Intern Med 2003; Tanabe Pharma Corporation, and Bristol-Myers of a randomized study. Diabetes Care 2018;41: 253:169–180 Squibb outside the submitted work. No other 1275–1284 6. Baigent C, Blackwell L, Emberson J, et al.; potential conflicts of interest relevant to this ar- 3. McKinney JS, Kostis WJ. Statin therapy and the Cholesterol Treatment Trialists’ (CTT) Collabora- ticlewerereported. risk of intracerebral hemorrhage: a meta-analysis tion. Efficacy and safety of more intensive low- of 31 randomized controlled trials. Stroke 2012; ering of LDL cholesterol: a meta-analysis of data References 43:2149–2156 from 170,000 participants in 26 randomised 1. Donzelli A, Schivalocchi A, Giudicatti G, 4. Matsuzaki M, Kita T, Mabuchi H, et al.; J-LIT trials. Lancet 2010;376:1670–1681 Battaggia A. Comment on Itoh et al. Intensive Study Group. Large scale cohort study of the 7. Ferreira-Gonzalez´ I, Busse JW, Heels-Ansdell D, treat-to-target statin therapy in high-risk Jap- relationship between serum cholesterol con- et al. Problems with use of composite end points in anese patients with hypercholesterolemia and centration and coronary events with low-dose cardiovascular trials: systematic review of rando- diabetic retinopathy: report of a randomized simvastatin therapy in Japanese patients with mised controlled trials. BMJ 2007;334:786–792