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 3 月 24 日 8:30-8:55 ８階 医局 ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011 Mar 3;364(9):818-28. Zheng W, McLerran DF, Rolland B, Zhang X, Inoue M, Matsuo K, He J, Gupta PC, Ramadas K, Tsugane S, Irie F, Tamakoshi A, Gao YT, Wang R, Shu XO, Tsuji I, Kuriyama S, Tanaka H, Satoh H, Chen CJ, Yuan JM, Yoo KY, Ahsan H, Pan WH, Gu D, Pednekar MS, Sauvaget C, Sasazuki S, Sairenchi T, Yang G, Xiang YB, Nagai M, Suzuki T, Nishino Y, You SL, Koh WP, Park SK, Chen Y, Shen CY, Thornquist M, Feng Z, Kang D, Boffetta P, Potter JD. Association between body-mass index and risk of death in more than 1 million Asians. N Engl J Med. 2011 Feb 24;364(8):719-29.

2. Original Article Effects of Intensive Glucose Lowering in Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes Study Group N Engl J Med Volume 358(24):2545-2559 June 12, 2008 The members of the writing group (Hertzel C. Gerstein, M.D., M.Sc., McMaster University and Hamilton Health Sciences, Population Health Research Institute, Hamilton, ON, Canada; Michael E. Miller, Ph.D., Robert P. Byington, Ph.D., and David C. Goff, Jr., M.D., Ph.D., Wake Forest University School of Medicine, Winston- Salem, NC; J. Thomas Bigger, M.D., Columbia University College of Physicians and Surgeons, New York; John B. Buse, M.D., Ph.D., University of North Carolina School of Medicine, Chapel Hill; William C. Cushman, M.D., Memphis Veterans Affairs Medical Center, Memphis, TN; Saul Genuth, M.D., and Faramarz Ismail- Beigi, M.D., Ph.D., Case Western Reserve University, Cleveland; Richard H. Grimm, Jr., M.D., Ph.D., Berman Center for Outcomes and Clinical Research, Minneapolis; Jeffrey L. Probstfield, M.D., University of Washington, Seattle; Denise G. Simons- Morton, M.D., Ph.D., National Heart, Lung, and Blood Institute, Bethesda, MD; and William T. Friedewald, M.D., Columbia University Mailman School of Public Health, New York) assume responsibility for the overall content and integrity of this article. Address reprint requests to Dr. Byington at the Division of Public Health Sciences, Wake Forest University School of Medicine, Medical Center Blvd., Winston- Salem, NC 27157, or at bbyingto@wfubmc. edu.

4. Characteristics of the Patients at Baseline The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

5. Median Glycated Hemoglobin Levels at Each Study Visit The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

6. Prescribed Glucose- Lowering Drugs

7. Adverse Events, Clinical Measures, Tobacco Use, and Use of Nonglycemic Medication after Randomization

9. Kaplan-Meier Curves for the Primary Outcome and Death from Any Cause

10. Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups

11. Hertzel C. Gerstein, M.D., McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Michael E. Miller, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Saul Genuth, M.D., Case Western Reserve University, Cleveland; Faramarz Ismail-Beigi, M.D., Ph.D., Case Western Reserve University, Cleveland; John B. Buse, M.D., Ph.D., University of North Carolina, Chapel Hill; David C. Goff, Jr., M.D., Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Jeffrey L. Probstfield, M.D., University of Washington, Seattle; William C. Cushman, M.D., Memphis Veterans Affairs Medical Center, Memphis; Henry N. Ginsberg, M.D., Columbia University College of Physicians and Surgeons, New York; J. Thomas Bigger, M.D., Columbia University College of Physicians and Surgeons, New York; Richard H. Grimm, Jr., M.D., Ph.D, University of Minnesota, Berman Center for Outcomes and Clinical Research, Minneapolis; Robert P. Byington, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Yves D. Rosenberg, M.D., National Heart, Lung, and Blood Institute, Bethesda, MD; and William T. Friedewald, M.D., Columbia University College of Physicians and Surgeons, New York the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study N Engl J Med 2011;364:818-28.

12. Background Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events.

13. Methods We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial.

19. Because of the equivalent rates of hypoglycemia in the post-transition period, severe hypoglycemia cannot be implicated. Further analyses should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the bloodpressure and glycemia trials with respect to mortality.

20. Results Before the intensive therapy was terminated, the intensive- therapy group did not differ significantly from the standard- therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P = 0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.

21. Conclusions As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.)

22. Message/Comments ACCORD 研究のような「既に進行した糖 尿病患者の血糖を無理やり正常化させよう とするアプローチはありえない」を介入後 の観察を含めても確認した。 しかし、理由は？ 低血糖はありえないので．．．

24. 男女別 BMI と疾病合併率の関係 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● 女性 BMI (kg/m 2 ) 2 ) 2.5 2.0 1.5 1.0 0.5 0 2.5 2.0 1.5 1.0 0.5 0 疾 病 合 併 率 疾 病 合 併 率 20 25 30 21.9 3.5 3.0 2.5 2.0 1.5 3.5 3.0 2.5 2.0 1.5 疾 病 合 併 率 疾 病 合 併 率 20 25 30 22.2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 男性 BMI (kg/m 2 ) 2 ) 地方公務員 3500 名 (20-60 歳 ) の検診結果で疾患合併率を調査 肥満症診断基準検討委員会：肥満研究 2000;6(1):18-28

25. 日本人のまとめ 中年期男女の生命予後の観点から、 – 肥満は、健康上問題である事が日本人でも確認された。 – 痩せも、健康上問題であり、特に、日本人男性では肥満より も、痩せ・痩せ傾向の方が公衆衛生上インパクトの大きな問 題であった。 – 最も死亡リスクの低い BMI は 男性では 23 ～ 27 辺り、 女性では 19 ～ 25 辺り であった。 International Journal of Obesity 2002;26:529-537 厚生労働省多目的コホート研究コホート I の 10 年間追跡結果

26. BMI と死亡危険率の関連 米国において約 100 万人を 14 年間追跡した統計成績 ( 癌研究の疫学調査 ) 1982 年 ( 平均 57 歳， 30 歳以上 ) ～ 1996 年 : 男 457,785 人，女 588,369 人 EUGENIAE. CALLEN et al: N Engl J Med 341:1097-105, 1999 From the Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, 1599 Clifton Rd. NE, Atlanta, GA 30329. 男 23.5-24.9 ，女 22.0-23.4 kg/m 2 が最低値

27. Association between BMI and all-cause mortality in men and women in the VHM&PP cohort 1985–2006, stratified by age at enrolement. Hazard Rate Ratios adjusted for smoking status. The reference category is BMI 22.5–24.9 kg/m 2. Error bars indicate 95% confidence intervals Eur J Epidemiol (2009) 24:83–91 Body mass index and mortality: results of a cohort of 184,697 adults in Austria

28. Body Weight and Mortality Among Men and Women in China 169 871 Chinese men and women aged 40 years or older Gu, D. et al. JAMA 2006;295:776-783

29. N Engl J Med 2010;363:2211-9. Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, Moore SC, Tobias GS, Anton-Culver H, Freeman LB, Beeson WL, Clipp SL, English DR, Folsom AR, Freedman DM, Giles G, Hakansson N, Henderson KD, Hoffman-Bolton J, Hoppin JA, Koenig KL, Lee IM, Linet MS, Park Y, Pocobelli G, Schatzkin A, Sesso HD, Weiderpass E, Willcox BJ, Wolk A, Zeleniuch-Jacquotte A, Willett WC, Thun MJ. Body-mass index and mortality among 1.46 million white adults. 2010 年 12 月 9 日

30. N Engl J Med 2011;364:719-29.

31. Background Most studies that have evaluated the association between the body-mass index (BMI) and the risks of death from any cause and from specific causes have been conducted in populations of European origin.

32. Methods We performed pooled analyses to evaluate the association between BMI and the risk of death among more than 1.1 million persons recruited in 19 cohorts in Asia. The analyses included approximately 120,700 deaths that occurred during a mean follow-up period of 9.2 years. Cox regression models were used to adjust for confounding factors.

38. N Engl J Med 2010;363:2211-9.

39. Results In the cohorts of East Asians, including Chinese, Japanese, and Koreans, the lowest risk of death was seen among persons with a BMI (the weight in kilograms divided by the square of the height in meters) in the range of 22.6 to 27.5. The risk was elevated among persons with BMI levels either higher or lower than that range — by a factor of up to 1.5 among those with a BMI of more than 35.0 and by a factor of 2.8 among those with a BMI of 15.0 or less. A similar U-shaped association was seen between BMI and the risks of death from cancer, from cardiovascular diseases, and from other causes. In the cohorts comprising Indians and Bangladeshis, the risks of death from any cause and from causes other than cancer or cardiovascular disease were increased among persons with a BMI of 20.0 or less, as compared with those with a BMI of 22.6 to 25.0, whereas there was no excess risk of either death from any cause or cause-specific death associated with a high BMI.

40. Conclusions Underweight was associated with a substantially increased risk of death in all Asian populations. The excess risk of death associated with a high BMI, however, was seen among East Asians but not among Indians and Bangladeshis.

41. Message/Comments BMI と死亡率は U 字の関係がアジア人でも示さ れた。