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 5 月 7 日 8:30-8:55 ８階 医局 Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1565-72. Young LH, Wackers FJ, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Heller GV, Iskandrian AE, Wittlin SD, Filipchuk N, Ratner RE, Inzucchi SE; DIAD Investigators. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 2009 Apr 15;301(15):1547-55.

2. Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Couri et al describe long-term follow-up and insulin secretion status of patients from their original study, in which they performed nonmyeloablative autologous stem cell transplantation to treat very recent–onset type 1 diabetes. Clinicians are left with trying to achieve an HbA1c goal of less than 7%, which reduces microvascular and cardiovascular disease over time, but no rationale to try to achieve an HbA1c of less than6%if more than lifestyle changes are required. Based on an analysis of registry data from a large ongoing epidemiologic cohort, the authors report that among elderly patients with type 2 diabetes who had no documented prior diagnoses of dementia, cognitive impairment, or memory complaints, episodes of hypoglycemia severe enough to result in emergency department or hospital treatment were associated with increased risk of being diagnosed with dementia. The DIAD study results suggest that more aggressive screening for coronary artery disease does not appear to improve the outcome of asymptomatic individuals with type 2 diabetes. In the observational study by Kosiborod et al, the occurrence of hypoglycemia was associated with higher mortality among patients who did not receive insulin (compared with patients who did not experience hypoglycemia), but not in patients who were treated with insulin.

3. Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus JAMA. 2009;301(15):1565-1572. JAMA Report Video This JAMA Report summarizes key findings from the article in video format and includes an interview with one of the authors. The video script and links to the video are available at http://pubs.ama-assn.org/media/2009j/0414.dtl#vnrscript.

4. 9.0 8.5 8.0 7.5 7.0 6.5 6.0 0 0123456 観察期間 5,109 5,119 4,774 4,768 4,588 4,585 3,186 3,165 1,744 1,706 455 476 436 471 症例数 通常療法 強化療法 HbA 1C 通常療法 強化療法 ACCORD ～ HbA 1C の推移～ 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（ HbA 1C 6.0% 未満、 SBP 120mmHg 未満）または 通常療法（ HbA 1C 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。 （年） （%）（%） ACCORD Study Group ： N.Engl.J.Med.,358,2545,2008. 中央値 バーは四分位範 囲

5. 25 5 0 （年） 20 15 10 0123456 5,128 5,123 4,843 4,827 4,390 4,262 2,839 2,702 1,337 1,186 475 440 448 395 症例数 強化療法 通常療法 強化療法 観察期間 （%）（%） 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（ HbA 1C 6.0% 未満、 SBP 120mmHg 未満）または 通常療法（ HbA 1C 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. ACCORD ～主要評価項目～ 【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 通常療法 ハザード 比 95% 信頼区間 p値p値 0.900.78,1.040.16

6. （年） 25 20 15 10 5 0 0123456 5128 5123 4972 4971 4803 4700 3250 3180 1748 1642 523 499 506 480 症例数 強化療法 通常療法 強化療法 通常療法 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（ HbA 1C 6.0% 未満、 SBP 120mmHg 未満）または 通常療法（ HbA 1C 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. 観察期間 ACCORD ～総死亡～ （%）（%） ハザード 比 95% 信頼区間 p値p値 1.221.01,1.460.04

7. ADVANCE trial ～ HbA 1C の推移～ The ADVANCE Collaborative Group ： N.Engl.J.Med.,358,2560,2008. 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、 HbA 1C 6.5% 以下を目指す。 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 0.0 0612182430364248546066 強化療法 観察期間 通常療法 p<0.001 平均 HbA 1C 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 HbA 1C 値 通常療法 強化療法 （ヵ月） （%）（%）

8. ADVANCE trial ～大血管症＋細小血管症への影響～ The ADVANCE Collaborative Group ： N.Engl.J.Med.,358,2560,2008. 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、 HbA 1C 6.5% 以下を目指す。 25 20 15 10 5 0 0612182430364248546066 強化療法 通常療法 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 観察期間 （ヵ月） （%）（%） ハザード 比 95% 信頼区間 p値p値 0.900.82,0.980.01

9. The ADVANCE Collaborative Group ： N.Engl.J.Med.,358,2560,2008. 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、 HbA 1C 6.5% 以下を目指す。 ADVANCE trial ～総死亡への影響～ 25 20 15 10 5 0 0612182430364248546066 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 （%）（%） 観察期間 （ヵ月） 症例数 強化療法 通常療法 ハザード 比 95% 信頼区間 p値p値 0.930.83,1.060.28

10. 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（ HbA 1C 6.0% 未満）、または 通常療法（ HbA 1C 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。 VADT ～ HbA 1C の推移～ 10.5 10.0 8.0 6.5 5.5 0 登録時 123456 9.0 7.0 6.0 9.5 7.5 8.5 通常療法 強化療法 観察期間 HbA 1C （年） 8.4% 6.9% * * * 中央値 Duckworth W et al: N Engl J Med 360:129-39, 2009 ～～～～ （%）（%）

11. 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（ HbA 1C 6.0% 未満）、または 通常療法（ HbA 1C 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。 0 100 60 40 20 80 007123465 観察期間 （年） VADT ～非致死性イベント～ ハザード 比 95% 信頼区間 p値p値 0.8450.704,1.0160.0725 Duckworth W et al: N Engl J Med 360:129-39, 2009 通常療法 強化療法

12. 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（ HbA 1C 6.0% 未満）、または 通常療法（ HbA 1C 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。 VADT ～総死亡～ 0 100 60 40 20 80 007123465 観察期間 （年） ハザード 比 95% 信頼区間 p値p値 1.0650.801,1.4160.67 Duckworth W et al: N Engl J Med 360:129-39, 2009 通常療法 強化療法

13. ACCORD ～医療処置を必要とする重症低血糖～ ACCORD Study Group ： ADA 68th Scientific Sessions,2008,San Francisco. 25 20 15 10 5 0 01234567 （年） 強化療法 5,128 5,123 4,601 4,699 4,494 4,589 2,965 3,066 1,549 1,556 437 478 414 452 強化療法群 通常療法群 （%）（%） 通常療法 強化療法群の低血糖発現率が高かった

14. ACCORD ～無作為割り付け後の使用薬剤の総死亡に対するハザード比～ ACCORD Study Group ： ADA 68th Scientific Sessions,2008,San Francisco. アカルボース Exenatide グリメピリド Glyburide メトホルミン Repaglinide Rosiglitazone ピオグリタゾン 基礎 l インスリン 混合型インスリン 追加インスリン 2.25 2.00 1.75 1.50 1.25 1.00 0.75 0.50 0.25 0.00 （ベースライン時患者背景で補正） 英語で表記している薬剤は日本では未発売です。 強化療法群の低血糖発現率が高かった

15. VADT 各因子と心血管死の関係 ハザード比 95% 信頼区間 p値p値 低血糖 4.042 （ 1.449 ， 11.276 ） 0.01 HbA 1C 1.213 （ 1.038 ， 1.417 ） 0.02 HDL 0.699 （ 0.536 ， 0.910 ） 0.01 年齢 2.090 （ 1.518 ， 2.877 ） <0.01 冠動脈疾患 イベントの既 往 3.116 （ 1.744 ， 5.567 ） <0.01 024106812 低血糖は心血管死の予測因子である Abraira C. ： ADA 68th Scientific Sessions,2008,San Francisco. 2 型糖尿病 1,791 例を強化療法群（目標値： HbA 1C 6.0% 未満）、または通常療法群（目標値： HbA 1C 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。

16. Original Article Long-Term Effect of Diabetes and Its Treatment on Cognitive Function The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group N Engl J Med Volume 356(18):1842-1852 May 3, 2007 The members of the writing committee — Alan M. Jacobson, M.D., and Gail Musen, Ph.D., Joslin Diabetes Center and Harvard Medical School, Boston; Christopher M. Ryan, Ph.D., and Nancy Silvers, R.N., University of Pittsburgh School of Medicine, Pittsburgh; Patricia Cleary, M.S., and Barbara Waberski, M.S., George Washington University, Rockville, MD; Amanda Burwood, B.S., and Katie Weinger, Ed.D., Joslin Diabetes Center, Boston; Meg Bayless, R.N., University of Iowa College of Medicine, Iowa City; William Dahms, M.D. (deceased), Case Western Reserve University, Cleveland; and Judith Harth, R.N., University of Western Ontario Schulich School of Medicine, London, ON, Canada — and the DCCT/EDIC Study Research Group assume responsibility for the overall content and integrity of the article. No evidence of substantial long-term declines in cognitive function

17. Effects of DCCT Treatment Group, Severe Hypoglycemia, and Glycated Hemoglobin on Changes in Cognition, from Entry into DCCT to Year 12 in the EDIC Study The bars show the changes within cognitive domains between cognitive testing at baseline in DCCT and follow-up testing (a mean of 18 years after baseline) expressed as changes in z scores for intensive versus conventional treatment (Panel A), frequency of episodes of severe hypoglycemia (coma or seizure) (Panel B), and mean glycated hemoglobin values (Panel C). Across the three groups, higher levels of glycated hemoglobin were associated with moderate declines in psychomotor efficiency (P<0.001) and motor speed (P=0.001), but no other cognitive domain was affected significantly. Cognitive domains are numbered as follows: 1, problem solving; 2, learning; 3, immediate memory; 4, delayed recall; 5, spatial information; 6, attention; 7, psychomotor efficiency; and 8, motor speed.

18. Division of Research, Section of Etiology and Prevention, Kaiser Permanente, Oakland, California (Drs Whitmer, Karter, Quesenberry, and Selby); Departments of Psychiatry, Neurology and Epidemiology, University of California, San Francisco (Dr Yaffe). JAMA. 2009;301(15):1565-1572

19. Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes. To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years. Background and Aim

20. Design, Setting, and Patients: A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California. Main Outcome Measure: Hypoglycemic events from 1980- 2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease. Methods

21. Cox Regression 打ち切り症例を含む生存データについて、従属変数に事象発生までの時間を使 用する有用な回帰モデルが 1972 年 David Cox によって紹介され、比例ハザード モデルあるいは Cox のモデルと呼ばれている。

22. Copyright restrictions may apply. Whitmer, R. A. et al. JAMA 2009;301:1565-1572. Population Characteristics by Hospital or Emergency Department- Associated Hypoglycemia

23. Copyright restrictions may apply. Whitmer, R. A. et al. JAMA 2009;301:1565-1572. Frequency of Hypoglycemic Episodes by Dementia Status

24. Copyright restrictions may apply. Whitmer, R. A. et al. JAMA 2009;301:1565-1572. Hypoglycemia and Risk of Incident Dementiaa

25. Copyright restrictions may apply. Whitmer, R. A. et al. JAMA 2009;301:1565-1572. Subgroup Analyses of Hypoglycemia and Dementia Riska

26. At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55). Results

27. Limitation A possible weakness is that our dementia diagnoses are based on clinical diagnoses obtained from electronic medical records, rather than the results of standardized neurological assessments administered periodically to all cohort members. Another potential concern is that due to the observational nature of our cohort study, we cannot be certain of the temporality of our findings, and cognitive problems due to undiagnosed dementia may have contributed to the occurrence of hypoglycemia. However, individuals with diagnoses of dementia, mild cognitive impairment, or general memory impairment before 2003 were excluded. In addition, we designed the study to increase the temporal separation of earlier hypoglycemic episodes from later occurrences of dementia and also conducted analyses with further lags between exposure to hypoglycemia and the beginning of observation for incident dementia. These lagged-model findings demonstrated similar associations. Even when considering only hypoglycemic episodes during the first 5 years of the study, when the patients were between the ages of 52 and 57 years (when dementia is highly unlikely), there was still an association with an elevated risk of dementia more than 2 decades later. Finally, our study involves the association between severe hypoglycemic episodes and risk of dementia; implications from our study do not address the role of less severe but more frequent episodes of hypoglycemia on dementia risk. The clinical significance of minor hypoglycemic episodes on dementia risk is unknown.

28. Conclusions Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown.

30. JAMA. 2009;301(15):1547-1555 Department of Internal Medicine, Section of Cardiovascular Medicine (Drs Young and Wackers and Ms Davey) and Section of Endocrinology (Dr Inzucchi), Yale University School of Medicine, New Haven, Connecticut; College of Nursing at the College of Dentistry, New York University, New York (Dr Chyun); Department of Endocrinology, University of Virginia, Charlottesville (Dr Barrett); Medecine Nucleaire, University of Montreal, Montreal, Quebec, Canada (Dr Taillefer); Department of Cardiology, Hartford Hospital, Hartford, Connecticut (Dr Heller); Department of Cardiology, University of Alabama, Birmingham (Dr Iskandrian); Department of Endocrinology, University of Rochester, Rochester, New York (Dr Wittlin); Cardiology Consultants, Calgary, Alberta, Canada (Dr Filipchuk); and MedStar Research Institute, Washington, DC (Dr Ratner).

31. Coronary artery disease (CAD) is the major cause of mortality and morbidity in patients with type 2 diabetes. But the utility of screening patients with type 2 diabetes for asymptomatic CAD is controversial. To assess whether routine screening for CAD identifies patients with type 2 diabetes as being at high cardiac risk and whether it affects their cardiac outcomes. Background and Aim

32. The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study is a randomized controlled trial in which 1123 participants with type 2 diabetes and no symptoms of CAD were randomly assigned to be screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) or not to be screened. Participants were recruited from diabetes clinics and practices and prospectively followed up from August 2000 to September 2007. Main Outcome Measure is Cardiac death or nonfatal myocardial infarction (MI). Methods

33. Copyright restrictions may apply. Young, L. H. et al. JAMA 2009;301:1547-1555. Flow of Study Participants

34. Copyright restrictions may apply. Young, L. H. et al. JAMA 2009;301:1547-1555. Baseline Characteristics According to Randomization

35. Copyright restrictions may apply. Young, L. H. et al. JAMA 2009;301:1547-1555. Events in No-Screening vs Screening Group

36. Copyright restrictions may apply. Young, L. H. et al. JAMA 2009;301:1547-1555. Cumulative Incidence of Cardiac Events in Participants With Type 2 Diabetes Without Symptomatic or Previously Diagnosed Coronary Artery Disease A, Cumulative incidence of cardiac events in 561 participants randomized to systematic baseline screening with stress myocardial perfusion imaging (MPI) and 562 participants randomized to receive no screening. B, Cumulative incidence of cardiac events according to results of systematic screening with stress MPI: normal, small defect, moderate or large defect, and nonperfusion abnormality. No cardiac events occurred in participants who were randomized to but did not complete screening MPI. The y-axis scale in blue indicates range from 0 to 0.06.

37. Copyright restrictions may apply. Young, L. H. et al. JAMA 2009;301:1547-1555. Events According to Findings of Screening Myocardial Perfusion Imaging (n = 522)

38. Copyright restrictions may apply. Young, L. H. et al. JAMA 2009;301:1547-1555. Follow-up and Medication Use

39. Copyright restrictions may apply. Young, L. H. et al. JAMA 2009;301:1547-1555. Factors Associated With Primary Events

40. The cumulative cardiac event rate was 2.9% over a mean (SD) follow-up of 4.8 (0.9) years for an average of 0.6% per year. Seven nonfatal MIs and 8 cardiac deaths (2.7%) occurred among the screened group and 10 nonfatal MIs and 7 cardiac deaths (3.0%) among the not-screened group (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.44-1.88; P=.73). Of those in the screened group, 409 participants with normal results and 50 with small MPI defects had lower event rates than the 33 with moderate or large MPI defects; 0.4% per year vs 2.4% per year (HR, 6.3; 95% CI, 1.9-20.1; P=.001). Nevertheless, the positive predictive value of having moderate or large MPI defects was only 12%. The overall rate of coronary revascularization was low in both groups: 31 (5.5%) in the screened group and 44 (7.8%) in the unscreened group (HR, 0.71; 95% CI, 0.45-1.1; P=.14). During the course of study there was a significant and equivalent increase in primary medical prevention in both groups. Results

41. Limitation The cardiac event rates were significantly lower than originally anticipated at the time of the design of the study and therefore the DIAD study does not have the power to exclude a small difference between the screened and unscreened participants. Based on the observed cardiac event rate, we would estimate that the study only had 14% power to detect a 20% difference between the 2 groups. A 3- to 4-fold larger study would be required to exclude such a difference, and it is not clear that a reduction in cardiac events from 0.6% to 0.5% per year even if proved would justify cardiac screening. Another potential limitation to consider is that nonprotocol stress tests were done during follow-up when clinically indicated in both groups. In addition, screening led to only a modest reduction in subsequent diagnostic testing. Testing was typically performed to evaluate potential cardiac symptoms but may have also been undertaken for risk stratification in some participants. In the no-screening group, such testing represents a crossover to a physician-directed screening strategy and theoretically might have counter-balanced a benefit of protocol- mandated systematic screening. However, because the DIAD study did not prohibit physician directed cardiac evaluation, the results are more applicable to current day medicine in which patients are often evaluated for symptoms or preoperative risk stratification or when considered particularly high risk by their physicians.

42. In this contemporary study population of patients with diabetes, the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years. Trial Registration clinicaltrials.gov Identifier: NCT00769275 Interpretation Conclusion