Differences Between Rosuvastatin and Atorvastatin in Lipid-Lowering Action and Effect on Glucose Metabolism in Japanese Hypercholesterolemic Patients With Concurrent Diabetes

– Lipid-Lowering With Highly Potent Statins in Hyperlipidemia With Type 2 Diabetes Patients (LISTEN) Study –

Abstract

Background: Little is known about the differences between standard-dose statins effects on glucose level and lipids in Japanese patients with diabetes mellitus (DM).

Methods and Results: The 1,049 patients were randomly assigned to either the rosuvastatin group or atorvastatin group. There were no significant differences between the 2 groups in the effect on non-high-density lipoprotein cholesterol (non-HDL-C) and HbA1c at 12 months. However, physicians tended to switch to more intensive therapy for DM in the atorvastatin group.

Conclusions: Rosuvastatin 5 mg and atorvastatin 10 mg have a similar lowering effect on non-HDL-C, but might be different in terms of adverse effect on glucose levels. (Circ J 2014; 78: 2512–2515)

The clinical benefit of preventing cardiovascular events by using statins in hypercholesterolemic patients is well established.^1,2 The benefit in hypercholesterolemic patients with diabetes mellitus (DM) has also been demonstrated in several randomized trials,^3–5 but recent data showed that statins are associated with an increased risk of new-onset DM^6,7 and that the risk is dose dependent.⁸ Some reports suggested the suppressive effect of statin on cardiovascular events outweighs the risk of DM onset.^9–11 The guidelines show the rationale for statin therapy to prevent cardiovascular events based on risk stratification for each patient, which includes DM.^12,13 However, few prospective, randomized, controlled studies have been conducted to investigate the effect of statin therapy on glucose levels in patients with DM, although such data would greatly contribute to decision making in the clinical setting. We conducted this study to examine the effects of statins on both glucose and lipid levels in Japanese patients with DM. The final result will be presented in a hot-line session of the ESC congress 2014.

Methods

This study was a 12-month multicenter open-label randomized, comparative study. The protocol was approved by the institutional review board. All patients provided written informed consent.

The study included hypercholesterolemic patients with type 2 DM whose HbA1c (Japan Diabetes Society [JDS]) was <7.0% (or <7.4%: National Glycohemoglobin Standardization Program [NGSP]). Patients were excluded if they had received rosuvastatin or atorvastatin before registration. Patients were randomly assigned to the rosuvastatin 5 mg group or the atorvastatin 10 mg group at registration.

The primary endpoints were the percentage change in non-high-density lipoprotein cholesterol (non-HDL-C) and the change in HbA1c. Secondary endpoints were changes in other lipids, glucose metabolism parameters, and any intensification of DM treatment (ie, drugs were added and/or increased for DM), which was assessed independently by 2 investigators. The original agreement on κ score was 0.6316, which was fairly good, and discrepancies were fixed by direct discussion.

Statistical Analysis

The 2-way repeated measures ANOVA was used to compare the groups for changes in lipid profiles and glucose metabolism parameters from baseline to each assessment time. The unpaired t-test adjusted by Holm’s method was used for intergroup comparison to avoid multiplicity at multiple time points. A log-rank test was used to compare intensification of DM treatment between the groups.

Results

A total of 1,049 patients were enrolled and randomized to the rosuvastatin or atorvastatin group from March to September 2012 at 132 institutions in Japan; 514 patients in the rosuvastatin group and 504 patients in the atorvastatin group were included in the full analysis set. There were no significant differences between the groups at baseline (Table S1).

Lipid Profiles and Glucose Levels

Non-HDL-C showed a significant reduction in both groups (−32.86% in the rosuvastatin group and −31.01% in the atorvastatin group at 12 months) without a significant difference between groups (Figure 1A). Low-density lipoprotein cholesterol levels were also decreased at 12 months: −34.79% in the rosuvastatin group and −32.78% in the atorvastatin group (Figure S1).

Figure 1.

Percent change in non-HDL-C (A) and change in HbA1c (B). The analyses were performed using repeated measures ANOVA for overall comparison between the 2 statin treatment groups. The unpaired t-test adjusted by Holm’s method was used for intergroup comparison to avoid multiplicity at multiple time points. Non-HDL-C, non-high-density lipoprotein cholesterol.

The changes in HbA1c were 0.11 in the rosuvastatin group and 0.12 in the atorvastatin group (Figure 1B). There was a significant difference at 6 months even after adjustment for multiple comparisons, but not significant difference between groups throughout the study period. Other glucose metabolism parameters did not show significant differences between groups (Figure S2). The cumulative incidence of intensification of DM treatment is shown in Figure 2. During the study period, 45 subjects in the rosuvastatin group and 64 subjects in the atorvastatin group were treated with increased DM therapy (Table S2). The hazard ratio was 1.46 (95% confidence interval 1.00–2.14) (Figure 2).

Figure 2.

Cumulative Kaplan-Meier estimates of the incidence of the patients who were switched to more intensive therapy for diabetes mellitus. The atorvastatin group had therapy intensified more often than the rosuvastatin group during the study period (P=0.05). CI, confidence interval.

Safety

Adverse effects occurred in 4.5% of the rosuvastatin group and 5.9% of the atorvastatin group. There were no cases of rhabdomyolysis or of liver function enzyme elevation greater than 3-fold the upper limit of normal.

Discussion

There were no significant changes in non-HDL-C or HbA1c in either group. However, there were difference in the effects on glucose levels and treatment decisions for DM. A meta-analysis has shown that statin therapy is associated with an increased risk of developing DM, but did not show any obvious differences among the individual statins,⁹ which are classified as hydrophilic or lipophilic. Takaguri et al reported that lipophilic but not hydrophilic statins significantly affected glucose uptake by adipocytes,¹⁴ and MUSASHI-AMI showed that cardiovascular events tended to be fewer with hydrophilic statins.¹⁵

To complement the results from previous studies, our results should be interpreted that the choice of statin be considered not only on the basis of potency of cholesterol-lowering effect but also glucose metabolism. In our study results, rosuvastatin and atorvastatin showed different patterns of change in HbA1c. The atorvastatin group tended to be changed to more intensive DM therapy. At 6 months, HbA1c levels showed a statistically significant difference between groups, and that would have influenced physicians’ behavior to change the intensity of DM treatment. Consequently, the overall change in HbA1c did not reach statistically significant difference. However, our results suggested rosuvastatin might be preferable to atorvastatin in this study population.

There are several limitations to this study. Firstly, we compared laboratory data mainly as the outcome; in addition, the long-term outcome is uncertain. Moreover, the differences in glucose levels between the 2 statins were determined by the changes in HbA1c levels, in addition to the treatment intensity for DM. Secondly, our study used small dosages based on the Japanese regulation, so the results might underestimate the effects of statins. Besides, this was an open-label study in which the possibility of bias cannot be entirely denied. However, both groups were treated aggressively for DM, as the results for HbA1c level at 12 months were similar between groups, although they were different at 6 months. We believe our findings would be close to the real clinical setting.

Conclusions

Rosuvastatin 5 mg and atorvastatin 10 mg have a similar lowering on non-HDL-C, but might be different in terms of adverse effect on glucose levels.

Funding Sources

LISTEN was funded by the investigator-sponsored study program of AstraZeneca.

Disclosures

H.O. has received grants from the Japan Heart Foundation, and has received research supports or honoraria or both from Astellas Pharma Inc, AstraZeneca KK, 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 KK, Novartis Pharma KK, Otsuka Pharmaceutical Co, Ltd, Pfizer Japan Inc, Sanofi KK, and Takeda Pharmaceutical Company Limited.

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

M.Y. 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 KK, Kissei Pharmaceutical Co, Ltd, Kyowa Hakko Kirin Co, Ltd, Mochida Pharmaceutical Co, Ltd, MSD KK, Otsuka Pharmaceutical Co, Ltd, Pfizer Japan Inc, Sanofi KK, and Teijn Pharma Limited.

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

Appendix

LISTEN 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, 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, Doniwa Ken-ichi, 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, Naoki Kawai, 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.

Supplementary Files

Supplementary File 1

Table S1. Baseline characteristics of subjects in the LISTEN Study

Table S2. Change in therapy for DM among subjects of the LISTEN Study

Figure S1. The changes of LDL-C (low-density lipoprotein cholesterol), TC (total-cholesterol), HDL-C (high-density lipoprotein cholesterol), TG (triglyceride). Analyses performed using repeated measures ANOVA for overall comparison between treatment groups.

Figure S2. The changes of Blood glucose, Insulin and 1,5-AG. Analyses performed using repeated measures ANOVA for overall comparison between treatment groups.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-14-0810

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