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The differences of the effects on lipid-lowering actions and glucose metabolisms

The differences of the effects on lipid-lowering actions and glucose metabolisms between Rosuvastatin and Atorvastatin in Japanese diabetic patients with hyperlipidemia. - LI pid lowering with highly potent S tatins in hyperlipidemia with T ype 2 diabetes pati EN ts –.

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The differences of the effects on lipid-lowering actions and glucose metabolisms

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  1. 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, HirotakaWatada, Minoru Yoshiyamaon behalf of the LISTEN Study investigators ESC Congress 2014 August 31, 2014 Barcelona – Spain

  2. 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., BoehringerIngelheim 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.

  3. 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., BoehringerIngelheim 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., BoehringerIngelheim 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.

  4. Background • The clinical benefit to prevent cardiovascular events by using statins in hypercholesterolemicpatients with diabetes has been demonstrated in several randomized trials. • Recent data showed that statinswere 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.

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

  6. Endpoints Primary endpoints ・PercentChange 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

  7. Study design Randomized Target population 1. Type2diabetes 2. 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 Rosuvastatin 5 mg/day as starting dose (n=500) Atorvastatin10 mg/day as starting dose (n=500) Informed consent/eligibility 0M 3M 6M 12M Multicenter, open-label, randomized, parallel-group study Primary endpoints : Percent Change in non-HDL-C level Change of HbA1c level Number of study sites : 132sites in Japan

  8. Participants Flow Enrolled and randomized (n = 1049) Allocated to Atorvastatin group (n = 524) Allocated to Rosuvastatin group (n = 525) Not administered study treatment (n = 18) Participant’s request (n = 12) Investigator’s decision (n = 4) Other reasons (n = 2) Not administered study treatment (n = 9) Participant’s request (n = 7) Investigator’s decision (n = 1) Other reasons (n = 1) Administered study treatment (n = 506) Administered study treatment (n = 516) Excluded from Full analysis set (n = 2) Not performed pre-dose examination (n = 1) Administered prohibit prior medication (n = 1) 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) Analyzed as Full analysis set (n = 504)

  9. Baseline characteristics (1)

  10. Baseline characteristics (2)

  11. Baseline characteristics (3) Mean ± SD

  12. Lipid parameters (1) Atorvastatin Rosuvastatin Non-HDL-C LDL-C -30 -25 Overall: P = 0.0922 Overall: P = 0.0399 90.6 P = 0.5374 P = 0.0475 P = 0.0780 87.7 113.6 85.9 -35 -30 111.0 88.1 109.6 Percentchange(%) Percentchange(%) 85.8 -40 -35 111.3 Value (mg/dL) 110.2 82.0 Value (mg/dL) 106.8 P = 0.3205 P = 0.0896 P = 0.0106 -45 -40 6 3 (months) 12 6 3 12 (months)

  13. Lipid parameters (2) Atorvastatin Rosuvastatin HDL-C TC 15 -15 Overall: P = 0.0764 TC: Total Cholesterol Overall: P = 0.1023 P = 0.3039 P = 0.4272 P = 0.0112 P = 0.0419 P = 0.4313 P = 0.1703 TG: Triglyceride 57.7 10 -20 57.4 171.4 170.0 56.5 167.1 Percent change (%) Percent change (%) 59.0 5 -25 168.7 167.8 57.8 57.5 Value (mg/dL) Value(mg/dL) 163.2 0 -30 (months) (months) 3 12 6 12 3 6 TG -5 Overall: P = 0.8555 Value (mg/dL) 126.7 123.9 117.8 -10 Percent change (%) -15 118.8 119.1 116.6 P = 0.5063 P = 0.8397 P = 0.2005 -20 (months) 3 12 6

  14. Glucose metabolism parameters (1) Atorvastatin Rosuvastatin Blood glucose HbA1c 0.3 15.0 Overall: P = 0.0846 Overall: P = 0.0683 P = 0.6695 P = 0.0104 P = 0.1661 P = 0.1882 P = 0.1259 P = 0.1492 0.2 10.0 126.0 6.52 6.50 122.8 Change (%) Change (mg/dL) 6.44 121.4 0.1 5.0 6.50 122.9 0.0 0.0 6.44 120.1 118.8 6.40 Value(%) Value(mg/dL) -0.1 -5.0 3 6 (months) 12 3 12 6 (months)

  15. Glucose metabolism parameters (2) Atorvastatin Rosuvastatin Insulin 1,5-AG 3.0 2.0 Overall: P = 0.4962 Overall: P = 0.3283 P = 0.2205 P = 0.7543 P = 0.9722 2.0 P = 0.1016 P = 0.2130 P = 0.6957 1.0 12.23 12.15 1.0 Value(μU/mL) 15.24 Value(μg/mL) 0.0 0.0 Change (µg/mL) Change(μU/mL) 14.53 14.40 -1.0 11.66 9.81 14.88 -1.0 10.98 -2.0 14.37 14.08 9.63 -3.0 -2.0 3 6 12 3 6 12 (months) (months)

  16. Change in diabetes therapies

  17. Change of therapies on diabetes

  18. The cumulative incidence of diabetes treatmentintensification 20 Hazard ratio: 1.46 (95%CI, 1.00-2.14) P = 0.05 15 10 Intensification of diabetes treatment (%) 5 0 (months) 0 12 3 6 No. at Risk Atorvastatin Rosuvastatin 504 514 471 480 451 466 182 190

  19. 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.

  20. 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.

  21. LISTEN Study investigators

  22. Appendices

  23. Details of therapy intensifications on diabetes (1)

  24. Details of therapy intensifications on diabetes (2)

  25. Safety - Cardiovascular event -

  26. Safety - Clinical and laboratory data - Myopathyinclude myalgia, backpain, muscle spasm, muscle weakness, contracture. Nephropathy include renal dysfunction, nephrotic syndrome .

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