SUPPLEMENTARY DATA Contents Leadership and …care.diabetesjournals.org/content/diacare/suppl/2018/04/05/dc17... · SUPPLEMENTARY DATA ©2018 American Diabetes Association. Published

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©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc17-2224/-/DC1

Contents Leadership and Investigators 2 Inclusion and Exclusion Criteria 6 Primary and Secondary Endpoints 8 Definitions of Endpoints 9 Definitions related to adverse events 11 Supplementary Figures Figure S1: Patient Flowchart 12 Figure S2: Changes in LDL-C Parameters Over Time 13 Figure S3: Non-lipid Parameters Over Time 14 Figure S4: Subgroup Analysis 15 Figure S5: Cumulative Event Curves for the 3-point MACE and the Primary Endpoint Excluding Renal Events (Exploratory Results) 16 Figure S6: EMPATHY Findings in Relation to CTT and Primary Prevention Study with Diabetes (Exploratory Results) 17 Figure S7: Trend Analysis for Primary Endpoint, in Subgroups Based on Mean LDL-C Level During Treatment (Exploratory Results) 18 Supplementary Tables Table S1: Mean Dose by Statin Type at Baseline and Last Visit 19 Table S2: Time Course of Lipid Parameters (TC, LDL-C, HDL-C, TG) 20 Table S3: Details of Each Event for Primary and Secondary Endpoints 21 Table S4: Change and %Change in CKD Parameters (Baseline vs. Month 36) 23

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Leadership and Investigators Principal Investigators: Hiroshi Itoh and Issei Komuro. Supervisors: Ryozo Nagai and Kazuwa Nakao. Steering Committee: Yoshiki Egashira, Jitsuo Higaki, Shun Ishibashi, Sadayoshi Ito, Atsunori Kashiwagi, Satoshi Kato, Masafumi Kitakaze, Masahiko Kurabayashi, Toyoaki Murohara, Koichi Node, Yoshihiko Saito, Masahiro Sugawara, Yasuo Terauchi, Hiroyuki Tsutsui, Shoei Yo, Michihiro Yoshimura, Nagahisa Yoshimura. Protocol Committee: Hideo Fujita, Ken-ichi Hirata, Katsumi Miyauchi, Tomoaki Murakami, Seigo Sugiyama, Kenji Ueshima,* Kazunori Utsunomiya, Tsutomu Yamazaki,* Koutaro Yokote. ( *: Chair) Statistical analysis: Masahiro Takeuchi. Event Evaluation Committee: Takashi Akasaka, Hiroyuki Daida, Takaaki Isshiki, Kazuo Kitagawa, Takanari Kitazono, Susumu Ogawa, Yoshihiko Seino, Takashi Shigeeda, Shunya Shindo, Masakazu Yamagishi,* Kiyoshi Yoshida. ( *: Chair) Independent Data Monitoring Committee: Tatsuro Ishibashi, Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University; Yasushi Saito,* Chiba University Graduate School of Medicine; Lee-Jen Wei, Harvard School of Public Health; Junichi Yoshikawa, Nishinomiya Watanabe Cardiovascular Center. ( *: Chair) Data Center: Mebix, Inc., Tokyo, Japan. Investigators: Aya Abe, Toshiyuki Abe, Norio Abiru, Ken-ichi Aihara, Nobuyuki Aizawa, Masaki Akahata, Hiroshi Akahori, Etsuko Akita, Kazumi Akiyama, Kuniki Amano, Jiro Ando, Jiichi Anzai, Hiromi Aoki, Keiko Arai, Masaru Arai, Tadashi Arai, Yoshiyuki Arai, Atsushi Araki, Zenei Arihara, Tetsuro Arimura, Shingo Asahara, Nobuteru Asahi, Takayuki Asahina, Taro Asakura, Akira Asano, Hiroshi Asano, Shogo Asano, Keiko Ashidate, Katsumi Aso, Kazuyoshi Aso, Keita Ato, Hiroshi Awasaki, Nobuyuki Azuma, Hidenori Bando, Yukihiro Bando, Toru Chiba, Rina Chin, Michiko Chosa, Hisashi Daido, Hirosuke Danno, Shuji Dodo, Kenji Doi, Kentaro Doi, Masatoshi Domen, Kenichi Doniwa, Kenji Dote, Isao Ebihara, Toyohisa Eguchi, Genshi Egusa, Yoichi Ehara, Mikiko Endo, Hiromitsu Enomoto, Tetsuya Enomoto, Kazuhiro Eto, Masahiro Eto, Hitomi Fujii, Yasuhiro Fujii, Makiko Fujikawa, Hiroshi Fujimoto, Yukari Fujimura, Kazuo Fujisawa, Motohiro Fujita, Nobuhiko Fujita, Hitoshi Fujiwara, Machiko Fukamizu, Yuka Fukazawa, Gen Fukuda, Ken Fukuda, Naofumi Fukuda, Nobuo Fukuda, Shuichi Fukuda, Masataka Fukue, Takeshi Fukui, Toshiki Fukui, Yoshihide Fukumoto, Takashi Fukushima, Kumiko Furui, Kenji D Furukawa, Toyokazu Furumoto, Nobutoshi Fushimi, Hajime Goichi, Shigeki Gondo, Hiromasa Goto, Shinobu Goto, Takashi Goto, Yoshie Goto, Koro Gotoh, Tatsuya Haga, Shigeru Hagimoto, Tomomi Hakoda, Yutaka Hamano, Masao Hanaki, Hisato Hara, Masumi Hara, Yasuhiko Hara, Hirofumi Harada, Kazuhiro Harada, Atsushi Hasegawa, Hisayoshi Hasegawa, Koichi Hasegawa, Yasuhiro Hashiguchi, Kunihiko Hashimoto, Naotake Hashimoto, Yoshiaki Hashimoto, Sumiko Hasumi, Katsuhiro Hatao, Masahiro Hatazaki, Yuji Hatsushika, Satomi Hayakawa, Tetsuo Hayakawa, Hitoshi Hayashi, Masayuki Hayashi, Tatsunobu Hayashi, Tsutomu Hayashi, Kazuyuki Hida, Senshu Hifumi, Takayuki Higashi, Hiroshi Higashihara, Yoshiki Hirabayashi, Yoshio Hiraiwa, Kazuhiro Hiramine, Tsutomu Hirano, Kanna Hirasawa, Hiromi Hirata, Tadanori Hirata, Hiroyoshi Hirayama, Yoshihide Hirohata, Kenichi Hirose, Hisayoshi Hirota, Naoko Hisakawa, Toru Hiyoshi, Yasuko Hori, Yuhji Hori, Hiroaki Horie, Shuji Horinouchi, Tetsuo Hoshino, Akiko Hosokawa, Kazuhiro Hosokawa, Takeshi Hosoya, Kaori Hosoyamada, Yoshisuke Hotchi, Myung Woo Hwang, Toshiki Ichimori, Yumiko Ide, Masahiko Igarashi, Kiyoshi Iha, Junpei Iinuma, Takashi Iizuka, Motoyoshi Ikebuchi, Hiroshi Ikegami,

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Yasuhide Ikenaka, Kiyomitsu Ikeoka, Hideya Imai, Tatsuro Imajima, Minoru Imamura, Haruyo Imanari, Shinobu Imoto, Takeshi Inazawa, Ikuo Inoue, Mamoru Inoue, Mari Inoue, Masanori Inoue, Takeshi Inoue, Tatsuhide Inoue, Kenichi Ishibashi, Ryoichi Ishibashi, Kazufumi Ishida, Keiichi Ishida, Yasushi Ishigaki, Motoyuki Ishiguro, Hisamitsu Ishihara, Hajime Ishii, Hiroyuki Ishii, Masashi Ishikawa, Naoto Ishikawa, Norikazu Ishikawa, Masahiko Ishimura, Akihiro Isogawa, Yukinori Isomura, Motohide Isono, Naoki Itabashi, Tokushichi Itai, Yasunori Itakura, Midoriko Itano, Chikako Ito, Junko Ito, Shun Ito, Toru Ito, Takahiko Iuchi, Yasushi Iwaita, Gensho Iwami, Suzuko Iwami, Tomoyuki Iwasaki, Fumiko Iwashima, Masatora Iwashina, Michihiro Iwata, Miwa Izaki, Kiyohiro Izumino, Kiyoshi Izumino, Yumi Jimbu, Kenji Kahara, Shoko Kajiya, Hitoshi Kakimoto, Fumitaka Kamada, Tetsuro Kamada, Hiroki Kamata, Nozomu Kamei, Takashi Kamiyama, Reibun Kanbara, Tsugiyasu Kanda, Hirosumi Kaneko, Yoshihito Kaneko, Masahiro Kaneshige, Mizuki Kaneshiro, Hiroyuki Kanno, Yuya Karube, Jin Kasahara, Yasushi Kasai, Soji Kasayama, Toshiyuki Kashiwagi, Hiromi Kato, Masakazu Kato, Sumio Kato, Taiya Katoh, Yasuhiro Katsura, Ikkyo Kawa, Toshihiro Kawabata, Ichiro Kawada, Kimiko Kawada, Toshio Kawada, Yasuhiko Kawade, Naoki Kawai, Toru Kawai, Shigeru Kawaida, Masahiro Kawakami, Akitoshi Kawakubo, Hideyasu Kawamura, Mitsunobu Kawamura, Tomonori Kawano, Satsuki Kawasaki, Yukinori Kawase, Kunihiro Kawashima, Osamu Kawashima, Kazuko Kawata, Hidenori Kido, Hajime Kihara, Noriyuki Kikuchi, Ryo Kikuchi, Takashi Kikuchi, Osamu Kimura, Shiro Kimura, Yuusuke Kimura, Mitsuo Kina, Saori Kinami, Kei Kiribayashi, Kiyohiko Kishi, Shiroshi Kitagawa, Hirohiko Kitakawa, Haruko Kitaoka, Kenichi Kobayashi, Kenji Kobayashi, Kunihisa Kobayashi, Kyoko Kobuke, Tetsuya Kogawa, Sawako Koishi, Kuniyoshi Kojima, Hitoshi Komaki, Rieko Komi, Manabu Komiyama, Yoshimi Komizo, Tadamitsu Komori, Eri Kondo, Hiroyasu Konishi, Ichiro Konno, Tadashi Konoshita, Hiroyuki Konya, Keisuke Kosugi, Kei Kotani, Hiroshi Kouno, Teruo Kowatari, Daisuke Koya, Kazunori Koyama, Kunihiko Koyama, Takeshi Kubota, Norishige Kudo, Isao Kumagai, Yuji Kumano, Makoto Kunishige, Hisamoto Kuroda, Norimitsu Kurogi, Shigetaka Kuroki, Teruji Kurosawa, Takaaki Kusaka, Masahiko Kushima, Hiroto Kusunose, Masamichi Kuwajima,Hiroyuki Machino, Kazuo Maeda, Shuichi Maeda, Hiroshi Maegawa, Michihiro Maeshima, Toru Majima, Takeshi Maki, Shinya Makino, Hideo Manaka, Yasuyuki Maruyama, Shoji Mashiba, Izuru Masuda, Hideki Masunari, Akira Matsuba, Tatsuaki Matsubara, Sunao Matsubayashi, Akira Matsuda, Shigeaki Matsukawa, Takayuki Matsuki, Koji Matsumoto, Tomoaki Matsumoto, Izumi Matsumura, Kentaro Matsumura, Kaneyuki Matsuo, Ko Matsuo, Miyuki Matsuo, Naoki Matsuoka, Kosho Matsuura, Naotaka Matsuura, Yoshifusa Matsuura, Jun Michiura, Masahiro Mimura, Fuyuki Minagawa, Shinya Minagawa, Shirou Minagawa, Daiki Minami, Naoto Minamitani, Toyoaki Miura, Yoshitaka Miura, Munenori Miyake, Nobuyuki Miyake, Takafumi Miyake, Yutaka Miyake, Yoshihiro Miyamoto, Kazunori Miyata, Hiroyuki Miyazaki, Kazuhiro Miyazawa, Ryuichi Mizubayashi, Kenji Mizuno, Yutaka Mizushima, Masahiro Mizutani, Hisaya Mori, Masanori Mori, Masaya Mori, Tsutomu Mori, Akizuki Morikawa, Taro Morimoto, Yuko Morita, Tadashi Mugihara, Yasunari Muramatsu, Koji Murao, Satoshi Murao, Kazuya Murata, Seiji Muro, Shigeo Nagafuchi, Sho Nagai, So Nagai, Shigeru Naganuma, Tadasu Nagaoka, Takao Nagasu, Masayuki Nagata, Koji Nagayama, Kotaro Naito, Satoru Naito, Masahiro Nakada, Kazuaki Nakai, Masahide Nakai, Kouji Nakajima, Masahiro Nakajima, Shigeru Nakajima, Taichiro Nakajima, Masayuki Nakamura, Shuji Nakamura, Takaaki Nakamura, Koji Nakanishi, Toshiaki Nakanishi, Hiroki Nakano, Junko Nakano, Kimisato Nakano, Masayuki Nakano, Masayuki Nakano, Eitaro Nakashima, Misuzu Nakasone, Masaya Nakata, Shiro Nakayama, Toru Nakayama, Fumiaki Nakazawa, Mitsuyoshi Namba, Masahiko Namiki, Hiroshi Nariko, Sachiko Narita, Takako Naruo, Chigure Nawa, Tetsuji Niiya, Masamichi Niizuma, Ichiro Ninomiya, Shigeo Nishi, Yusa Nishi, Haruo Nishimura, Masato Nishimura, Keiichiro Nishino, Kiyoshi Nishino, Naonobu Nishino, Yoshihiko Nishio, Mariko Nishioka, Tomoko Nishiumi, Masato Nishiwaki, Osamu Nogi, Kazuko Nomura, Naoki Nomura, Nobuyasu Noritake, Shuichi Nozaki, Hiroyuki Numata, Tatsuya Nunohiro, Kiyoshi Oda, Yoshiaki Oda, Yukinari Odagawa, Masashi Ogawa, Takanori Ogawa, Yoshihiro Ogawa, Yoshiji Ogawa, Masaro Ogimoto, Kazuro Ogurusu, Ichiro Ohara, Hiroshi Ohashi, Makoto Ohashi, Tetsuya Ohishi, Yasuhiro Ohno, Mitsuru Ohsugi, Itsuro Ohta, Kazuyasu Ohta, Masao Ohta, Hiromasa Ohtani, Hiroshi Ohtani, Sumire Ohtani, Takayuki Ohwada, Mariko Oishi, Yutaka Oiso,

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Susumu Oka, Mizuho Okada, Setsuro Okada, Yosuke Okada, Aki Okamoto, Hideki Okamoto, Yutaka Okamoto, Hiro-oki Okamura, Ken Okano, Yasuhiro Okauchi, Tetsuji Okawa, Masumi Okawara, Hisashi Okimoto, Kohei Okita, Ken Okubo, Takeshi Okuda, Fuminobu Okuguchi, Shinichiro Okuno, Mari Okuyama, Hiroaki Omori, Takashi Omura, Yukiko Onishi, Akira Ono, Koichi Ono, Masahiro Ono, Shigemitsu Ono, Takuya Ono, Yasuhiro Ono, Yoshiaki Ono, Hikari Ooka, Tadatoshi Oomiya, Katsuya Oshima, Kayo Oshita, Akira Ota, Tsuguhito Ota, Masayuki Otaki, Fumiko Otsuka, Morihiro Ozaki, Noriyuki Ozawa, Masahide Sagara, Koumei Sagawa, Jun Saito, Kazuko Saito, Kazuyuki Saito, Shumpei Saito, Setsuya Sakagashira, Daisuke Sakaguchi, Ichiro Sakaguchi, Eiji Sakai, Naoshi Sakai, Noriko Sakamoto, Koichiro Sakota, Hiroya Sakuma, Ichiro Sakuma, Kenichi Sakurai, Shunichiro Sakurai, Hisako Sameshima, Yutaka Sasagawa, Hiromitsu Sasaki, Iwao Sasaki, Takashi Sasaki, Masataka Sata, Atsushi Sato, Kazutoshi Sato, Koichi Sato, Koichiro Sato, Naoichi Sato, Nobuyuki Sato, Takako Sato, Tatsuyuki Sato, Ken Sawada, Tadashi Sawada, Kimikazu Sawai, Hideaki Sawaki, Yoshitaka Sayo, Ikuo Segawa, Tadashi Seguchi, Hiroaki Seino, Naoto Seki, Taiji Sekigami, Naotaka Sekiguchi, Syunji Sekiguchi, Nobuo Sekine, Nobuko Sera, Yasunori Sera, Osamu Seto, Kozo Shaura, Masaaki Shibamoto, Hirotaka Shibata, Toshiro Shibata, Makoto Shibuya, Ryutaro Shigeta, Takao Shimada, Ryuji Shimamura, Ikki Shimizu, Kazuhiko Shimizu, Masashi Shimizu, Mitsuo Shimizu, Satoshi Shimizu, Masashi Shimoda, Shigeto Shimoda, Yoshio Shindo, Kouichiro Shiojima, Toshihiko Shiraiwa, Takuhiro Shirakawa, Nobuhiro Shiroyama, Yoshihito Shoda, Tetsuo Shoji, Hirohisa Shono, Hiroshi Shuto, Satoshi Soda, Kuninori Soejima, Shoichi Suemori, Minoru Suezawa, Muneki Sugata, Tatsushi Sugiura, Toru Sugiyama, Yasuhiro Sumida, Hiroshi Sunagawa, Katsuo Suyama, Hitoshi Suzuki, Susumu Suzuki, Takanori Suzuki, Tsunehito Suzuki, Haruyuki Taguchi, Shigeru Tai, Tsuyoshi Taira, Ichitaro Takada, Yoshihisa Takada, Junko Takagi, Shuichi Takagi, Yusuke Takagi, Kazuko Takahashi, Kazunori Takahashi, Kenro Takahashi, Kiyoshi Takahashi, Nobuo Takahashi, Shunsuke Takahashi, Soichiro Takahashi, Tadayoshi Takahashi, Toru Takahasi, Masato Takaki, Ichiro Takamura, Toshinari Takamura, Noriyuki Takano, Tatsuro Takano, Ken Takao, Taizo Takase, Hiroshi Takeda, Tomoo Takeda, Masanori Takeishi, Kiyoshi Takekawa, Yuji Takemoto, Ken Takenaka, Yoshio Taketani, Naohide Takeuchi, Yasuo Takeuchi, Hirofumi Takino, Toru Tamai, Kazuhiro Tamaki, Noboru Tamaki, Toshio Tamaki, Hideki Tamura, Hiroyuki Tamura, Yukihiro Tamura, Akihiko Tanaka, Hideki Tanaka, Hiroaki Tanaka, Kenji Tanaka, Masayuki Tanaka, Toru Tanaka, Toru Tanaka, Tsuyoshi Tanaka, Yasushi Tanaka, Makio Tani, Ken Tanigawa, Masato Taniguchi, Matsuo Taniyama, Toshihiro Tanzawa, Eiji Tatsumi, Noriyasu Taya, Jin Temma, Shouji Terada, Yasushi Terada, Yoshio Terada, Naoki Tezuka, Hisako Toda, Haruhiko Tokuda, Eiichi Tokutake, Kenichi Tokuyama, Takahiko Tokuyama, Katsuyuki Tome, Naruya Tomita, Yukio Tone, Rieko Totani, Jo Toyota, Tetsuo Tsubone, Akihito Tsuchida, Atsushi Tsuchiya, Hiroaki Tsuchiya, Norihiro Tsuchiya, Masahiro Tsuji, Tetsuro Tsujimoto, Motoyoshi Tsujino, Kazuhisa Tsukamoto, Taku Tsunekawa, Masatoshi Tsuru, Masahiro Tsutsui, Akihito Tsutsumi, Sachie Tsuzura, Daigaku Uchida, Yasuko Uchigata, Kazuaki Uchiyama, Hiroo Ueda, Junichi Ueda, Kazuya Ueda, Naohiko Ueda, Nobuyuki Ueda, Yasuo Ueda, Koichiro Uehara, Hiroaki Ueno, Makoto Ujihara, Fumio Umeda, Nobuo Uno, Satoshi Uramoto, Toshihiko Urushibara, Yoshihide Ushitani, Mikiya Usukura, Satoko Wada, Yutaka Wakasa, Takanobu Wakasugi, Masako Waki, Genichi Watanabe, Hitoshi Watanabe, Ikuo Watanabe, Ryouichiro Watanabe, Yoshiyuki Watanabe, Matahiro Yabuta, Ken Yaga, Kunimasa Yagi, Kenji Yaginuma, Ryuichiro Yagyu, Hiroharu Yamada, Hiroshi Yamada, Kenji Yamada, Masayo Yamada, Mitsutoshi Yamada, Satoru Yamada, Shoichi Yamada, Tetsuhiro Yamada, Tsutomu Yamada, Yoshihiko Yamada, Shigeru Yamaga, Toshiharu Yamagata, Toru Yamaguchi, Kouzaburo Yamaji, Ikuko Yamamori, Chifumi Yamamoto, Hidefumi Yamamoto, Isotoshi Yamamoto, Kenichi Yamamoto, Koji Yamamoto, Manabu Yamamoto, Masahiro Yamamoto, Yoshikazu Yamamoto, Ritsuko Yamamoto-Honda, Hidetoshi Yamashita, Iwao Yamashita, Shigeo Yamashita, Tetsuji Yamashita, Kazuhiko Yamauchi, Kenji Yamauchi, Yuichiro Yamauchi, Seiichi Yamawaki, Jun Yan, Tatsuo Yanagawa, Katsuyuki Yanagisawa, Masatoshi Yanagisawa, Toshihiko Yanase, Harumi Yano, Mayumi Yano, Yutaka Yano, Hideki Yasuda, Koichiro Yasuda, Takahiro Yazu, Mineto Yokoi, Tamotsu Yokota, Akihiro Yokoyama, Kazunori Yokoyama, Hidetada Yoshida, Katsumi Yoshida, Kenichi Yoshida, Masanori Yoshida, Reiki Yoshida, Tomoki Yoshida, Toshimi Yoshida,

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Naomi Yoshimura, Mototaka Yoshinari, Gen Yoshino, Munenori Yoshizumi, Atsuyoshi Yuhara, Masakatsu Yuito, Yasuo Yumori. Inclusion and Exclusion Criteria

Inclusion criteria 1) Inclusion criteria for the run-in period Patients who meet all of the following criteria are eligible for the run-in period. a) Have given written informed consent to participate in this study b) Age at least 30years (at the time of giving informed consent) c) Man, or woman not of child-bearing potential during the study d) Outpatient e) Hypercholesterolemia with LDL-C * ≥120mg/dL for previously untreated patients or ≥100mg/dL for those treated with a single statin† or other lipid-lowering drug f ) Type 2 diabetes g) No history of CAD (myocardial infarction, angina, or coronary revascularization) 2) Inclusion criteria for the treatment period Patients who meet the inclusion criteria for the run-in period and have documented diabetic retinopathy are eligible for the treatment period. Exclusion criteria 1) Exclusion criteria for the run-in period Patients who meet any of the following criteria are excluded from the study. a) History of hypersensitivity to statins b) History of drug-associated muscle disorder c) History of CAD (myocardial infarction, angina, or coronary revascularization) d) History of stroke (including revascularization) e) Symptomatic PAD (Fontaine class II or higher) f ) Uncontrolled hypertension with DBP ≥120mmHg or SBP ≥200mmHg, or hypertensive emergency g) New York Heart Association class IIM or higher h) Valvular heart disease with serious hemodynamic abnormality i) Hypercholesterolemia treated with two or more lipid-lowering drugs j) Familial hypercholesterolemia k) Serious coexisting illness such as malignancy tumor, or severely limited life expectancy (patients are eligible if they have received no treatment for at least 5 years and have experienced no relapse of malignancy) l ) Renal failure necessitating transplantation or dialysis m) Patient is pregnant, could be pregnant, or wishes to become pregnant during the study n) Patient is considered ineligible by the investigator 2) Exclusion criteria for the treatment period Patients who meet any of the following criteria are withdrawn from the study. a) Ischemia confirmed by resting electrocardiogram b) Aspartate aminotransferase ≥100 IU/L or alanine aminotransferase ≥100 IU/L c) Serum creatinine ≥ 2.0mg/dL or eGFR <30mL/min/1.73m2 d) Nephrotic syndrome e) Serum TG ≥1000mg/dL f ) Patient is considered ineligible by the investigator * Values were calculated using the Friedewald equation: LDL-C = total cholesterol (TC) - [high-density lipoprotein cholesterol (HDL-C) + TG/5] (when TG values were less than 400mg/dL) or obtained by direct homogeneous assay (when TG values were 400mg/dL or above). Values obtained within 3 months before obtaining informed consent can be used for assessing eligibility.

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† If patients are treated with atorvastatin, pitavastatin, or rosuvastatin, they should receive no more than the following doses: atorvastatin 10mg/day, pitavastatin 2mg/day, rosuvastatin 2.5mg/day. LDL-C, low-density lipoprotein cholesterol; CAD, coronary artery disease; PAD, peripheral artery disease; DBP, diastolic blood pressure; SBP, systolic blood pressure; eGFR, estimated glomerular filtration rate; TG, triglyceride.

Primary and Secondary Endpoints Primary endpoints The primary endpoint is the combined incidence of cardiovascular events or death related to cardiovascular events. Cardiovascular events are defined as follows. 1) Cardiac events: myocardial infarction or unstable angina requiring unscheduled hospitalization, or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) 2) Cerebral events: cerebral infarction or cerebral revascularization 3) Renal events: initiation of chronic dialysis, increase in serum creatinine level by at least 2-fold (and >1.5mg/dL) 4) Vascular events: aortic disease or PAD (aortic dissection, mesenteric artery thrombosis, severe lower limb ischemia [ulceration], revascularization, or finger/lower limb amputation caused by arteriosclerosis obliterans) Secondary endpoints The secondary endpoints are defined as follows. 1) Death from any cause 2) Individual incidence of cardiac, cerebral, renal, or vascular event as defined for the primary endpoint 3) Incidence of stroke (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage) 4) Change in laboratory variables related to chronic kidney disease (eGFR, urinary albumin, or urinary protein) 5) Safety PAD, peripheral artery disease; eGFR, estimated glomerular filtration rate

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Definitions of Endpoints

Myocardial infarction Myocardial infarction is defined as an increase in cardiac biomarkers (preferably troponin or, if unavailable, CK-MB), as well as any one of the following: • Chest pain • New ischemic ECG changes • Loss of myocardial viability or the presence of wall motion abnormality on imaging If more than 30days has elapsed since onset, evidence of any of the following: • New pathological Q wave on ECG • New myocardial thinning, loss of myocardial viability, and contractile dysfunction on imaging If pathological findings indicate the occurrence of new myocardial infarction, that occurrence will be considered to satisfy the myocardial infarction endpoint. Unstable angina requiring unscheduled hospital admission Unstable angina requiring unscheduled hospital admission is defined as the occurrence of either typical chest pains or new ischemic ECG changes, in combination with significant stenotic lesions on coronary angiogram (or filling defect evident on scintigram, if coronary angiography is not possible). This is equivalent to severity class II or III and clinical circumstances class B under the Braunwald classification of unstable angina (1989). Coronary arterial revascularization (PCI, CABG) All revascularizations by PCI or CABG will be included, unless already scheduled at the time of acquisition of informed consent. Such prescheduled procedures will be excluded from consideration. Cerebral infarction Cerebral infarction is clinically defined as new local neurological symptoms with appropriate lesions confirmed on CT or MRI (MRA). Cerebral hemorrhage Cerebral hemorrhage is clinically defined as new-onset local neurological symptoms with fresh hematoma in the cerebrum, cerebellum, and/or brain stem evident on MRI/CT scans of the head. Cerebral hemorrhage does not include cerebral infarction. Subarachnoid hemorrhage Onset is characterized by sudden headache and disturbed consciousness with bleeding and hematoma in the subarachnoid cavity or blood-stained cerebrospinal fluid evident on MRI/CT scans of the head. Cerebrovascular revascularization Carotid endarterectomy, percutaneous transluminal coronary angioplasty, stenting, bypass surgery, unless already scheduled at the time of acquisition of informed consent. Such prescheduled procedures will be excluded from consideration. Permanent dialysis Patients who require permanent dialysis, unless the introduction of dialysis is clearly due to other diseases (chronic glomerulonephritis, etc.); such dialysis due to other diseases will be excluded from consideration. Serum creatinine increased ≥2-fold Serum creatinine >1.5mg/dL with increase ≥2-fold above the value at registration, as measured in verified testing at onset or within 6 months after onset, and results from hematology and urinalysis rule out other disease (heart failure, bladder cancer, renal calculus, infection, etc.)

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Large artery disease or peripheral arterial disease (aortic dissection, mesenteric artery thrombosis, occurrence of critical lower limb ischemia [ulcers], revascularization or amputation of digit or lower limb due to obstructive arteriosclerosis) Aortic dissection: Refers to evidence of aortic splitting on imaging (transesophageal echocardiogram, CT, MRI/MRA, etc.). Mesenteric artery thrombosis: Refers to evidence of ischemic findings in the superior mesenteric artery (mainly the origin of the artery) on abdominal ultrasound, CT, or angiogram. Occurrence of critical lower limb ischemia [ulcers] due to obstructive arteriosclerosis, revascularization or amputation of digit or lower limb will refer to the occurrence of any of the following: Critical lower limb ischemia (Fontaine grade IV) with ulceration due to obstructive arteriosclerosis, revascularization (percutaneous transluminal coronary angioplasty, CABG), or amputation of digit or lower limb. Death: To be confirmed by death certificate if at all possible. Death due to events: This category includes death due to events stipulated by endpoints in the study protocol. However, deaths will be excluded if other clear causes are identified in the relationship between the death and the event. Total mortality: All deaths will be included. The cause of death, if other than death due to events, will be identified wherever possible. CK, creatine kinase; ECG, electrocardiogram; CT, computed tomography; MRI, magnetic resonance imaging; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; MRA, magnetic resonance angiography

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Definitions related to adverse events

Definition of an adverse event An adverse event is defined as follows. An “adverse event” is defined as “any unfavorable medical event experienced by a patient or subject receiving a drug. It does not necessarily refer only to those events for which there is a clear causal relationship with the said drug. Briefly, an adverse event means any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of a drug that may or may not be considered related to, or caused by, the drug.” Developments such as a change in blood glucose, etc., aggravation of diabetes mellitus, or a change in serum lipid levels associated with the target disease (diabetic retinopathy complicated by hypercholesterolemia) do not constitute adverse events unless the change is excessive and contraindicates continuation of the study. In addition, if abnormal changes in laboratory findings, vital signs, or ECG results associated with signs, symptoms, or disease are observed, the sign, symptom, or disease will be reported as an adverse event. Laboratory findings outside the range specified in the Study Protocol will be reported as additional information regarding the adverse event. Definition of a serious adverse event Those adverse events that satisfy any of the following definitions will be regarded as “serious adverse events.” 1) Events resulting in death 2) Events that are life-threatening 3) Events requiring hospitalization or prolongation of existing hospitalization for treatment 4) Events resulting in a permanent or significant disability/incapacity 5) Events resulting in a congenital abnormality 6) Events or reactions resulting in another medically significant condition 6) refers to medically significant events or reactions that may put patients at risk and require action or treatment to prevent an outcome such as those described in a) to e), even if they are not immediately lifethreatening or do not result in death or hospital admission. Definition of an adverse reaction All adverse events other than those classified as “not related” to statin therapy will be handled as adverse reactions due to statin therapy. If an adverse event occurs, the investigator will record the name of the adverse event, date of onset, severity, seriousness/non-seriousness, changes (if any) in statin therapy, changes (if any) in treatment with drugs other than statin, outcome and date outcome confirmed, causal relationship with statin, and causal relationship with concomitant drugs. The survey of adverse events will be performed during the observation period and the study treatment period.

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Supplementary Figure S1. Patient Flowchart

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Supplementary Figure S2. Changes in LDL-C Parameters Over Time

Data are mean values and SD. *P<0.001, calculated using a mixed model repeated measures (MMRM) approach. The model included group, observation time point, and interaction betw een group and observation time point as fixed effects, assuming equal mean response at baseline. LDL-C, low-density lipoprotein cholesterol

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Supplementary Figure S3. Non-lipid Parameters Over Time

Data are mean and SD. *P<0.001, calculated using a mixed-effects model repeated measures ( MMRM) approach. The model included group, observation time point, and interaction between group and observation time point as fixed effects, assuming equal response at baseline. hsCRP, high-sensitivity C-reactive protein

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Supplementary Figure S4. Subgroup Analysis

P-value was obtained from the interaction between treatment assi gnment and potential prognostic factor in a stratified Cox proportional hazards model with gender (male , female), age (<60, ≥60), and baseline HbA1c [<8.4, ≥8.4 (NGSP%)] at time of actual enrollment as stra tification factors. LDL, low-density lipoprotein; eGFR, estimated glomerular filtrat ion rate

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Supplementary Figure S5. Cumulative Event Curves for the 3-point MACE and the Primary Endpoint Excluding Renal Events (Exploratory Results)

P-value was calculated using a stratified log-rank test with gender (male, female), age (<60, ≥60), and baseline HbA1c [<8.4, ≥8.4 (NGSP%)] at time of actual enrollmen t.

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Supplementary Figure S6. EMPATHY Findings in Relation to CTT and Primary Prevention Studies in Diabetes (Exploratory Results)

Data from individual studies (squares) are plotted with bars indicating one standard e rror. The size of the square is proportional to the number of endpoints in the st udy. The regression lines were forced to go through the origin and indicates the relative decrease in m ajor vascular events (major coronary events, coronary revascularisation, stroke) per mmol/L LDL cholesterol reduction. The figure was adapted with permission from Baigent C, et al. La ncet.2005;366:1267-78. LDL, low-density lipoprotein; CTT, Cholesterol Treatment Trialists, HPS, Heart Protection Study; DM, Diabetes Mellitus; CARDS, Collaborative Atorvastatin Diabetes Study; ASCOT-LLA, Anglo- Scandinavian Cardiac Outcomes Trial, Lipid-Lowering Arm

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Supplementary Figure S7. Trend Analysis for Primary Endpoint, in Subgroups Based on Mean LDL-C Level During Treatment (Exploratory Results)

Method: The mean LDL-C for each patient was calculated from measurement s obtained at scheduled visits, starting 6 months after randomization to the intensive therapy group or the standard therapy group and continuing to the final visit for those who developed no eve nts or to the nearest day before onset for those who developed any events. Post-hoc analysis was condu cted for 4 subgroups (mean LDL-C <70, 70 to <100, 100 to <120, and ≥120 mg/dL). A Cox proportional hazards model was used to analyze trends in incidence of the primary endpoint. Covariate factors included in the model were HbA1c (<8.4, ≥8.4 [NGSP%]), estimated glomerular filtration rate (<60, ≥60 [mL/min/1.73 m2]), funduscopy, smoking, hypertension, sex, diabetic nephropathy and diabetic n europathy. LDL-C, low-density lipoprotein cholesterol

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Supplementary Table S1. Mean Dose by Statin Type at Baseline and Last Visit

Data are mg.

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Supplementary Table S2. Time Course of Lipid Parameters (TC, LDL-C, HDL-C, TG)

* Values were calculated using the Friedewald equation; LDL-C = total cholesterol (TC) - [high-density lipoprotein cholesterol (HDL-C) + TG/5]. P-value was calculated using a mixed model repeated measures (MMRM) approach. The model included group, observation time point, and interaction between group and observation time point as fixed effects, assuming equal mean response at baseline. TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides

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Supplementary Table S3. Details of Each Event for Primary and Secondary Endpoints A) Primary endpoint

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B) Secondary endpoints

* “Stroke” included first occurrence of cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage, but excluded one incident of cerebral hemorrhage subsequent to cerebral infarction (one patient in the intensive group). P-value was calculated using a stratified log-rank test with sex (male, female), age (<60, ≥60) and baseline HbA1c [<8.4, ≥8.4 (NGSP%)] as stratification factors. HR (95%CI) was estimated using a stratified Cox proportional hazards model with sex (male, female), age (<60, ≥60) and baseline HbA1c [<8.4, ≥8.4 (NGSP%)] as stratification factors. Incidence rate (=number of events / person-years * 1000) is expressed as events per 1000 person-years.

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Supplementary Table S4. Change and %Change in CKD Parameters (Baseline vs. Month 36)

Data are mean (SD). Change and %change were calculated using summary statistics. P-value was calculated using a mixed-effects model repeated measures (MMRM) approach. The model included group, observation time point, and interaction between group and observation time point as fixed effects. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate

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