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 2009 年 10 月１日 8:30-8:55 ８階 医局 Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ. 2009 Aug 18;339:b2942. doi: 10.1136/bmj.b2942. Takahisa Sawada1*, Hiroyuki Yamada1, Bjo¨ rn Dahlo¨ f 2, and Hiroaki Matsubara1, for the KYOTO HEART Study Group Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study European Heart Journal doi:10.1093/eurheartj/ehp363

3. Study Rosiglitazone Group Control Group Odds Ratio （ 95% Cl ） P Value no. of events / total no. （ % ） Myocardial infarction Small trials combined 44 / 10,280 （ 0.43 ） 22 / 6,105 （ 0.36 ） 1.45 （ 0.88-2.39 ） 0.15 DREAM 15 / 2,635 （ 0.57 ） 9 / 2,634 （ 0.34 ） 1.65 （ 0.74-3.68 ） 0.22 ADOPT 27 / 1,456 （ 1.85 ） 41 / 2,895 （ 1.44 ） 1.33 （ 0.80-2.21 ） 0.27 Overall 1.43 （ 1.03-1.98 ） 0.03 Death from cardiovascular causes Small trials combined 25 / 6,557 （ 0.38 ） 7 / 3,700 （ 0.19 ） 2.40 （ 1.17-4.91 ） 0.02 DREAM 12 / 2,365 （ 0.51 ） 10 / 2,634 （ 0.38 ） 1.20 （ 0.52-2.78 ） 0.67 ADOPT 2 / 1,456 （ 0.14 ） 5 / 2,854 （ 0.18 ） 0.80 （ 0.17-3.86 ） 0.78 Overall 1.64 （ 0.98-2.74 ） 0.06 Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Nissen SE.:N Engl J Med.356.2007.May 21.Online

4. Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Assessment of the cardiovascular risks and health benefits of rosiglitazone David J. Graham, MD, MPH Office of Surveillance and Epidemiology Food and Drug Administration July 30, 2007 David J. Graham, MD, MPH Office of Surveillance and Epidemiology Food and Drug Administration July 30, 2007

5. Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Does CV risk with RSG differ from that with PIO? Yes From DREAM, relatively low-risk population: RSG increased risk by ~40% c/w PBO From PROactive, high risk population: PIO decreased risk by ~15% c/w PBO From RSG meta-analysis: RSG increased risk of serious IHD by ~40% c/w all comparators & by ~70% c/w PBO From PIO meta-analysis: PIO decreased risk by ~25% c/w all comparators From head-to-head GLAI: RSG increased risk 3.5-fold c/w PIO Yes From DREAM, relatively low-risk population: RSG increased risk by ~40% c/w PBO From PROactive, high risk population: PIO decreased risk by ~15% c/w PBO From RSG meta-analysis: RSG increased risk of serious IHD by ~40% c/w all comparators & by ~70% c/w PBO From PIO meta-analysis: PIO decreased risk by ~25% c/w all comparators From head-to-head GLAI: RSG increased risk 3.5-fold c/w PIO

6. 10 8 6 4 2 0 020406080100120140 7,836 8,554 6,470 6,556 5,509 5,370 4,133 4,026 3,735 3,679 3,534 3,505 2,826 2,810 2,143 2,146 症例数 対照群 アクトス群 アクトスのイベントに及ぼす影響（メタ解析） （週 ） 0.0050.72,0.940.82 ピオグリタゾ ン vs 対照群 p値p値 95% 信頼区間ハザード比 （%）（%） 総死亡、心筋梗塞、脳卒中 19 の臨床試験から 16,390 例を対象にピオグリタゾン群と対照群（プラセボ、 SU 薬、 BG 薬、インスリン）に おける、 イベントの発症率をメタ解析した。 対照群 ピオグリタゾン群 Lincoff A.M. et al.:JAMA,298,1180,2007.

7. 1 Division of Clinical Pharmacology and Toxicology, Department of Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5 2 Department of Medicine, University of Toronto 3 Department of Pediatrics, University of Toronto 4 Department of Health Policy, Management, and Evaluation, University of Toronto 5 Institute for Clinical Evaluative Sciences, Toronto 6 Women’s College Hospital, Toronto 7 Department of Public Health Sciences, University of Toronto 8 Applied Health Research Centre, Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto BMJ 2009;339:b2942

8. AIM To compare the risk of acute myocardial infarction, heart failure, and death in patients with type 2 diabetes treated with rosiglitazone and pioglitazone.

9. Method Setting Ontario, Canada. Participants Outpatients aged 66 years and older who were started on rosiglitazone or pioglitazone between 1 April 2002 and 31 March 2008. Main outcome measure Composite of death or hospital admission for either acute myocardial infarction or heart failure. In a secondary analysis, each outcome was also examined individually.

17. Results 39 736 patients who started on either pioglitazone or rosiglitazone were identified. During the six year study period, the composite outcome was reached in 895 (5.3%) of patients taking pioglitazone and 1563 (6.9%) of patients taking rosiglitazone. After extensive adjustment for demographic and clinical factors and drug doses, pioglitazone treated patients had a lower risk of developing the primary outcome than did patients treated with rosiglitazone (adjusted hazard ratio 0.83, 95% confidence interval 0.76 to 0.90). Secondary analyses revealed a lower risk of death (adjusted hazard ratio 0.86, 0.75 to 0.98) and heart failure (0.77, 0.69 to 0.87) with pioglitazone but no significant difference in the risk of acute myocardial infarction (0.95, 0.81 to 1.11). One additional composite outcome would be predicted to occur annually for every 93 patients treated with rosiglitazone rather than pioglitazone.

18. Conclusion Among older patients with diabetes, pioglitazone is associated with a significantly lower risk of heart failure and death than is rosiglitazone. Given that rosiglitazone lacks a distinct clinical advantage over pioglitazone, continued use of rosiglitazone may not be justified.

19. Message Rosiglitazone と pioglitazone の比較では両者 の差が存在する。 Pioglitazone が有利であれば rosiglitazone を使う理由がない。

21. Ca 拮抗薬 ARB/ACE 阻害薬利尿薬 β 遮断薬 左室肥大 ●● 心不全 ●*1●*1 ●●*1●*1 心房細動（予防） ● 頻脈 ●*2●*2 ● 狭心症 ●●*3●*3 心筋梗塞後 ●● 蛋白尿 ● 腎不全 ●●*4●*4 脳血管障害慢性期 ●●● 糖尿病 /MetS* 5 ● 高齢者 ●*6●*6 ●● * 1 少量から開始し、注意深く漸増する * 2 非ジヒドロピリジン系 Ca 拮抗薬 * 3 冠攣縮性狭心症に は注意 * 4 ループ利尿薬 * 5 メタボリックシンドローム * 6 ジヒドロピリジン系 Ca 拮抗薬 高血圧治療ガイドライン 2009. 主要降圧薬の積極的適応

22. * 血圧が 130-139/80-89mmHg で生活習慣の修正で降圧目標が見込める場合は、 3 か月を超えない範囲で生活習慣の修正により降圧を図る 治療開始血圧 130/80mmHg 以上 生活習慣の修正・血糖管理と同時に薬物療法 * 第一選択薬： ACE 阻害薬、 ARB 効果不十分 用量を増加 Ca 拮抗薬、利尿薬を併用 効果不十分 3 剤併用： ARB あるいは ACE 阻害薬、 Ca 拮抗薬、利尿薬 降圧目標 130/80mmHg 未満 高血圧治療ガイドライン 2009. 糖尿病を合併する高血圧の治療計画

23. P110 PI 3-kinase P-Ser- -Tyr-P P-Ser- AⅡAⅡ AT-R P-Ser- -Tyr-P α β Insulin Receptor IRS-1 P85 Diagram of A Ⅱ signaling interactions with the insulin receptor, IRS-1, and PI 3 kinase in RASMC Folli et al: J. Clin. Invest. 100:2158–2169, 1997

24. ARB の種類と糖尿病の発症 （２型糖尿病治療における ARB の意義） 名称投与薬糖尿病の発症リスク比較対照薬 VALUEARB Ca 拮抗薬 LIFEARB  遮断薬 SCOPEARB通常薬 SHEP利尿薬偽薬 CAPPP ACE 阻害薬 利尿薬 /  遮断薬 HOPE ACE 阻害薬 偽薬 INSIGHT Ca 拮抗薬 配合利尿薬 (%) (2001) (2004) (2002) (2005) (2004) (2003) VALUE, LIFE, SCOPE, CHARM のメタ解析の発症リスクは -23% NAVIGATOR, ONTARGET, TRANSCEND が進行中

25. 糖尿病予防効果 ONTARGET20084.7 ARB399854210.0ACEI36685769.2 ONTARGET20084.7 ARB+ACEI3238502 8.1ACEI36685769.2 松田昌文： DREAM study 内分泌・糖尿病科 26(1):35-41, 2008.

28. JIKEI HEART 1 従来治療群（ Ca 拮抗剤や ACE 阻害薬の増量・新規使用などによる）のサブ解析がさ れていない。 （解析中と思われるが Ca 拮抗剤、 ACE 阻害薬あるいは両方使用の３群の差を知りた い） バルサルタン群には ACE 阻害薬がすでに投与されている患者も入っている。 従って ACEI と ARB の併用という患者のバイアスがかかっていないか。 （参考）バルサルタン群とは 従来治療群にバルサルタンを追加投与する 群 従来治療群で ACE 阻害薬使用群と非使用群の比較検討は？ CKD 予防としての ARB の観点から腎不全進行抑制ができなかったのは不思議である。 （従来治療群に ACE 阻害薬が多く使われていて、そのために差が出なかった？） 腎機能低下例でのサブ解析で ACE 阻害薬 and/orARB 群と非 ACE 阻害薬 and/orARB 群 で差が出るかも知れない。 （ Solomon SD Circulation １１４ ;26 ： 2006 ） 患者数がスタートから終了時点で バルサルタン群 １５４１例から３６８例 従来治療群 １５４０例から３４３例 に減少している。この減少数は 一般的な数なのか？ http://blog.m3.com/reed/20070910/JIKEI__HEART_Study_2_

29. JIKEI HEART 2 http://rockymuku.sakura.ne.jp/zyunnkannkinaik a/JIKEI%20HEART%20STUDY%20to%20PRO BEhou.pdf http://rockymuku.sakura.ne.jp/zyunnkannkinaik a/JIKEI%20HEART%20STUDY%20to%20PRO BEhou.pdf PROBE を用いた時は 「入院」のような介入 方法はエンドポイントにいれてはいけない。

31. Aim The objective was to assess the add-on effect of valsartan on top of the conventional treatment for high-risk hypertension in terms of the morbidity and mortality.

32. Method The KYOTO HEART Study was of a multicentre, Prospective Randomised Open Blinded Endpoint (PROBE) design, and the primary endpoint was a composite of fatal and non-fatal cardiovascular events (clintrials.gov NCT00149227). A total of 3031 Japanese patients (43% female, mean 66 years) with uncontrolled hypertension were randomized to either valsartan add-on or non-ARB treatment.

37. Procedure After confirming eligibility, patients were randomized in accordance with the minimization method with eight factors (age, gender, dyslipidaemia, diabetes mellitus, smoking, obesity, history of CAD and/or cerebrovascular disease, and history of congestive heart failure), either to the valsartan add-on group or to the conventional treatment group. For the valsartan add-on group, valsartan 80 mg once daily in the morning was administered to the patient as an initial dose, the dose was doubled after 4 weeks if the initial dose could not achieve the target blood pressure of less than 140/ 90 mmHg (in patients with diabetes or renal disease, target blood pressure was set to less than 130/80 mmHg). After 8 weeks, an additional administration of other antihypertensive drugs with flexible dosing regimen other than ARBs and ACE inhibitors was allowed if necessary. Meanwhile, for the conventional treatment group, the antihypertensive drugs other than ARB and ACE inhibitors were provided for the patients to reach the target blood pressure. The periodical follow-up was implemented every 6 months after setting the sustainable dose.

38. Blood pressure at baseline was 157/88 and 133/76 mmHg at the end of study

39. stroke (hospitalization and diagnosed by CT and/or MRI), new or recurrent TIA (hospitalization and diagnosed by CT and/or MRI and sudden onset of neurological deficit persisting for less than 24 h without the history of atrial arrhythmia that causes embolism), new or recurrent acute myocardial infarction (hospitalization, ECGchange, and biomarkers for myocardial infarction), new occurrence or exacerbation of angina pectoris (hospitalization and diagnosed by both ECG changes corresponding with chest symptoms and coronary angiography showing.75% stenosis according to AHA/ACC guidelines), new occurrence or exacerbation of heart failure (hospitalization and clinical symptoms together with left ventricular dysfunction by echocardiography according to the guidelines of the AHA/ACC), dissecting aneurysm of the aorta (hospitalization and diagnosed by imaging technique), lower limb arterial obstruction, emergency thrombosis, transition to dialysis, and doubling of plasma Cr levels. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee.

42. Results Median follow-up period was 3.27 years. In both groups, blood pressure at baseline was 157/88 and 133/76 mmHg at the end of study. Compared with non-ARB arm, valsartan add-on arm had fewer primary endpoints (83 vs. 155; HR 0.55, 95% CI 0.42–0.72, P. 0.00001).

43. Conclusion Valsartan add-on treatment to improve blood pressure control prevented more cardiovascular events than conventional non-ARB treatment in high-risk hypertensive patients in Japan. These benefits cannot be entirely explained by a difference in blood pressure control.

44. Message PROBE 法 ( まぁ色々問題点もあるが ) で血圧が同 じにもかかわらず valsartan の優位性がしめされ た。 糖尿病の発症も減少！ （ JIKEI HEART はどうだったの？）