Journal Club

1. Journal Club The BARI 2D Study Group A Randomized Trial of Therapies for Type 2 Diabetesand Coronary Artery Disease N Engl J Med 360: June 11,2009 THE INTERNATIONAL EXPERT COMMITTEE International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009 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6月11日　8:30-8:55 ８階　医局

2. 糖尿病者非心筋梗塞発症例の心筋梗塞発症 (7年)

3. GISSI-Prevenzione Study Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico Prevenzione 心筋梗塞時非糖尿病者の糖尿病発症 心筋梗塞11323名 → 2139は既に糖尿病 3.2年の観察期間に12% 糖尿病発症 37例/1000例・年 一般集団：8-16例/1000例・年 33% 糖尿病・IFG110発症 123例/1000例・年 非糖尿病状態 62% 糖尿病・IFG100発症 321例/1000例・年 (年) D.Mozaffarian et al.:

4. the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group Robert L. Frye, M.D., Mayo Clinic, Rochester, MN; Phyllis August, M.D., M.P.H., New York Hospital Queens, Queens, NY; Maria Mori Brooks, Ph.D., Regina M. Hardison, M.S., Sheryl F. Kelsey, Ph.D., Joan M. MacGregor, M.S., and Trevor J. Orchard, M.B., B.Ch., University of Pittsburgh, Pittsburgh; Bernard R. Chaitman, M.D., Saint Louis University, St. Louis; Saul M. Genuth, M.D., Case Western Reserve University, Cleveland; Suzanne H. Goldberg, R.N., M.S.N., National Heart, Lung, and Blood Institute, Bethesda, MD; Mark A. Hlatky, M.D., Stanford University, Palo Alto, CA; Teresa L.Z. Jones, M.D., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; Mark E. Molitch, M.D., Feinberg School of Medicine, Northwestern University, Chicago; Richard W. Nesto, M.D., Lahey Clinic Medical Center, Burlington, MA; Edward Y. Sako, M.D., Ph.D., University of Texas Health Science Center, San Antonio; and Burton E. Sobel, M.D., University of Vermont, Burlington N Engl J Med 360: June 11,2009

5. Background Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established. (ClinicalTrials.gov number, NCT00006305.)

6. Although the effectiveness of coronary revascularization in relieving angina is well established, its benefit in reducing the rates of subsequent myocardial infarction and death has been shown only in patients with high-risk profiles or acute coronary syndromes. Among patients with diabetes, studies have indicated that increased insulin levels predict adverse outcomes and that control of hyperglycemia by reducing insulin resistance, rather than by providing insulin, might improve cardiovascular outcomes. This approach is tempered by data suggesting a limited benefit or possible harm associated with the use of newer insulin- sensitizing thiazolidinedione drugs and the failure of three recent trials to show reductions in cardiovascular events from intensifying glucose control beyond the current recommendations of the American Diabetes Association.

7. Methods We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention.

8. Eligibility criteria included a diagnosis of both type 2 diabetes and coronary artery disease. The diagnosis of type 2 diabetes was based on the need for treatment with insulin or oral hypoglycemic drugs or a confirmed elevated blood glucose level. The diagnosis of coronary artery disease was documented on angiography (≥50% stenosis of a major epicardial coronary artery associated with a positive stress test or ≥70% stenosis of a major epicardial coronary artery and classic angina). All patients had to be candidates for elective percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG). Patients were excluded if they required immediate revascularization or had left main coronary disease, a creatinine level of more than 2.0 mg per deciliter (177 μmol per liter), a glycated hemoglobin level of more than 13.0%, class III or IV heart failure, or hepatic dysfunction or if they had undergone PCI or CABG within the previous 12 months.

9. Our study was designed to compare coronary revascularization with intensive medical therapy, not to compare CABG with PCI. Figure 1. Enrollment and Randomization.

10. Table 1. Use of Medications, Risk Factors, and Adverse Events.

11. Table 1. Use of Medications, Risk Factors, and Adverse Events.

12. Standard群 Intensive群 収縮期血圧(mmHg) 127±17 126±17 拡張期血圧(mmHg) 68±11 67±11 LDLコレステロール(mg/dl) 91±34 91±34 ＡＣＣＯＲＤ Standard群 Intensive群 収縮期血圧(mmHg) 138±18 136±18 拡張期血圧(mmHg) 74±10 74±10 LDLコレステロール(mg/dl) 102±41 102±37 ＡＤＶＡＮＣＥ ＶＡＤＴ Standard群 Intensive群 P value 収縮期血圧(mmHg) 125±15 127±16 0.27 拡張期血圧(mmHg) 69±10 68±10 0.20 LDLコレステロール(mg/dl) 80±31 80±33 0.98

13. 亀田クリニック　糖尿病内分泌内科　糖尿病患者亀田クリニック　糖尿病内分泌内科　糖尿病患者 2008年度 計算によるLDL-chol 105mg/dl 2008年４月～2009年３月　最終受診時データ

14. Table 1. Use of Medications, Risk Factors, and Adverse Events.

15. Table 1. Use of Medications, Risk Factors, and Adverse Events.

25. Results At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P = 0.97) or between the insulin- sensitization group (88.2%) and the insulin-provision group (87.9%, P = 0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P = 0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P = 0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P = 0.01; P = 0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P = 0.003).

26. Conclusion Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision.

28. 糖尿病 とは？ 血糖が上昇する病気です 空腹時 126mg/dl以上， 随時血糖 200mg/dl以上， 負荷後２時間 200mg/dl以上 放置すると合併症(網膜症) （糖尿病の診断基準の血糖値は合併症発症で決めている！）

29. International Expert Committee members: David M. Nathan, MD (Chair); Beverly Balkau, PhD; Enzo Bonora, MD, PhD; Knut Borch-Johnsen, MD, DMSc; John B. Buse, MD, PhD; Stephen Colagiuri, MD; Mayer B. Davidson, MD; Ralph DeFronzo, MD; Saul Genuth, MD; Rury R. Holman, FRCP; Linong Ji, MD; Sue Kirkman, MD; William C. Knowler, MD, Dr PH; Desmond Schatz, MD; Jonathan Shaw, MD; Eugene Sobngwi, MD; Michael Steffes, MD, PhD; Olga Vaccaro, MD; Nick Wareham, MD; Bernard Zinman, MD; and Richard Kahn, PhD. DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009

30. BACKGROUND Diagnosing diabetes based on thedistribution of glucose levels Historically, the measurement of glucose has been the means of diagnosing diabetes. In 1979, the National Diabetes Data Group (NDDG) provided the diagnostic criteria that would serve as the blueprint for nearly two decades When selecting the threshold glucose values, the NDDG acknowledged that “there is no clear division between diabetics and nondiabetics in the FPG concentration or their response to an oral glucose load,” and consequently, “an arbitrary decision has been made as to what level justifies the diagnosis of diabetes.” Diagnosing diabetes based on the relationship between glucose levels and long-term complications In 1997, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus reexamined the basis for diagnosing diabetes

32. CAN THE A1C TEST BE USED TO DIAGNOSE DIABETES?

33. 海外文献のHbA1Cに注意 NGSP-HbA1C JDS/JSCC HbA1C Swedish-HbA1C & DOF (N-[1 deoxyfructos-1-yl] hemoglobin beta chain) 米国・欧州 日本 スェーデン

34. 米国のA1C =6.8% 日本のHbA1Cの値は 米国のものより0.288低い 日本のHbA1C =6.5%

35. IFCCのHbA1C=5.2% =52mmol/mol DOF (N-[1 deoxyfructos-1-yl] hemoglobin beta chain) y = -1.741 + 1.068 x 日本のHbA1C =6.5%

36. WHAT IS THE MOST APPROPRIATE A1C CUT POINT FOR THE DIAGNOSIS OF DIABETES? This analysis included almost 19,000 subjects from nine countries and showed that the glycemic level at which the prevalence of “any” retinopathy begins to rise above background levels (any retinopathy includes minor changes that can be due to other conditions, such as hypertension), and for the more diabetes-specific “moderate” retinopathy, was 6.5% when the data were examined in 0.5% increments

37. LIMITATIONS OF A1C AS THE RECOMMENDED MEANS OF DIAGNOSING DIABETES There are patient conditions that either will require a specific A1C assay method or will preclude A1C testing. • Some hemoglobin traits, such as HbS, HbC, HbF, and HbE, interfere with some A1C assay methods • Any condition that changes red cell turnover, such as hemolytic anemia, chronic malaria, major blood loss, or blood transfusions, will lead to spurious A1C results • Racial disparities in A1C, based on putative differences in the relationship between glucose levels and A1C, have been suggested • A1C levels appear to increase with age • There are rare clinical settings, such as rapidly evolving type 1 diabetes, where the A1C level will not have had time to “catch up” with the acute elevations in glucose levels

38. CAN A1C MEASUREMENTS DEFINE A SPECIFIC SUBDIABETIC “HIGHRISK” STATE? As A1C levels approach the diagnostic level for diabetes, the risk of developing diabetes becomes greatest.

39. SHOULD A1C TESTING BE USED TO IDENTIFY INDIVIDUALS AT HIGH RISK FOR DIABETES? The screening tests to identify individuals at elevated risk for diabetes are the same as the diagnostic tests; therefore, the technical advantages of A1C testing compared with glucose testing apply to the detection of individuals at high risk as they do to the diagnosis of diabetes. Committee is implying not that populations at lower A1C levels are not at risk but, rather, that they are at lower risk. Other risk factors for diabetes development in addition to A1C have been identified, including elevated levels of triglycerides, blood pressure, BMI, and family history of diabetes, and these should be taken into account in determining when to initiate interventions in individuals with A1C ≧6.0%.

40. WHAT ARE THE PRACTICAL ISSUES RELATED TO A1C TESTING? In circumstances when A1C testing cannot be performed, the diagnostic glucose tests are acceptable alternatives. Whichever of the three different tests now available to diagnose diabetes (A1C, FPG, and 2HPG) is used, both initial and confirmatory testing should be performed with the same test. The only exception to the need to confirm the diagnosis of diabetes with the same test would be the presence of clinical symptoms characteristic of diabetes and glucose levels ≧200 mg/dl (≧11.1 mmol/ l). Confirmatory testing is also not required to establish risk status in individuals identified as in the highest-risk group for diabetes (A1C of 6.0 to ＜6.5%).

41. Recommendation of the International Expert Committee For the diagnosis of diabetes: ● The A1C assay is an accurate, precise measure of chronic glycemic levels and correlates well with the risk of diabetes complications. ● The A1C assay has several advantages over laboratory measures of glucose. ● Diabetes should be diagnosed when A1C is ≧6.5%. Diagnosis should be confirmed with a repeat A1C test. Confirmation is not required in symptomatic subjects with plasma glucose levels ≧200 mg/dl (≧11.1 mmol/l). ● If A1C testing is not possible, previously recommended diagnostic methods (e.g., FPG or 2HPG, with confirmation) are acceptable. ● A1C testing is indicated in children in whom diabetes is suspected but the classic symptoms and a casual plasma glucose ≧200 mg/dl (≧11.1 mmol/l) are not found. For the identification of those at high risk for diabetes: ● The risk for diabetes based on levels of glycemia is a continuum; therefore, there is no lower glycemic threshold at which risk clearly begins. ● The categorical clinical states pre-diabetes, IFG, and IGT fail to capture the continuum of risk and will be phased out of use as A1C measurements replace glucose measurements. ● As for the diagnosis of diabetes, the A1C assay has several advantages over laboratory measures of glucose in identifying individuals at high risk for developing diabetes. ● Those with A1C levels below the threshold for diabetes but ≧6.0% should receive demonstrably effective preventive interventions. Those with A1C below this range may still be at risk and, depending on the presence of other diabetes risk factors, may also benefit from prevention efforts. ● The A1C level at which population-based prevention services begin should be based on the nature of the intervention, the resources available, and the size of the affected population

42. 糖尿病 とは？ 血糖が上昇する病気です A1C≧6.5% （JDS/JSCCHbA1C≧6.2%） 放置すると合併症(網膜症) （糖尿病の診断基準の血糖値は合併症発症で決めている！）