1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2010 年 8 月 5 日 8:30-8:55 ８階 医局 Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, Mora S, MacFadyen JG, Glynn RJ, Kastelein JJ; JUPITER Trial Study Group. HDL-cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. 2010 Jul 31;376(9738):333-9. Epub 2010 Jul 23. White NH, Sun W, Cleary PA, Tamborlane WV, Danis RP, Hainsworth DP, Davis MD; DCCT-EDIC Research Group. Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes. 2010 May;59(5):1244-53. Epub 2010 Feb 11.

3. 3 Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279 LaRosa JC et al. N Engl J Med 2005;352:1425-1435 LDL-C achieved mg/dL (mmol/L) WOSCOPS – Placebo AFCAPS - Placebo ASCOT - Placebo AFCAPS - RxWOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Placebo LIPID - Rx 4S - Placebo CARE - Rx LIPID - Placebo CARE - Placebo HPS - Rx 0 5 10 15 20 25 30 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Event rate (%) 6 Secondary Prevention Primary Prevention Rx - Statin therapy PRA – pravastatin ATV - atorvastatin 200 (5.2) PROVE-IT - PRA PROVE-IT – ATV TNT – ATV10 TNT – ATV80 LDL-Cholesterol and Coronary event rate

4. GALAXY PROGRAMME

5. The GALAXY Programme™ is designed to confirm the hypothesis that: 1.the statin with the best effects on the atherogenic lipid profile and beneficial changes on inflammatory markers will 2.deliver profound benefits on atherosclerosis 3.in turn leading to the best reductions in cardiovascular morbidity and mortality.

6. JUPITER trial ■ Effect of Rosuvastatin ・ Compliance; 75% -37% -50% +4% -17% N Engl J Med 2008;359:2195-207.

7. NNT: 95 31 ･･ 25 (2years) (4years) (5years) N Engl J Med 2008;359:2195-207. 20 mg occurrence of a first major cardiovascular event, defined as nonfatal MI, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes

8. Lancet 2010; 376: 333–39 Center for Cardiovascular Disease Prevention (Prof P M Ridker MD, S Mora MD, J G MacFadyen BA, R J Glynn ScD) and the Division of Cardiovascular Medicine (P M Ridker, S Mora, Prof P Libby MD), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; McGill University Health Centre, Montreal, Quebec, Canada (Prof J Genest MD); Weill Cornell Medical College of Cornell University, New York, NY, USA (Prof A M Gotto MD); Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Denmark (Prof B G Nordestgaard MD); and Departments of Cardiology and Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands (S M Boekholdt MD, Prof J J P Kastelein MD)

9. HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. Background

10. Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3 ・ 37 (130mg/dl) mmol/L and highsensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer- generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT00239681. Methods

11. 20 mg N Engl J Med 2008;359:2195-207.

13. HDL-C (mg/dl) men0-3838-4545-5555- HDL-C (mg/dl) women0-4646-5454-6666- LDL-C (mg/dl) men106109110107

14. HDL-C (mg/dl) men0-3838-4545-5555- HDL-C (mg/dl) women0-4646-5454-6666- 34425063 40506074 34425165 41516175 34425063 40506074 36445368 42536378

17. Results For 17 802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0 ・ 0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2 ・ 80 (108) mmol/L [IQR 2 ・ 43–3 ・ 24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0 ・ 54, 95% CI 0 ・ 35–0 ・ 83, p=0 ・ 0039) and on-treatment (0 ・ 55, 0 ・ 35–0 ・ 87, p=0 ・ 0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1 ・ 42 (55) mmol/L [IQR 1 ・ 14–1 ・ 86]), no signifi cantrelationships were noted between quartiles of HDL- cholesterol concentration and vascular risk either at baseline (1 ・ 12, 0 ・ 62–2 ・ 03, p=0 ・ 82) or on-treatment (1 ・ 03, 0 ・ 57–1 ・ 87, p=0 ・ 97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group.

18. Conclusion Although measurement of HDL- cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol.

19. Editorial Comments With the advent of more potent drugs, the issue of whether raising HDL cholesterol concentrations reduces cardiovascular risk in patients with very low LDL cholesterol needs to be tested in clinical studies. Dissociating HDL cholesterol from cardiovascular risk *Derek J Hausenloy, Lionel Opie, Derek M Yellon Vol 376:305-306 July 31, 2010

20. Message/Comments スタチン治療の使用指標として LDL- C/HDL-C が言われるが、 LDL-C を低下さ せてしまえば比について有用性は？

22. (n=730) (n=711)

23. 76% 54%

24. 1Washington University, St. Louis, Missouri; 2The George Washington University, The Biostatistics Center, Rockville, Maryland; the 3the School of Medicine, Yale University, New Haven, Connecticut; the 4University of Wisconsin–Madison, Madison, Wisconsin; and the 5University of Missouri, Columbia, Missouri. Diabetes 59:1244–1253, 2010

25. Background The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT).

26. During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents. Methods adults: 18–39 years vs. adolescents: 13–17

27. Flow Diagram of Subjects in EDIC Year 10 Retinopathy Evaluation By Adults and Adolescents

32. FIG. 2. Estimated cumulative incidence of further 3-step progression of retinopathy from DCCT closeout, by DCCT treatment group, through EDIC year 4, for adolescents (A) and for adults (B); through EDIC year 10, for adolescents (C) and for adults (D). Subjects with prior scatter photocoagulation during DCCT (7 adolescents and 29 adults) were excluded from analyses. Based on Weibull regression models adjusted for the level of retinopathy at the end of the DCCT, primary vs. secondary cohort, the A1C value on entry to the DCCT, and diabetes duration at DCCT baseline. Hazard reduction was for intensive therapy compared with conventional therapy.

35. FIG. 3. Sensitivity of further retinopathy progression in EDIC to difference in DCCT mean A1C for adolescents and adults, for a 10% increase in A1C in INT (A) and CON (B), and a 10% decrease in A1C in INT (C) and CON (D). Based on separate Weibull regression models in INT and CON, adjusted for the level of retinopathy at the end of the DCCT, primary vs. secondary cohort, A1C value on entry to the DCCT, diabetes duration at DCCT baseline, log transformation of DCCT mean A1C, age (adult vs. adolescent), and interaction of DCCT mean A1C and age.

36. Results During 10 years of follow-up, HbA1c (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P < 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%).

37. Conclusion Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.

38. Message 糖尿病性網膜症に対しては血糖管理はやはりと ても重要で血糖管理の継続も必要！ 中学生くらいで血糖管理を一生懸命しても継続 しないと管理しなかった人と差が出なくなるら しい？

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