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Journal Club

Journal Club. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.

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Journal Club

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  1. Journal Club Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.  Lancet. 2009 May 23;373(9677):1765-72. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review andmeta-analysis. Lancet. 2009 May 23;373(9677):1773-9. 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 2009年5月28日　8:30-8:55 ８階　医局

  2. ACCORD　～HbA1Cの推移～ （%） 9.0 中央値 バーは四分位範囲 8.5 8.0 7.5 通常療法 HbA1C 7.0 6.5 強化療法 6.0 0 （年） 0 1 2 3 4 5 6 観察期間 症例数 通常療法 強化療法 5,109 5,119 4,774 4,768 4,588 4,585 3,186 3,165 1,744 1,706 455 476 436 471 2型糖尿病10,251例（平均年齢62.2歳）を無作為に強化療法群（HbA1C 6.0%未満、SBP 120mmHg未満）または通常療法（HbA1C 7.0～7.9%、SBP 140mmHg）に割り付けた。なお、脂質代謝異常に関してはシンバスタチンでLDL-Cをコントロールした状態でフェノフィブラートまたはプラセボを二重盲験下で投与した。そして、非致死性心筋梗塞、非致死性脳卒中、心血管死の複合エンドポイントを主要評価項目とし、平均3.5年のフォローアップを行った。 ACCORD Study Group：N.Engl.J.Med.,358,2545,2008.

  3. ACCORD　～主要評価項目～ （%） 25 累積イベント発症率 通常療法 20 15 10 強化療法 5 0 （年） 0 1 2 3 4 5 6 観察期間 症例数 強化療法 通常療法 5,128 5,123 4,843 4,827 4,390 4,262 2,839 2,702 1,337 1,186 475 440 448 395 【主要評価項目】初発の非致死心筋梗塞または非致死脳卒中、心血管死（心筋梗塞、心不全、不整脈、侵襲的冠インターベンション、心血管以外の手術後による心血管イベント、脳卒中、症状発現24時間以内における突然の心血管疾患死または心血管疾患が推定される死亡、他の血管疾患による死亡など）の複合エンドポイント 2型糖尿病10,251例（平均年齢62.2歳）を無作為に強化療法群（HbA1C 6.0%未満、SBP 120mmHg未満）または通常療法（HbA1C 7.0～7.9%、SBP 140mmHg）に割り付けた。なお、脂質代謝異常に関してはシンバスタチンでLDL-Cをコントロールした状態でフェノフィブラートまたはプラセボを二重盲験下で投与した。そして、非致死性心筋梗塞、非致死性脳卒中、心血管死の複合エンドポイントを主要評価項目とし、平均3.5年のフォローアップを行った。 ACCORD Study Group：N.Engl.J.Med.,358,2545,2008.

  4. ACCORD　～総死亡～ （%） 25 累積イベント発症率 20 15 強化療法 10 5 通常療法 0 （年） 0 1 2 3 4 5 6 観察期間 症例数 強化療法 通常療法 5128 5123 4972 4971 4803 4700 3250 3180 1748 1642 523 499 506 480 2型糖尿病10,251例（平均年齢62.2歳）を無作為に強化療法群（HbA1C 6.0%未満、SBP 120mmHg未満）または通常療法（HbA1C 7.0～7.9%、SBP 140mmHg）に割り付けた。なお、脂質代謝異常に関してはシンバスタチンでLDL-Cをコントロールした状態でフェノフィブラートまたはプラセボを二重盲験下で投与した。そして、非致死性心筋梗塞、非致死性脳卒中、心血管死の複合エンドポイントを主要評価項目とし、平均3.5年のフォローアップを行った。 ACCORD Study Group：N.Engl.J.Med.,358,2545,2008.

  5. ADVANCE trial ～HbA1Cの推移～ （%） 10.0 9.5 9.0 8.5 8.0 p<0.001 通常療法 7.5 平均HbA1C 7.0 6.5 強化療法 6.0 5.5 5.0 0.0 0 6 12 18 24 30 36 42 48 54 60 66 （ヵ月） 観察期間 HbA1C値 通常療法 強化療法 7.32 7.01 7.30 6.93 7.29 6.70 7.29 6.53 7.31 6.50 7.33 6.52 7.29 6.53 2型糖尿病患者11,140例を通常療法群と強化療法群に無作為に割り付け、5年間（中央値）にわたり大血管症と細小血管症の発症を検討した。なお、強化療法群はグリクラジド徐放性製剤30～120mg/日に他の糖尿病治療薬を併用し、HbA1C 6.5%以下を目指す。 The ADVANCE Collaborative Group：N.Engl.J.Med.,358,2560,2008.

  6. ADVANCE trial ～大血管症＋細小血管症への影響～ （%） 25 通常療法 累積イベント発症率 20 強化療法 15 10 5 0 0 6 12 18 24 30 36 42 48 54 60 66 （ヵ月） 観察期間 症例数 強化療法 通常療法 5,570 5,569 5,457 5,448 5,369 5,342 5,256 5,240 5,100 5,065 4,957 4,903 4,867 4,808 4,756 4,703 4,599 4,545 4,044 3,992 1,883 1,921 447 470 2型糖尿病患者11,140例を通常療法群と強化療法群に無作為に割り付け、5年間（中央値）にわたり大血管症と細小血管症の発症を検討した。なお、強化療法群はグリクラジド徐放性製剤30～120mg/日に他の糖尿病治療薬を併用し、HbA1C 6.5%以下を目指す。 The ADVANCE Collaborative Group：N.Engl.J.Med.,358,2560,2008.

  7. ADVANCE trial ～総死亡への影響～ （%） 25 累積イベント発症率 20 15 通常療法 10 強化療法 5 0 0 6 12 18 24 30 36 42 48 54 60 66 （ヵ月） 観察期間 症例数 強化療法 通常療法 5,571 5,569 5,533 5,537 5,490 5,503 5,444 5,445 5,411 5,399 5,361 6,354 5,312 5,301 5,246 5,237 5,189 5,178 4,653 4,643 2,211 2,240 523 544 2型糖尿病患者11,140例を通常療法群と強化療法群に無作為に割り付け、5年間（中央値）にわたり大血管症と細小血管症の発症を検討した。なお、強化療法群はグリクラジド徐放性製剤30～120mg/日に他の糖尿病治療薬を併用し、HbA1C 6.5%以下を目指す。 The ADVANCE Collaborative Group：N.Engl.J.Med.,358,2560,2008.

  8. VADT ～HbA1Cの推移～ （%） 10.5 10.0 9.5 * 9.0 8.4% 8.5 8.0 HbA1C 7.5 7.0 * 6.9% 6.5 6.0 通常療法 強化療法 5.5 *中央値 ～ ～ 0 登録時 1 2 3 4 5 6 （年） 観察期間 2型糖尿病1,791例を無作為にロシグリタゾンを中心とした治療により強化療法群（HbA1C 6.0%未満）、または通常療法（HbA1C 8.0～9.0%）に割り付けた。そして、主要心血管イベント（心血管死、心筋梗塞、脳卒中、うっ血性心不全、手術できない冠動脈疾患）、虚血部位の切断、冠動脈疾患へのインターベンション、末梢血管疾患を主要評価項目とした。 Duckworth W et al: N Engl J Med 360:129-39, 2009

  9. VADT ～非致死性イベント～ 100 非発症率 80 60 40 通常療法 強化療法 20 0 0 0 1 2 3 4 5 6 7 （年） 観察期間 2型糖尿病1,791例を無作為にロシグリタゾンを中心とした治療により強化療法群（HbA1C 6.0%未満）、または通常療法（HbA1C 8.0～9.0%）に割り付けた。そして、主要心血管イベント（心血管死、心筋梗塞、脳卒中、うっ血性心不全、手術できない冠動脈疾患）、虚血部位の切断、冠動脈疾患へのインターベンション、末梢血管疾患を主要評価項目とした。 Duckworth W et al: N Engl J Med 360:129-39, 2009

  10. VADT ～総死亡～ 100 非発症率 80 60 40 通常療法 強化療法 20 0 0 0 1 2 3 4 5 6 7 （年） 観察期間 2型糖尿病1,791例を無作為にロシグリタゾンを中心とした治療により強化療法群（HbA1C 6.0%未満）、または通常療法（HbA1C 8.0～9.0%）に割り付けた。そして、主要心血管イベント（心血管死、心筋梗塞、脳卒中、うっ血性心不全、手術できない冠動脈疾患）、虚血部位の切断、冠動脈疾患へのインターベンション、末梢血管疾患を主要評価項目とした。 Duckworth W et al: N Engl J Med 360:129-39, 2009

  11. Myocardial Infarction Mannucci E et al: NMCD 2009 in press

  12. Stroke Mannucci E et al: NMCD 2009 in press

  13. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (K K Ray MD, S R Kondapally Seshasai MD, S Wijesuriya BA, R Sivakumaran BA, S Nethercott BA, S Erqou MD); Department of Cardiology, Addenbrooke’s Hospital, Cambridge, UK (K K Ray); and Department of Medicine, University of Glasgow, Glasgow, UK (D Preiss MRCP, Prof N Sattar FRCPath) Lancet 2009; 373: 1765–72

  14. Background and Aim Whether intensive control of glucose reduces macrovascular events and all-cause mortality in individuals with type 2 diabetes mellitus is unclear. We undertook a meta-analysis of randomised controlled trials to determine whether intensive treatment is beneficial.

  15. Methods We selected fi ve prospective randomised controlled trials of 33 040 participants to assess the effect of an intensive glucose-lowering regimen on death and cardiovascular outcomes compared with a standard regimen. We gathered information about events of non-fatal myocardial infarction, coronary heart disease (fatal and non-fatal myocardial infarction), stroke, and all-cause mortality, and did a random-effects meta-analysis to obtain summary effect estimates for the clinical outcomes with use of odds ratios calculated from the raw data of every trial. Statistical heterogeneity across trials was assessed with the χ2 and I2 statistics.

  16. Summary The five trials provided information on 1497 events of non-fatal myocardial infarction, 2318 of coronary heart disease, 1127 of stroke, and 2892 of all-cause mortality during about 163 000 person-years of follow-up. The mean haemoglobin A1c concentration (HbA1c) was 0・9% lower for participants given intensive treatment than for those given standard treatment. Intensive glycaemic control resulted in a 17% reduction in events of non-fatal myocardial infarction (odds ratio 0・83, 95% CI 0・75–0・93), and a 15% reduction in events of coronary heart disease (0・85, 0・77–0・93). Intensive glycaemic control had no significant effect on events of stroke (0・93, 0・81–1・06) or all-cause mortality (1・02, 0・87–1・19).

  17. Conclusion Overall, intensive compared with standard glycaemic control significantly reduces coronary events without an increased risk of death. However, the optimum mechanism, speed, and extent of HbA1c reduction might be different in differing populations.

  18. Northwick Park Hospital, London, UK (L Bellamy MBBS); Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (J-P Casas MD); Department of Epidemiology and Public Health, University College London, London, UK (Prof A D Hingorani FRCP); and Institute for Women’s Health, University College London, London, UK (D Williams FRCP) Lancet 2009; 373: 1773–79

  19. Aim Women with gestational diabetes are at increased risk of developing type 2 diabetes, but the risk and time of onset have not been fully quantified. We therefore did a comprehensive systematic review and meta-analysis to assess the strength of association between these conditions and the effect of factors that might modify the risk.

  20. Methods We identified cohort studies in which women who had developed type 2 diabetes after gestational diabetes were followed up between Jan 1, 1960, and Jan 31, 2009, from Embase and Medline. 205 relevant reports were hand searched. We selected 20 studies that included 675,455 women and 10,859 type 2 diabetic events. We calculated and pooled unadjusted relative risks (RRs) with 95% CIs for each study using a random-effects model. Subgroups analysed were the number of cases of type 2 diabetes, ethnic origin, duration of follow-up, maternal age, body-mass index, and diagnostic criteria.

  21. Figure 1: Study selection process Modified with permission from Centre for Reviews and Dissemination.

  22. AGT=abnormal glucose tolerance. FPG=fasting plasma glucose. IGT=impaired glucose tolerance. i=median values at follow-up only. ii=includes all individuals diagnosed with diabetes ≥90 days after delivery living within Ontario, Canada. iii=report is cited as a case-control study in the summary but as a cohort study in the methods. iv=two or more FPG concentrations ≥5・8 mmol/L or 1 h glucose ≥10・6 mmol/L, 2 h glucose ≥9・2 mmol/L, 3 h glucose ≥8・1 mmol/L after 100 g glucose load. v=matched by age. vi=FPG concentrations ≥7 mmol/L only. vii=FPG concentrations ≥7 mmol/L or 2 h glucose ≥11・1 mmol/L, or both, after 75 g oral glucose load. viii=FPG concentrations ≥7 mmol/L, or 2 h glucose ≥11・1 mmol/L after 75 g glucose load. ix=FPG concentrations ≥7 mmol/L or 2 h glucose ≥11・1 mmol/L, or both, after 75 g glucose load. x=FPG concentrations ≥5・3 mmol/L or 2 h plasma glucose ≥8・6 mmol/L, or 3 h glucose ≥7・7 mmol/L after 100 g oral glucose load. xi=matched by ethnic origin. xii=matched by parity. xiii=FPG concentrations ≥5・5 mmol/L or 2 h glucose ≥8・0 mmol/L after 75 g glucose load (before Jan 01, 1999, FPG ≥7・8 mmol/L, 1 h glucose ≥9 mmol/L and 2 h glucose ≥7・0 mmol/L after 50 g glucose load). xiv=matched by year of delivery. xv=FPG concentrations ≥7 mmol/L or 2 h glucose ≥11・1 mmol/L, or both, (group also included gestational impaired glucose tolerance=FPG <7 mmol/L and 2 h glucose 7・8–11・1 mmol/L) after 75 g oral glucose load. xvi=matched by body-mass index. xvii=two or more FPG concentrations ≥5・3 mmol/L, 1 h glucose ≥10・0 mmol/L, 2 h glucose ≥8・6 mmol/L, 3 h glucose ≥7・8 mmol/L after 100 g glucose load. xviii=matched by gestational age at study entry. xix=FPG concentrations ≥4・8 mmol/L or 1 h glucose ≥10・0 mmol/L, or 2 h glucose ≥8・7 mmol/L after 75 g oral glucose load. xx=medications obtained from central drug register with complete population coverage plus questionnaire. xxi=two or more FPG concentrations ≥5・8 mmol/L, 1 h glucose ≥10・6 mmol/L, 2 h glucose ≥9・2 mmol/L, 3 h glucose ≥8・1 mmol/L after glucose (75 g) load. xxii=FPG concentrations ≥6 mmol/L or 2 h glucose ≥9 mmol/L after 75 g glucose load. xxiii=FPG concentrations ≥7・8 mmol/L, or 2 h glucose ≥11・1 mmol/L after 75 g oral glucose load. xxiv=2 h glucose concentration ≥9 mmol/L after 75 g glucose load. xxv=matched by waist to hip ratio. xxvi=2 h glucose concentration >10 mmol/L after 75 g glucose load. xxvii=matched by social background. xxviii=two or more FPG concentrations ≥5・0 mmol/L or 1 h glucose ≥9・5 mmol/L, 2 h glucose ≥8・1 mmol/L, 3 h glucose ≥7・0 mmol/L after 50 g glucose load. xxix=study included a third group of 15 women who were not included in this meta-analysis. xxx=FPG concentrations ≥7・8 mmol/L or 2 h glucose 11・1 mmol/L after 75 g glucose load. xxxi=two or more venous plasma glucose concentrations >3 SD from the mean in women without gestational diabetes after 50 g glucose load (0 min: 6・4 mmol/L; 30 min: 10・1 mmol/L; 1 h: 10・1 mmol/L; 90 min: 8・7 mmol/L; 2 h: 7・6 mmol/L; 150 min: 7・6 mmol/L; 3 h: 6・6 mmol/L). xxxii=fasting venous whole blood glucose concentration ≥5 mmol/L or 2 h venous whole blood glucose ≥8・0 mmol/L or 3 h glucose ≥6・9 mmol/L) after 100 g glucose load. xxxiii=matched by length of follow-up. xxxiv=FPG concentrations ≥7 mmol/L and 2 h glucose ≥7・8 mmol/L after 75 g oral glucose load. xxxv=matched by prepregnancy weight and weight gain. Table: Gestational diabetes mellitus (GDM) and development of type 2 diabetes mellitus (T2DM)

  23. Figure 2: Risk of type 2 diabetes mellitus (T2DM) after gestational diabetes mellitus (GDM) x-axis is log scale. Each solid square represents a relative risk. Horizontal lines indicate 95% CIs. df=degrees of freedom. *Dates not available.

  24. Figure 3: Funnel plot of 20 cohort studies included in meta-analysis x-axis is log scale. Dotted line is the summary relative risk (7・43).

  25. Figure 4: Risk of type 2 diabetes mellitus (T2DM) grouped by study characteristics (A), participant characteristics (B), and diagnostic criteria (C) x-axis is log scale. Each solid square represents a relative risk. Horizontal lines indicate 99% CIs. ADA=American Diabetes Association. BMI=body-mass index. df=degrees of freedom. EASD=European Association for Study of Diabetes. GDM=gestational diabetes mellitus. N/A=heterogeneity not applicable because one study analysed. NDDG=National Diabetes Data Group. *Average ages of women with and without GDM were not similar; therefore eff ect of maternal age could not be assessed. †Includes databases and obstetric reports (table).

  26. Results Women with gestational diabetes had an increased risk of developing type 2 diabetes compared with those who had a normoglycaemic pregnancy (RR 7・43, 95% CI 4・79–11・51). Although the largest study (659 164 women; 9502 cases of type 2 diabetes) had the largest RR (12・6, 95% CI 12・15–13・19), RRs were generally consistent among the subgroups assessed.

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