The differences of the effects on lipid-lowering actions
and 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 2014
August 31, 2014
Barcelona – Spain
Conflict of interest disclosure
LISTEN 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 disclosure
Yoshihiko 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.
Background
 The 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
Target population
1. Type 2 diabetes
2. HbA1c ≤ 7.4%
3. Hyper-LDLcholesterolemia
Randomized
Rosuvastatin 5 mg/day as starting dose (n=500)
(LDL-C ≥ 120 mg/dL
without ASCVD
[atherosclerotic
cardiovascular disease],
≥ 100 mg/dL with ASCVD)
Atorvastatin 10 mg/day as starting dose (n=500)
4. ≥ 20 years of age
Informed consent
/eligibility
0M
3M
6M
Multicenter, open-label, randomized, parallel-group study
Primary endpoints
: Percent Change in non-HDL-C level
Change of HbA1c level
Number of study sites : 132 sites in Japan
12M
Participants Flow
Enrolled and randomized (n = 1049)
Allocated to Rosuvastatin group (n = 525)
Not administered study
treatment (n = 9)
Participant’s request (n = 7)
Investigator’s decision (n = 1)
Other reasons (n = 1)
Administered study treatment (n = 516)
Excluded from Full analysis set
(n = 2)
Not performed pre-dose
examination (n = 2)
Administered prohibit prior
medication (n = 0)
Analyzed as Full analysis set (n = 514)
Allocated to Atorvastatin group (n = 524)
Not administered study
treatment (n = 18)
Participant’s request (n = 12)
Investigator’s decision (n = 4)
Other reasons (n = 2)
Administered study treatment (n = 506)
Excluded from Full analysis set
(n = 2)
Not performed pre-dose
examination (n = 1)
Administered prohibit prior
medication (n = 1)
Analyzed as Full analysis set (n = 504)
Baseline characteristics (1)
All participants
Rosuvastatin
Atorvastatin
(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
P value
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
Baseline characteristics (2)
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
Hypertension
645 (63.4%) 338 (65.8%) 307 (60.9%)
0.12
Baseline characteristics (3)
All participants
(n = 1018)
Rosuvastatin
(n = 514)
Atorvastatin
(n = 504)
P
value
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
3.30 ± 1.20
2.69 ± 0.86
3.36 ± 1.31
2.73 ± 0.91
3.25 ± 1.07
2.66 ± 0.81
0.43
0.36
0.584 ± 0.298
0.584 ± 0.299
0.585 ± 0.297
0.91
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
Lipid parameters
Non-HDL-C/HDL-C ratio
LDL-C/HDL-C ratio
FFA (mEq/L)
Glucose metabolism parameters
Mean ± SD
Lipid parameters (1)
Atorvastatin
Rosuvastatin
Non-HDL-C
Overall: P = 0.0922
Percent change (%)
P = 0.0475
Overall: P = 0.0399
P = 0.5374
113.6
-30
109.6
-35
111.0
111.3
110.2
90.6
P = 0.0780
Percent change (%)
-25
LDL-C
-30
87.7
85.9
-35
88.1
85.8
-40
Value (mg/dL)
82.0
Value (mg/dL)
106.8
P = 0.0106
P = 0.3205
P = 0.0896
-45
-40
3
6
12 (months)
6
3
No. of
participants
0 month
3 months
6 months
12 months
Atorvastatin
504
494
482
472
Rosuvastatin
514
493
485
468
12 (months)
Lipid parameters (2)
Atorvastatin
HDL-C
15
-15
Overall: P = 0.0764
Overall: P = 0.1023
P = 0.3039 P = 0.4272 P = 0.0112
P = 0.0419 P = 0.4313 P = 0.1703
10
57.7
57.4
56.5
59.0
5
57.8
Value (mg/dL)
57.5
Percent change (%)
Percent change (%)
Rosuvastatin
TC
0
TC: Total Cholesterol
-20
170.0
TG: Triglyceride
171.4
167.1
-25
167.8
168.7
Value (mg/dL)
163.2
-30
3
6
12 (months)
3
6
12 (months)
TG
-5
Overall: P = 0.8555
Percent change (%)
126.7
Value (mg/dL)
123.9
-10
-15
119.1
117.8
118.8
116.6
-20
P = 0.5063 P = 0.8397 P = 0.2005
3
6
12 (months)
No. of
participants
0 month
3 months
6 months
12 months
Atorvastatin
504
494
482
472
Rosuvastatin
514
493
485
468
Glucose metabolism parameters (1)
Atorvastatin
Rosuvastatin
Blood glucose
HbA1c
P = 0.1661
Change (%)
15.0
Overall: P = 0.0846
0.2
0.1
P = 0.6695
P = 0.0104
6.52
6.50
6.44
6.50
0.0
10.0
P = 0.1882
P = 0.1259
126.0
122.8
121.4
5.0
122.9
0.0
6.44
6.40
Overall: P = 0.0683
P = 0.1492
Change (mg/dL)
0.3
118.8
Value(%)
-0.1
120.1
Value(mg/dL)
-5.0
3
6
12 (months)
3
12 (months)
6
No. of
participants
0
month
3
months
6
months
12
months
No. of
participants
0
month
3
months
6
months
12
months
Atorvastatin
504
494
482
472
Atorvastatin
503
493
481
471
Rosuvastatin
514
493
485
468
Rosuvastatin
514
492
485
468
Glucose metabolism parameters (2)
Atorvastatin
Rosuvastatin
Insulin
3.0
1,5-AG
2.0
Overall: P = 0.4962
1.0
P = 0.2205
P = 0.7543
P = 0.9722
1.0
12.23
12.15
Change (µg/mL)
Change (μU/mL)
2.0
Value(μU/mL)
0.0
-1.0
-2.0
11.66
9.81
10.98
Overall: P = 0.3283
P = 0.2130
P = 0.1016
15.24
Value(μg/mL)
0.0
14.53
-1.0
14.40
14.88
14.08
9.63
-3.0
P = 0.6957
14.37
-2.0
3
6
12 (months)
3
6
No. of
participants
0 month
3 months
6 months
12 months
Atorvastatin
503
493
481
471
Rosuvastatin
514
493
485
468
12 (months)
Change in diabetes therapies
Change in diabetes therapies
Addition of new drug
DPP-4 inhibitor
Biguanide
Sulfonylurea
α-glucosidase inhibitor
Insulin sensitizer
Insulin analogue
GLP-1 analogue
Insulin secretagogue
Increase in dosage
Sulfonylurea
Biguanide
DPP-4 inhibitor
Insulin sensitizer
Drug changes
(judged as therapy intensification)
DPP-4 inhibitor change
+Metformin hydrochloride
Subtotal of therapy intensification
Rosuvastatin
(n = 514)
61
(11.9%)
29
(5.6%)
13
(2.5%)
11
(2.1%)
4
(0.8%)
0
(0.0%)
2
(0.4%)
0
(0.0%)
1
(0.2%)
0
(0.0%)
15
(2.9%)
7
(1.4%)
5
(1.0%)
4
(0.8%)
1
(0.2%)
1
(0.2%)
Atorvastatin
P value
(n = 504)
83
(16.5%)
0.04
54
(10.7%)
35
(6.9%)
7
(1.4%)
6
(1.2%)
5
(1.0%)
2
(0.4%)
2
(0.4%)
0
(0.0%)
1
(0.2%)
10
(2.0%)
4
(0.8%)
4
(0.8%)
2
(0.4%)
0
(0.0%)
0
(0.0%)
1
(0.2%)
0
(0.0%)
45
(8.8%)
64
(12.7%)
0.04
Change of therapies on diabetes
Rosuvastatin
Atorvastatin
P value
(n = 514)
Change in diabetes therapies
(n = 504)
61
(11.9%)
83
(16.5%)
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
other than the above
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%)
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%)
0.04
The cumulative incidence of diabetes
treatment intensification
Intensification of diabetes treatment (%)
20
Hazard ratio: 1.46 (95%CI, 1.00-2.14)
P = 0.05
15
10
5
0
No. at Risk
Atorvastatin
Rosuvastatin
0
3
6
504
514
471
480
451
466
12 (months)
182
190
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.
Conclusions
Rosuvastatin 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 investigators
Hisao 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
YuichiroNakamura
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)
Change of therapies on diabetes
Addition of new drug
gliclazide
glimepiride
metformin hydrochloride
Rosuvastatin
Atorvastatin
(n = 514)
(n = 504)
61
(11.9%)
83
(16.5%)
29
0
4
11
(5.6%)
(0.0%)
(0.8%)
(2.1%)
54
2
4
7
(10.7%)
(0.4%)
(0.8%)
(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%)
P value
0.0386
Details of therapy intensifications on diabetes (2)
Rosuvastatin
Atorvastatin
(n = 514)
(n = 504
P value
Change of therapies on diabetes
Increase of dosage
61
(11.9%)
83
(16.5%)
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
0.0386
(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
Safety - Cardiovascular event Rosuvastatin
Atorvastatin
P value
(n = 514)
Occurrence of cardiovascular event
9
(1.8%)
(n = 504)
5
(1.0%)
Coronary artery disease
3
(0.6%)
0
(0.0%)
Heart failure
2
(0.4%)
2
(0.4%)
cerebrovascular disease
3
(0.6%)
3
(0.6%)
Peripheral arterial disease
0
(0.0%)
0
(0.0%)
Aortic disease
1
(0.2%)
0
(0.0%)
0.42
Safety - Clinical and laboratory data -
Myopathy
Rosuvastatin
Atorvastatin
(n = 514)
(n = 504)
15
(2.9%)
13
(2.6%)
Nephropathy
0
(0.0%)
3
(0.6%)
Proteinuria
0
(0.0%)
1
(0.2%)
Abnormal fluctuations of ALT
1
(0.2%)
2
(0.4%)
Abnormal fluctuations of AST
1
(0.2%)
2
(0.4%)
Abnormal fluctuations of γ-GTP
1
(0.2%)
3
(0.6%)
Abnormal fluctuations of CK
5
(1.0%)
4
(0.8%)
Myopathy include myalgia, backpain, muscle spasm, muscle weakness, contracture.
Nephropathy include renal dysfunction, nephrotic syndrome .