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 2011 年 6 月 23 日 8:30-8:55 ８階 医局 Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellström B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Grönhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R; on behalf of the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011 Jun 8. [Epub ahead of print] Grøntved A, Hu FB. Television viewing and risk of type 2 diabetes, cardiovascular disease, and all-cause mortality: a meta-analysis. JAMA. 2011 Jun 15;305(23):2448-55.

2. スタチン介入大規模臨床試験における LDL-C と冠動脈疾患イベント発症率の関係 Fisher M:Heart,90(3),336-340(2004) Mean LDL cholesterol ( mmol / l ) (mg/dl) CARE DM (placebo) 4S DM (placebo) LIPID DM (placebo) 4S DM (simvastatin) CARE DM (pravastatin) LIPID DM (pravastatin) 4S (placebo) LIPID (placebo) CARE (pravastatin) LIPID (pravastatin) CARE (placebo) AFCAPS (lovastatin ) AFCAPS (placebo) WOSCOPS (pravastatin) WOSCOPS (placebo) Patient with CHD event (mean%) Diabetes secondary Secondary prevention Primary prevention 1.52.02.53.03.54.04.55.05.5 0 5 10 15 20 30 4S (simvastatin) 5877 116 154 193

3. Ezetimibe 高脂血症治療剤 2007 年 6 月 11 日新発売 －小腸コレステロールトランスポーター阻害剤 － 薬価： 250.9 円 Ezetimibe diminishes intestinal cholesterol absorption by inhibiting the Niemann–Pick C1- like 1 (NPC1L1) enterocyte receptor, License to eat! "Take this pill and I can eat as much eggs and cake as I want." 223.9 円

4. Ezetimibe Simvastatin

5. Effects of Simvastatin and Combined Therapy with Simvastatin plus Ezetimibe on Levels of Cholesterol and Triglycerides N Engl J Med 358(14):1431-1443, 2008 ENHANCE

6. Mean (±SE) Intima- Media Thickness of the Carotid Artery during 24 Months of Therapy N Engl J Med 358(14):1431-1443, 2008 ENHANCE

8. www.thelancet.com Published online June 9, 2011 DOI:10.1016/S0140-6736(11)60739-3 1 Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK (Prof C Baigent FRCP, M J Landray FRCP, C Reith MRCP, J Emberson PhD, D Lewis MRCP, W Herrington MRCP, M Mafh am MD, K Wallendszus MSc, Prof J Armitage FRCP, A Baxter BA, C Bray PhD, Y Chen DPhil, Prof Z Chen DPhil, M Hill DPhil, C Knott MSc, S Parish DPhil, D Simpson, A Young DPhil, Prof R Collins FMedSci); University College London, London, UK (D C Wheeler FRCP); North Bristol NHS Trust, Bristol, UK (C Tomson DM); Department of Medicine 1, Division of Nephrology, University of Wuerzburg, Wuerzburg, Germany (Prof C Wanner MD, V Krane MD); The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia (Prof A Cass FRACP, Prof B Neal FRCP); Sydney School of Public Health, Children’s Hospital at Westmead, University of Sydney, Sydney, NSW, Australia (Prof J Craig PhD); China Oxford Centre for International Health Research, Fuwai Hospital, Beijing, Chinese Academy of Medical Sciences and Peking Union Medical College, China (L Jiang MD); Department of Medicine and Haemodialysis Unit, Sultanah Aminah Hospital, Johor Bahru, Malaysia (L S Hooi FRCP); University of British Columbia, Vancouver, BC, Canada (Prof A Levin FRCPC); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA (Prof L Agodoa FACP); Harvard Medical School, VA Boston, Brigham and Women’s Hospital, Boston, MA, USA (Prof M Gaziano MD); University of Minnesota, Minneapolis, MN, USA (Prof B Kasiske FACP); Dunedin School of Medicine, University of Otago, Otago, New Zealand MD); Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (Prof B Feldt-Rasmussen MD); Division of Nephrology, Department of Medicine, Rajavithi Hospital, Bangkok, Thailand (U Krairittichai MD); Renal Division, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand (V Ophascharoensuk MD); University Hospital, Uppsala, Sweden (Prof B Fellstrom MD); Renal Section, Department of Organ Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway (H Holdaas MD); Department of Nephrology, First School of Medicine and General University Hospital, Charles University, Prague, Czech Republic (Prof V Tesar FASN); Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland (Prof A Wiecek FRCP); Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands (Prof D Grobbee FESC); Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, Netherlands (Prof D de Zeeuw MD); Helsinki University Hospital, Helsinki, Finland (Prof C Gronhagen-Riska MD); Oxford Radcliff e Hospitals NHS Trust, Oxford, UK (T Dasgupta MRCP); Royal Darwin Hospital, Darwin, NT, Australia (W Majoni FRACP); Berman Center for Outcomes and Clinical Research, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN, USA (Prof R Grimm MD); University of Oslo and Centre of Preventive Medicine, Oslo University Hospital Ulleval, Oslo, Norway (Prof T Pedersen MD); Tobert Medical Consulting LLC, Warren, NJ, USA (J Tobert PhD); and Nuffi eld Department of Clinical Medicine, John Radcliff e Hospital, Oxford, UK (Prof P Sleight MD)

9. Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.

10. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607.

11. Figure 1: Trial profile Patients aged 40 years and older were eligible to participate if they had chronic kidney disease with more than one previous measurement of serum or plasma creatinine of at least 150 μmol/L (1 ・ 7 mg/dL) in men or 130 μmol/L (1 ・ 5 mg/dL) in women, whether receiving dialysis or not.

12. Table 1: Baseline demographic features and laboratory measurements by treatment allocation Chol mg/dl x 0.0259 = 1 mmol/L 100mg/dl = 2.59 mmol/L TG mg/dl x 0.0113 = 1 mmol/L 100mg/dl = 1.13 mmol/L

14. major vascular events in SHARP (defined as non-fatal myocardial infarction or any cardiac death, any stroke, or any arterial revascularisation excluding dialysis access procedures)

16. Figure 4: Major atherosclerotic events by baseline characteristics χ2 tests on 1 degree of freedom are shown for heterogeneity between rate ratios within dichotomous categories and for trend within other categories. BP=blood pressure. MDRD=Modified Diet in Renal Disease formula.17 GFR=glomerular filtration rate.

17. Figure 5: Cause-specific and overall mortality CHD=coronary heart disease.

18. Table 3: Cancer incidence and cancer mortality by site

19. ULN=upper limit of normal. *Myopathy, defi ned as creatine kinase greater than ten times the ULN with muscle symptoms, occurred in nine (0 ・ 19%) versus fi ve (0 ・ 11%) patients, of whom eight (0 ・ 17%) versus three (0 ・ 06%) were taking allocated treatment (and not taking any non- study statin) at the time of the event (both p=NS); for rhabdomyolysis, defi ned as myopathy with creatine kinase greater than 40 times the ULN (and hence included in counts of myopathies), the corresponding numbers were four (0 ・ 09%) versus one (0 ・ 02%) and four (0 ・ 09%) versus none, again both p=NS. †Consecutive increases of alanine or aspartate transaminase greater than three times the ULN. Table 4: Eff ects of allocation to simvastatin plus ezetimibe on muscle and hepatobiliary system

20. Panel: Research in context Systematic review The Cholesterol Treatment Trialists’ collaborative meta-analysis of individual participant data from 26 randomised trials5 has shown that lowering LDL cholesterol with a statin regimen reduces the risk of myocardial infarction, coronary death, ischaemic stroke, and coronary revascularisation procedures by about a fifth per 1 mmol/L LDL cholesterol reduction in a wide range of people. However, none of the three trials19–21 in patients with chronic kidney disease included in that meta-analysis reported a signifi cant reduction in its primary vascular disease outcome, leading to uncertainty about whether lowering of LDL cholesterol is effective in renal patients. Interpretation The SHARP randomised trial has now shown that lowering of LDL cholesterol with simvastatin plus ezetimibe safely reduces the risk of major atherosclerotic events in a wide range of patients with chronic kidney disease. When the SHARP results are compared with those of the previous statin trials in renal patients, it appears that the absence of significant reductions in earlier trials could have been due both to the much smaller number and the much smaller proportion of vascular events in their primary outcomes that were related to atherosclerosis and, hence, preventable by lowering of LDL cholesterol.

21. Figure 6: Effects of LDL-lowering therapy on particular vascular outcomes in four trials in patients with chronic kidney disease and 23 trials in other patients Data from the Cholesterol Treatment Trialists’ Collaboration.5 χ² tests are shown for heterogeneity between rate ratios for each outcome in the four trials (4D,19 ALERT,21 AURORA,20 and SHARP) in patients with chronic kidney disease. MI=myocardial infarction. LDL-C=LDL-cholesterol.

22. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0 ・ 85 mmol/L (SE 0 ・ 02; with about two-thirds compliance) during a median follow-up of 4 ・ 9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11 ・ 3%] simvastatin plus ezetimibe vs 619 [13 ・ 4%] placebo; rate ratio [RR] 0 ・ 83, 95% CI 0 ・ 74–0 ・ 94; log-rank p=0 ・ 0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4 ・ 6%] vs 230 [5 ・ 0%]; RR 0 ・ 92, 95% CI 0 ・ 76–1 ・ 11; p=0 ・ 37) and there were significant reductions in non-haemorrhagic stroke (131 [2 ・ 8%] vs 174 [3 ・ 8%]; RR 0 ・ 75, 95% CI 0 ・ 60–0 ・ 94; p=0 ・ 01) and arterial revascularisation procedures (284 [6 ・ 1%] vs 352 [7 ・ 6%]; RR 0 ・ 79, 95% CI 0 ・ 68–0 ・ 93; p=0 ・ 0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional eff ects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0 ・ 2%] vs 5 [0 ・ 1%]). There was no evidence of excess risks of hepatitis (21 [0 ・ 5%] vs 18 [0 ・ 4%]), gallstones (106 [2 ・ 3%] vs 106 [2 ・ 3%]), or cancer (438 [9 ・ 4%] vs 439 [9 ・ 5%], p=0 ・ 89) and there was no significant excess of death from any non-vascular cause (668 [14 ・ 4%] vs 612 [13 ・ 2%], p=0 ・ 13).

23. Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Funding Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

24. Message/Comments これまで Ezetimibe の有用性は？だったが、 やっとスタチンの併用で有意差のあるもの が出た。 今回 CKD が対象。今後 IMPROVE-IT が出 る予定。

26. JAMA. 2011;305(23):2448-2455 Institute of Sport Science and Clinical Biomechanics, Department of Exercise Epidemiology, Center of Research in Childhood Health, University of Southern Denmark, Odense (Mr Grøntved); and Departments of Nutrition (Mr Grøntved and Dr Hu) and Epidemiology (Dr Hu), Harvard School of Public Health, Channing Laboratory, Harvard Medical School and Brigham and Women’s Hospital (Dr Hu), Boston, Massachusetts.

27. Context Prolonged television (TV) viewing is the most prevalent and pervasive sedentary behavior in industrialized countries and has been associated with morbidity and mortality. However, a systematic and quantitative assessment of published studies is not available. Objective To perform a meta-analysis of all prospective cohort studies to determine the association between TV viewing and risk of type 2 diabetes, fatal or nonfatal cardiovascular disease, and all-cause mortality.

28. Data Sources and Study Selection Relevant studies were identified by searches of the MEDLINE database from 1970 to March 2011 and the EMBASE database from 1974 to March 2011 without restrictions and by reviewing reference lists from retrieved articles. Cohort studies that reported relative risk estimates with 95% confidence intervals (CIs) for the associations of interest were included. Data Extraction Data were extracted independently by each author and summary estimates of association were obtained using a random-effects model.

33. Data Synthesis Of the 8 studies included, 4 reported results on type 2 diabetes (175 938 individuals; 6428 incident cases during 1.1 million person-years of followup), 4 reported on fatal or nonfatal cardiovascular disease (34 253 individuals; 1052 incident cases), and 3 reported on all-cause mortality (26 509 individuals; 1879 deaths during 202 353 person-years of follow-up). The pooled relative risks per 2 hours of TV viewing per day were 1.20 (95% CI, 1.14-1.27) for type 2 diabetes, 1.15 (95% CI, 1.06-1.23) for fatal or nonfatal cardiovascular disease, and 1.13 (95% CI, 1.07- 1.18) for all-cause mortality. While the associations between time spent viewing TV and risk of type 2 diabetes and cardiovascular disease were linear, the risk of all-cause mortality appeared to increase with TV viewing duration of greater than 3 hours per day. The estimated absolute risk differences per every 2 hours of TV viewing per day were 176 cases of type 2 diabetes per 100 000 individuals per year, 38 cases of fatal cardiovascular disease per 100 000 individuals per year, and 104 deaths for all- cause mortality per 100 000 individuals per year.

34. Conclusion Prolonged TV viewing was associated with increased risk of type 2 diabetes, cardiovascular disease, and all- cause mortality. We observed RRs of 1.20 for type 2 diabetes, 1.15 for cardiovascular disease, and 1.13 for all-cause mortality per every 2-hour increase in TV viewing per day.

35. Message/Comments テレビの視すぎはよくない！