Journal Club

1. Journal Club Aruna DP, Brendan ME, Nancy RC, Nader R, Paul MR Effects of Initiating Insulin and Metformin on Glycemic Control and Inflammatory Biomarkers Among Patients With Type 2 Diabetes The LANCET Randomized Trial JAMA. 2009;302(11):1186-1194 Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. Epub 2009 Aug 30. 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９月17日　8:30-8:55 ８階　医局

2. The Lantus for C-reactive Protein Reduction in Early Treatment of Type 2 Diabetes (LANCET) trial Center for Cardiovascular Disease Prevention (Drs Pradhan, Everett, Cook, and Ridker), Donald W. Reynolds Center for Cardiovascular Research (Drs Pradhan, Everett, Cook, and Ridker), Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (Dr Ridker), Divisions of Cardiovascular Medicine (Drs Everett and Ridker) and Preventive Medicine (Drs Pradhan, Everett, Cook, and Ridker), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; Department of Pathology (Dr Rifai), Children’s Hospital Medical Center and Harvard Medical School, Boston; and Division of Cardiovascular Medicine (Dr Pradhan), Boston VA Medical Center, Boston. JAMA. 2009;302(11):1186-1194

3. Background and Aim Context:  As diabetes is in part an inflammatory condition,the initiation of insulin and/or metformin may beneficiallyreduce levels of inflammatory biomarkers such as high-sensitivityC-reactive protein (hsCRP). Objective:  To determine whether insulin alone or combinedwith metformin lowers levels of hsCRP, IL-6, and soluble tumornecrosis factor receptor 2 (sTNFr2) in patients with recent-onsettype 2 diabetes mellitus.

4. Method Design, Setting, and Participants:  Randomized 2 x 2factorial trial of open-label insulin glargine and placebo-controlledmetformin in 500 adults with type 2 diabetes (median time fromdiagnosis, 2.0 years), suboptimal glycemic control, and elevatedhsCRP levels. Patients were recruited from US office-based practicesbetween October 2006 and December 2008. Intervention:  Random allocation to 1 of 4 treatments (placebometformin only, placebo metformin and insulin glargine, activemetformin only, or active metformin and insulin glargine) withdose titration targeting fasting blood glucose less than 110mg/dL. Main Outcome Measures:  Change in hsCRP level (primary endpoint) and change in IL-6 and sTNFr2 levels (secondary end points)from baseline to 14 weeks.

5. Study Flow Diagram Pradhan, A. D. et al. JAMA 2009;302:1186-1194.

6. Baseline Characteristics of the Study Population Pradhan, A. D. et al. JAMA 2009;302:1186-1194.

7. Impact of Individual Treatments on Levels of Glucose, HbA1c, and Weight Pradhan, A. D. et al. JAMA 2009;302:1186-1194.

8. Effects of Study Medications on hsCRP Level: Main Effects and Individual Treatment Groups Pradhan, A. D. et al. JAMA 2009;302:1186-1194.

9. Impact of Individual Treatments on Inflammatory Biomarkers Pradhan, A. D. et al. JAMA 2009;302:1186-1194.

10. Occurrence of Adverse Events Pradhan, A. D. et al. JAMA 2009;302:1186-1194.

11. Results Levels of glucose and glycated hemoglobin (HbA1c)were significantly reduced with active treatment vs placebo(all P values <.001). Levels of hsCRP were reduced in all4 groups. There was no significant difference in hsCRP reductionamong those allocated to insulin (–11.8%; 95% CI, –18.7%to –4.4%) or to no insulin (–17.5%; 95% CI, –23.9%to –10.5%) (P for difference = .25), or amongthose allocated to active metformin (–18.1%; 95% CI, –24.4%to –11.1%) or placebo metformin (–11.2%; 95% CI,–18.1% to –3.7%) (P for difference = .17).In the individual treatment groups, despite a differential impacton glucose control, reductions in hsCRP in the metformin (–16.1%;95% CI, –25.1% to –6.1%) and metformin plus insulin(–20.1%; 95% CI, –28.8% to –10.4%) groupswere no different than reductions with placebo alone (–19.0%;95% CI, –27.8% to –9.1%; P = .67 and .87vs placebo, respectively). By contrast, hsCRP reduction wasattenuated with insulin alone (–2.9%, 95% CI, –13.2%to 8.6%; P = .03 vs placebo). Similar findings werenoted for levels of IL-6 and sTNFr2.

12. Conclusion In patients with recent-onset type 2 diabetes,treatment with insulin or metformin compared with placebo didnot reduce inflammatory biomarker levels despite improving glucosecontrol. Trial Registration  clinicaltrials.gov Identifier: NCT00366301

13. Message ランタスやメトホルミンで血糖を下げるだけでは炎症（大血管障害につながる）は簡単には改善しない。 何か他のことが必要！

15. vs

16. Original ArticleTicagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes Lars Wallentin, M.D., Ph.D., Richard C. Becker, M.D., Andrzej Budaj, M.D., Ph.D., Christopher P. Cannon, M.D., Håkan Emanuelsson, M.D., Ph.D., Claes Held, M.D., Ph.D., Jay Horrow, M.D., Steen Husted, M.D., D.Sc., Stefan James, M.D., Ph.D., Hugo Katus, M.D., Kenneth W. Mahaffey, M.D., Benjamin M. Scirica, M.D., M.P.H., Allan Skene, Ph.D., Philippe Gabriel Steg, M.D., Robert F. Storey, M.D., D.M., Robert A. Harrington, M.D., for the PLATO Investigators N Engl J Med Volume 361(11):1045-1057 September 10, 2009

17. Background • Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.

18. Method • In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.

19. Baseline Characteristics of the Patients, According to Treatment Group Wallentin L et al. N Engl J Med 2009;361:1045-1057

20. Randomized Treatment, Other Treatments, and Procedures, According to Treatment Group Wallentin L et al. N Engl J Med 2009;361:1045-1057

21. Major Efficacy End Points at 12 Months Wallentin L et al. N Engl J Med 2009;361:1045-1057

22. Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point Wallentin L et al. N Engl J Med 2009;361:1045-1057

23. Cumulative Kaplan-Meier Estimates of the Time to the First Major Bleeding End Point, According to the Study Criteria Wallentin L et al. N Engl J Med 2009;361:1045-1057

24. Safety of the Study Drugs Wallentin L et al. N Engl J Med 2009;361:1045-1057

25. Conclusion • In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrelsignificantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding

26. Study Overview • In a multicenter, randomized trial, ticagrelor - a reversible inhibitor of the adenosine diphosphate receptor P2Y12 - was compared with clopidogrel in patients who had an acute coronary syndrome with or without ST-segment elevation • At 12 months, the primary end point of death from vascular causes, myocardial infarction, or stroke occurred less often with ticagrelor • Ticagrelor was not associated with an increase in the risk of major bleeding

27. Message Clopidgrelがよく売れているが、 （売上　Plavix $ 6,057,000,0002006年世界 $ 3,796,221,0002008年USA Bristol-Myers Squibb/Sanfi-Aventis） これからはTicagrelorが主流になるかもしれない。