The differences of the effects on lipid-lowering actionsand glucose metabolisms

between Rosuvastatin and Atorvastatin in Japanese diabetic patients with hyperlipidemia.

- LIpid lowering with highly potent Statins in hyperlipidemia with Type 2 diabetes patiENts –

Hisao Ogawa, Yoshihiko Saito, Hideaki Jinnouchi, Masahiro Sugawara, Seigo Sugiyama, Izuru. Masuda, Kunihiko Matsui, Hisao Mori, Masako Waki, Hirotaka Watada, Minoru Yoshiyama on behalf of the LISTEN Study investigators

ESC Congress 2014August 31, 2014

Barcelona – Spain

Conflict of interest disclosureLISTEN study was funded by the Non-Profit Organization, Hokkaido Kenkoukagaku Institute and the Investigator Sponsored Study Program of AstraZeneca K.K.

Hisao Ogawa, MD, PhD has received research supports or honoraria or both from Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Company, Limited, Dainippon Sumitomo Pharma Co., Ltd., Kowa Company, Ltd., MSD K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., and Takeda Pharmaceutical Company Limited.

Conflict of interest disclosureYoshihiko Saito, MD, PhD is an adviser at Ono Pharmaceutical Co., Ltd. YS has a clinical commission for an advisor from Ono Pharmaceutical Co., Ltd. YS has received research supports or honoraria or both from Astellas Pharma Inc., AstraZeneca K.K., Daiichi Sankyo Company, Limited, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd., St. Jude Medical Japan Co., Ltd., and Takeda Pharmaceutical Company Limited. YS has endowed departments by MSD Co., Ltd.

Hiroyuki Watada, MD, PhD has received research supports or honoraria or both from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Dainippon Sumitomo Pharma Co., Ltd., Eli Lilly Japan K.K., Johnson & Johnson K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., MSD K.K., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Ltd., and Takeda Pharmaceutical Company Limited.

Minoru Yoshiyama, MD, PhD has received research supports or honoraria or both from Astellas Pharma Inc., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mochida Pharmaceutical Co., Ltd., MSD K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., and Teijn Pharma Limited.

BackgroundThe clinical benefit to prevent cardiovascular events by

using statins in hypercholesterolemic patients with diabetes has been demonstrated in several randomized trials.

Recent data showed that statins were associated with an increased dose-dependent risk of new-onset diabetes.

However, few prospective, randomized, controlled trials have been conducted to investigate the impact of statin on glucose levels in patients with diabetes.

Purpose

The LISTEN study was conducted to examine the effects of statins on both lipids and glucose control in Japanese patients with diabetes.

Endpoints

Primary endpoints

・ Percent Change in non-HDL-C level

・ Change in HbA1c level

Secondary endpoints

・ Changes in other lipids, and glucose metabolism parameters

・ Any intensification in diabetic treatment status

Study design

Atorvastatin 10 mg/day as starting dose (n=500)

0M 3M 12MInformed consent/eligibility

Target population1. Type 2 diabetes2. 6.5% ≤ HbA1c ≤ 7.4%3. Hyper-LDL- cholesterolemia (LDL-C ≥ 120 mg/dL without ASCVD [atherosclerotic cardiovascular disease], ≥ 100 mg/dL with ASCVD)4. ≥ 20 years of age 　

6M

Rosuvastatin 5 mg/day as starting dose (n=500)

Multicenter, open-label, randomized, parallel-group study

Primary endpoints : Percent Change in non-HDL-C level Change of HbA1c levelNumber of study sites : 132 sites in Japan

Randomized

Participants FlowEnrolled and randomized (n = 1049)

Allocated to Atorvastatin group (n = 524)

Allocated to Rosuvastatin group (n = 525)

Analyzed as Full analysis set (n = 504)

Analyzed as Full analysis set (n = 514)

Administered study treatment (n = 516)

Not administered study treatment (n = 9)Participant’s request (n = 7)Investigator’s decision (n = 1)Other reasons (n = 1)

Excluded from Full analysis set (n = 2)Not performed pre-dose examination (n = 2)Administered prohibit prior medication (n = 0)

Administered study treatment (n = 506)

Not administered study treatment (n = 18)Participant’s request (n = 12)Investigator’s decision (n = 4)Other reasons (n = 2)

Excluded from Full analysis set (n = 2)Not performed pre-dose examination (n = 1)Administered prohibit prior medication (n = 1)

Baseline characteristics (1)All participants Rosuvastatin Atorvastatin

P value(n = 1018) (n = 514) (n = 504)

Male 466 (45.8%) 235 (45.7%) 231 (45.8%) 1.00

Age (years) Mean ± SD 66.4 ± 11.1 66.3 ±11.6 66.6 ±10.6 0.99

Statin administration before entry 241 (23.7%) 121 (23.5%) 120 (23.8%) 0.94

Cardiovascular and Cerebrovascular events before entry

206 (20.2%) 103 (20.0%) 103 (20.4%) 0.88

Myocardial infarction 14 (1.4%) 7 (1.4%) 7 (1.4%) 1.00

Angina pectoris 62 (6.1%) 31 (6.0%) 31 (6.2%) 1.00

Heart failure 18 (1.8%) 8 (1.6%) 10 (2.0%) 0.64

Revascularization 12 (1.2%) 9 (1.8%) 3 (0.6%) 0.14

Cardiac arrhythmias 57 (5.6%) 26 (5.1%) 31 (6.2%) 0.50

Cerebral haemorrhage 9 (0.9%) 6 (1.2%) 3 (0.6%) 0.51

Cerebral infarction 51 (5.0%) 30 (5.8%) 21 (4.2%) 0.25

Transient ischaemic attack 9 (0.9%) 4 (0.8%) 5 (1.0%) 0.75

All participants

Rosuvastatin Atorvastatin

P value

(n = 1018) (n = 514) (n = 504)

Complications related to diabetes

116 (11.4%)

67 (13.0%) 49 (9.7%) 0.11

Diabetic retinopathy 13 (1.3%) 9 (1.8%) 4 (0.8%) 0.26

Diabetic nephropathy 34 (3.3%) 21 (4.1%) 13 (2.6%) 0.22

Diabetic neuropathy 46 (4.5%) 23 (4.5%) 23 (4.6%) 1.00

Diabetic foot 1 (0.1%) 1 (0.2%) 0 (0.0%) 1.00

Hypertension645

(63.4%)338

(65.8%)307

(60.9%)0.12

Baseline characteristics (2)

All participants Rosuvastatin AtorvastatinP

value(n = 1018) (n = 514) (n = 504)

Lipid parameters

Non-HDL-C (mg/dL) 168.9 ± 33.3 168.9 ± 35.8 169.0 ± 30.6 0.41

LDL-C (mg/dL) 139.4 ± 30.0 139.2 ± 31.9 139.6 ± 27.9 0.45

HDL-C (mg/dL) 54.9 ± 14.1 54.1 ± 13.6 55.8 ± 14.6 0.08

TC (mg/dL) 223.9 ± 34.0 223.0 ± 36.0 224.8 ± 31.8 0.15

TG (mg/dL) 152.1 ± 115.8 154.5 ± 137.1 149.6 ± 89.1 0.73

Non-HDL-C/HDL-C ratio 3.30 ± 1.20 3.36 ± 1.31 3.25 ± 1.07 0.43LDL-C/HDL-C ratio 2.69 ± 0.86 2.73 ± 0.91 2.66 ± 0.81 0.36

FFA (mEq/L) 0.584 ± 0.298 0.584 ± 0.299 0.585 ± 0.297 0.91

Glucose metabolism parameters

HbA1c (%) (NGSP value) 6.39 ± 0.63 6.40 ± 0.66 6.38 ± 0.59 0.80

Blood glucose (mg/dL) 118.9 ± 29.2 119.1 ± 31.2 118.8 ± 27.0 0.54

Insulin (μU/mL) 11.77 ± 19.39 12.57 ± 20.07 10.95 ± 18.66 0.13

1,5-AG (μg/mL) 15.40 ± 8.01 15.39 ± 8.10 15.40 ± 7.91 0.97

Baseline characteristics (3)

Mean ± SD

Lipid parameters (1)

87.7

90.6

82.0

85.8

88.1

Overall: P = 0.0399

P = 0.0106 P = 0.3205 P = 0.0896

Atorvastatin

Rosuvastatin

No. of participants

0 month 3 months 6 months 12 months

Atorvastatin 504 494 482 472

Rosuvastatin 514 493 485 468

12 3 (months) 12 3 (months)

Value (mg/dL)Value (mg/dL)

Lipid parameters (2)

57.5

59.0

57.8

56.5

57.7

Overall: P = 0.0764

P = 0.3039 P = 0.4272 P = 0.0112

Overall: P = 0.1023

P = 0.0419 P = 0.4313 P = 0.1703

P = 0.2005

Overall: P = 0.8555

P = 0.5063 P = 0.8397

57.4

Atorvastatin

Rosuvastatin

TC: Total Cholesterol

TG: Triglyceride

No. of participants

0 month 3 months 6 months 12 months

Atorvastatin 504 494 482 472

Rosuvastatin 514 493 485 468

3 12 3 12

3 12 (months)

(months) (months)

Value (mg/dL) Value (mg/dL)

Value (mg/dL)

Glucose metabolism parameters (1) C

hang

e (%

)

Overall: P = 0.0846

P = 0.1661 P = 0.0104 P = 0.6695

6.44

6.40

6.52

6.44

6.50

6.50

Cha

nge

(mg/

dL)

Overall: P = 0.0683

P = 0.1492 P = 0.1259 P = 0.1882

121.4

118.8

126.0

122.9

120.1

122.8

Atorvastatin

Rosuvastatin

No. of participants

0 month

3 months

6 months

12 months

Atorvastatin 504 494 482 472

Rosuvastatin 514 493 485 468

No. of participants

0 month

3 months

6 months

12 months

Atorvastatin 503 493 481 471

Rosuvastatin 514 492 485 468

12 3 12 3(months) (months)

Value(%)

Glucose metabolism parameters (2)C

hang

e (μ

U/m

L)

Overall: P = 0.4962

P = 0.2205 P = 0.7543 P = 0.9722

12.15

10.98

11.66

12.23

9.63

9.81 Cha

nge

(µg/

mL

)

Overall: P = 0.3283

P = 0.2130 P = 0.1016 P = 0.6957

15.24

14.88

14.08

14.53

14.37

14.40

Atorvastatin

Rosuvastatin

No. of participants

0 month 3 months 6 months 12 months

Atorvastatin 503 493 481 471

Rosuvastatin 514 493 485 468

12 3 12 3(months) (months)

Value(μU/mL)

Change in diabetes therapiesRosuvastatin Atorvastatin

P value(n = 514) (n = 504)

Change in diabetes therapies 61 (11.9%) 83 (16.5%) 0.04 　Addition of new drug 29 (5.6%) 54 (10.7%) 　

DPP-4 inhibitor 13 (2.5%) 35 (6.9%)Biguanide 11 (2.1%) 7 (1.4%)Sulfonylurea 4 (0.8%) 6 (1.2%)α-glucosidase inhibitor 0 (0.0%) 5 (1.0%)Insulin sensitizer 2 (0.4%) 2 (0.4%)Insulin analogue 0 (0.0%) 2 (0.4%)GLP-1 analogue 1 (0.2%) 0 (0.0%)Insulin secretagogue 0 (0.0%) 1 (0.2%)

Increase in dosage 15 (2.9%) 10 (2.0%) 　Sulfonylurea 7 (1.4%) 4 (0.8%)Biguanide 5 (1.0%) 4 (0.8%)DPP-4 inhibitor 4 (0.8%) 2 (0.4%)Insulin sensitizer 1 (0.2%) 0 (0.0%)

Drug changes (judged as therapy intensification)

1 (0.2%) 0 (0.0%) 　

DPP-4 inhibitor change+Metformin hydrochloride

1 (0.2%) 0 (0.0%)

Subtotal of therapy intensification 45 (8.8%) 64 (12.7%) 0.04

Change of therapies on diabetesRosuvastatin Atorvastatin

P value(n = 514) (n = 504)

Change in diabetes therapies 61 (11.9%) 83 (16.5%) 0.04 　

Drug Changes (other than the intensification)

4 (0.8%) 8 (1.6%) 　

Decreased dosage 5 (1.0%) 6 (1.2%) 　

Drug withdrawal 7 (1.4%) 5 (1.0%) 　

Change timing after the first dose in this study

therapy intensification

0 to 3 months 14 (2.7%) 20 (4.0%) 　

3 to 6 months 8 (1.6%) 12 (2.4%) 　

6 to 12 months 23 (4.5%) 32 (6.3%) 　

other than the above

0 to 3 months 5 (1.0%) 6 (1.2%) 　

3 to 6 months 5 (1.0%) 5 (1.0%) 　

6 to 12 months 6 (1.2%) 8 (1.6%) 　

Hazard ratio: 1.46 (95%CI, 1.00-2.14)P = 0.05

20

15

10

5

0

The cumulative incidence of diabetes treatment intensification

(months)

No. at RiskAtorvastatin Rosuvastatin

504514

471480

451466

182190

Limitations

This was an open-label study, and changing or intensifying the treatment for diabetes was left to the judgment of the investigator, possible bias cannot be excluded.

This was a rather small size study and compared laboratory data mainly as the outcome, in addition to short-term observation period.

We used low doses based on the Japanese regulation compared to those in U.S. and European countries.

ConclusionsRosuvastatin did not reduce non-HDL-C compared with Atorvastatin, but overall did reduce LDL-C significantly.

The intensification of diabetic treatments was significantly less frequent in the Rosuvastatin group than in the Atorvastatin group.

Further prospective studies are required to confirm the differences in the effects on diabetes among statins.

LISTEN Study investigatorsHisao Mori Takao Nagasu Kazuo Maeda Kumio Iroden Kazuaki Uchiyama Toshibumi Hogi Fumiaki Ono

Hideki Kikuchi Masahiko Kuroda Eiichi Tokutake Tsutomu Hayashi Keiichi Chin Hareaki Yamamoto Yoshihisa Takada

Nobuaki Oka Masako Waki Shuji Kagawa Masaru Murakami Toshihiro Arizumi Hifumi Atsuko Akira Maki

Hiroo Miyagi Kentarou Yata Shinsuke Takei Masami Kogure Masayuki Nakano Youichi Ehara Akira Ota

Hideo Ayame Masahiro Sugawara Tetsuo Munakata Koichi Hasegawa Shoshi Matsuda Takashi Fujimoto Shinichi

Matsumoto

Osame Tanaka Akira Soejima Tomoyuki Shibuya Soichi Honda Shuji Mizumachi Yutaka Wakasa Hirokuni Etsuda

Toshifumi Matsuno

Tetsuya Tsurumachi Nobushige Ote Hisataka Tegoshi Masaki Matsuoka Kengo Matsumoto Nobuyuki

Enomoto

Masayuki Yanagi Katsumi Yoshida Koji Oida Masahiro Fukuda Koji Takaki Tomohiro Katsuya Takuma Eto

Hiroki Kamata Kohsuke Minamisawa Hiroaki Seino Ichitaro Takada Hideto Ishii Yoshiko Kubota Hidetaka

Kanazawa

Shinya Hiramitsu Yoshihiro Fujii Yuichiro Nakamura

Yasuhiro Hashiguchi Shinya Okamoto Kazuo Ikeda Hiroshi Nishimura

Takahiko Kawagishi

Kazuya Shigenobu Masaaki Arima Kenichi

Yamamoto Yasushi Suzuki Naomi Yoshimura Takahiro Hayashi

Satoru Hasegawa Ken-ichi Doniwa Masatoshi Yanagisawa Toshiki Tatsumura Kimikazu Sawai Hiroto Moriyasu Masaru Matsuda

Shuichi Kawano Kazuo Sakabe Akiyo Shinoda Ken Takenaka Ichiro Kanamori Toshiyuki Kashiwagi Arata Iwasaki

Naoto Yokota Kou Arakawa Masanori Inoue Masahiro Ueno Yuji Nakatani Takayuki Higashi Kiyohito Takahashi

Shuichi Matsuo Yoshiyuki Ishii Shoichi Kitano Hiroshi Tanaka Hideaki Jinnouchi Naotaka Kusunose

Toshimitsu Jikuhara

Hiroshi Kobayashi Yasuhiko Kawade Yasuhiko Kawade Junpei Iinuma Kuniyuki Takai Takao Yasue Tsuguo Niimi

Yukinori Kawase Reiki Yoshida Koji Ishimura Hatsumi Masaki Joji Koike Naoto Ishikawa Jun Arao

Toru Kinugawa Haruyoshi Nakao Mikio Yamaguchi Shinichiro Otake Michio Tamatani Yumiko Ide Haruyuki Taguchi

Nobuyuki Azuma Izuru Masuda Harunori Oda Kazuhiko Takano Ren Horibe Junichiro Kondo

Appendices

Details of therapy intensifications on diabetes (1)

Rosuvastatin AtorvastatinP value

(n = 514) (n = 504)

Change of therapies on diabetes 61 (11.9%) 83 (16.5%) 0.0386 　Addition of new drug 29 (5.6%) 54 (10.7%) 　

gliclazide 0 (0.0%) 2 (0.4%)

glimepiride 4 (0.8%) 4 (0.8%)

metformin hydrochloride 11 (2.1%) 7 (1.4%)

pioglitazone hydrochloride 2 (0.4%) 2 (0.4%)

sitagliptin phosphate hydrate 6 (1.2%) 14 (2.8%)

alogliptin benzoate 4 (0.8%) 7 (1.4%)

vildagliptin 3 (0.6%) 10 (2.0%)

linagliptin 0 (0.0%) 3 (0.6%)

teneligliptin hydrobromide hydrate 0 (0.0%) 1 (0.2%)

voglibose 0 (0.0%) 2 (0.4%)

miglitol 0 (0.0%) 3 (0.6%)

mitiglinide calcium hydrate 0 (0.0%) 1 (0.2%)

liraglutide 1 (0.2%) 0 (0.0%)

insulin glargine 0 (0.0%) 2 (0.4%)

Details of therapy intensifications on diabetes (2)

Rosuvastatin AtorvastatinP value

(n = 514) (n = 504

Change of therapies on diabetes 61 (11.9%) 83 (16.5%) 0.0386 　

Increase of dosage 15 (2.9%) 10 (2.0%) 　

gliclazide 0 (0.0%) 1 (0.2%)

glimepiride 7 (1.4%) 3 (0.6%)

metformin hydrochloride 5 (1.0%) 4 (0.8%)

pioglitazone hydrochloride 1 (0.2%) 0 (0.0%)

sitagliptin phosphate hydrate 3 (0.6%) 2 (0.4%)

vildagliptin 1 (0.2%) 0 (0.0%)

Drug Changes (judged as therapy intensification)

1 (0.2%) 0 (0.0%) 　

DPP-4 inhibitor change+metformin hydrochloride

1 (0.2%) 0 (0.0%)

Subtotal of therapy intensification 45 (8.8%) 64 (12.7%) 0.0432