Screening for CAD in Diabetes. Silvio E. Inzucchi MD Yale University

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1 Screening for CAD in Diabetes Silvio E. Inzucchi MD Yale University

2 Dualities of Interest The DIAD Study was an investigator-initiated trial which was funded by Dupont Radiopharmaceuticals (which later became BMS Radiopharmaceuticals Division) and Fujisawa (which later became Astellas.) The funders had no role in the design/conduct of the study, data interpretation, or manuscript preparation. Dr. Inzucchi has no recent conflicts pertaining to this topic.

Context Coronary artery disease (CAD) is a leading cause of morbidity & mortality in patients with diabetes. Myocardial ischemia may be silent in diabetic patients.

3 Context Coronary artery disease (CAD) is a leading cause of morbidity & mortality in patients with diabetes. Myocardial ischemia may be silent in diabetic patients. The first presentation of CAD may be acute myocardial infarction or sudden death. CAD can be easily identified in a pre-clinical stage. Patients with silent ischemia will benefit from aggressive risk factor reduction, and, potentially, CAD-specific therapy such as medications or revascularization.

4 Silent Myocardial Ischemia (SMI) in Diabetes Angina during MI is less severe or absent in patients with diabetes compared to those without diabetes. (Bradley & Schonfeld 1962, Soler 1975) Nearly 1 in 3 patients with diabetes but without antemortem history of angina or MI have evidence of previous MI at and those patients with clinically unrecognized MI at autopsy have a significantly higher incidence of known diabetes. (Bradley & Partamian 1963; Cabin & Roberts 1975) Ischemia occurs without symptoms more commonly in patients with diabetes during exercise testing, ambulatory ECG monitoring, and during balloon inflation at angioplasty. (Nesto 1988, Chiarello 1985, Titus 1991)

Pathogenesis of Silent Myocardial Ischemia in Diabetes Less active lifestyles, and, as a result, reduced myocardial workload in the obese diabetic patient.

5 Pathogenesis of Silent Myocardial Ischemia in Diabetes Less active lifestyles, and, as a result, reduced myocardial workload in the obese diabetic patient. Highly vulnerable atherosclerotic plaques that result in low-grade stenoses not leading to myocardial ischemia under normal circumstances. Cardiac autonomic neuropathy (CAN) (afferent sensory fibers in sympathetic nerves)

6 The Hope CAD PCI CABG Medical Therapy Risk Factor Modification DM Patient CAD Screening Risk Factor Modification

7 Electron Beam Computed Tomography (EBCT) How to Screen for Coronary Artery Disease in Patients with Diabetes ECG Exercise Tolerance Testing (ETT) Myocardial Perfusion Imaging (MPI) Exercise Pharmacological Stress Stress-Echocardiography (SE) Exercise Pharmacological Stress

8 Screening for Silent Ischemia in Diabetes Study Pts Screening Method % SMI Nesto Dipyr-Th % Koistinen h ECG; ETT-ECG/Th % Langer ETT-Th % Naka ECG-ETT 31% MiSAD ETT-ECG/Th 201 6% Janand-Delenne ETT-ECG/Th 201; Dipyr-Th % Valensi ETT-ECG; Dipyr-Th % Penformis ETT-ECG/Th 201; Dobut. Stress Echo 25-29%* Bacci ETT-ECG 19% Gazzaruso ETT-ECG/ Th 201 9% De Lorenzo ETT-Sestamibi-SPECT 26%

9 Detection of Ischemia in Asymptomatic Diabetics

10 The DIAD Study Group University of Alabama, Birmingham, AL University of Rochester, N.Y. Soundview Research Assoc, Norwalk, CT Tulane University, New Orleans, LA University of Virginia, Charlottesville,VA Yale University, New Haven, CT, Coordinating Center Coordinating Center Frans Wackers MD Lawrence Young MD Silvio Inzucchi MD Deborah Chyun RN PhD Jan Davey RN (coord.) Shanti Bansal MD University of Montreal, QE Hartford Hospital, CT Medstar CRC, Washington, D.C. Cardiology Consultants, Calgary, AL Maine Cardiology, Portland, ME Midwest Cardiology, Columbus, OH University of North Carolina, Chapel Hill Kansas City Cardiology, MO

11 The DIAD Study DIAD 1 Prevalence / predictors of SMI in T2DM DIAD 2 Progression / regression of CAD DIAD 3 Cardiac event rates (vs. control group)

DIAD 1: Study Aims To determine prospectively the prevalence & clinical predictors of inducible myocardial ischemia in asymptomatic patients with T2DM using myocardial perfusion imaging

12 DIAD 1: Study Aims To determine prospectively the prevalence & clinical predictors of inducible myocardial ischemia in asymptomatic patients with T2DM using myocardial perfusion imaging (Adenosine- Sestamibi SPECT.) Hypotheses: Silent ischemia is highly prevalent and patients so affected could be identified through risk factor analysis. Wackers et al. Diabetes Care 27; 1954, 2004

13 Normal Adenosine Vasodilator Stress Sestamibi SPECT Imaging Stress Rest

14 Abnormal Adenosine Vasodilator Stress Sestamibi SPECT Imaging Stress Rest

Patients 562 Patients MPI No Testing 5-yr follow-up

15 Asymptomatic T2DM Patients 1123 Eligible Consented Patients Screening Randomization Natural History 561 Patients 562 Patients MPI No Testing 5-yr follow-up 5-yr follow-up Wackers et al. Diabetes Care 27:1954, 2004

DIAD Study: Inclusion Criteria Type 2 diabetes mellitus Age 50-75 years No history of CAD; no angina

16 DIAD Study: Inclusion Criteria Type 2 diabetes mellitus Age years No history of CAD; no angina No clinical indication for stress testing Normal resting ECG Wackers et al. Diabetes Care 27:1954, 2004

17 Baseline Data in Screened Patients Age T2DM Duration HbA1c BMI LDL-C TG HDL-C ASA use 60 ±7 yr 8 ±7 yr± 7 yr % kg/m mg/dl mg/dl mg/dl 44% Wackers et al. Diabetes Care 27:1954, 2004

18 Results: Myocardial SPECT Imaging 522 Pts Adenosine-Sestamibi SPECT Normal 409 (78%) Abnormal 113 (22%) Wackers et al. Diabetes Care 27:1954, 2004

19 Results: Myocardial SPECT Imaging N=522 Normal 409 (78%) 83 (73%) 30 (27%) Perfusion Abnormality Non-Perfusion Abnormality Abnormal 113 (22%) 50 (60%) 33 (40%) Mild Defect N=83 Mod-Large Defect ackers et al. Diabetes Care 2004 Wackers et al. Diabetes Care 27:1954, 2004

20 Table 1-- Indications for cardiac testing in diabetic patients Testing for CAD is warranted in patients with the following: 1. Typical or atypical cardiac symptoms 2. Resting electrocardiograph suggestive of ischemia or infarction 3. Peripheral or carotid occlusive disease 4. Sedentary lifestyle, age > 35 years, and plans to begin a vigorous exercise program 5. Two or more of the risk factors listed below (a-e) in addition to diabetes a) Total cholesterol > 240 mg/dl, LDL cholesterol > 160 mg/dl, or HDL cholesterol < 35 mg/dl b) Blood pressure > 140/90 mmhg c) Smoking d) Family history of premature CAD e) positive micro/macroalbuminuria Diabetes Care 1998:21;1551 American Diabetes Association. Diabetes Care. 1998;21:

21 Prevalence of Silent Ischemia & Consensus Statement Risk Factors < 2 Risk Factors 23% 41% of all abnormal tests > 2 Risk Factors 22% 77% N=204 78% N=306 Silent Ischemia Wackers et al. Diabetes Care 2004 Normal Abnormal (Lower Risk) Abnormal (Higher Risk)

DIAD-1: Conclusions Abnormal myocardial perfusion imaging (MPI) occurred in 22% of asymptomatic T2DM patients on contemporary therapies (1 in 5). Markedly abnormal MPI in 6% of patients (1 in 16).

22 DIAD-1: Conclusions Abnormal myocardial perfusion imaging (MPI) occurred in 22% of asymptomatic T2DM patients on contemporary therapies (1 in 5). Markedly abnormal MPI in 6% of patients (1 in 16). In univariate analysis, routine clinical (BMI, DM duration) and biochemical variables (A1c, lipids, CRP) commonly associated with CAD were NOT predictive. In multivariate analysis, cardiac autonomic neuropathy (OR 5.6), DM duration (5.2), and male gender (2.5) were predictive of mod-large defects. Wackers et al. Diabetes Care 27:1954, 2004

23 DIAD 1 Hypothesis: Silent ischemia is highly prevalent and affected patients could be easily identified through risk factors.

24 DIAD 1 Lessons: Silent ischemia is not as common as we had thought. Most of the perfusion defects identified were small and not necessarily suitable for revascularization. A high-risk profile from routine risk factors could not be constructed (except for gender & DM duration for mod-large defects).

25 Screening for Silent Ischemia in Diabetes Study Pts Screening Method % SMI Nesto Dipyr-Th % Koistinen h ECG; ETT-ECG/Th % Langer ETT-Th % Naka ECG-ETT 31% MiSAD ETT-ECG/Th 201 6% Janand-Delenne ETT-ECG/Th 201; Dipyr-Th % Valensi ETT-ECG; Dipyr-Th % Penformis ETT-ECG/Th 201; Dobut. Stress Echo 25-29%* Bacci ETT-ECG 19% Gazzaruso ETT-ECG/ Th 201 9% De Lorenzo ETT-Sestamibi-SPECT 26% DIAD Adenosine- Sestamibi-SPECT 22%

DIAD 2 Repeat Adenosine Sestamibi SPECT @ 3 Years Hypothesis: In patients with Type 2 diabetes,

26 DIAD 2 Repeat Adenosine Sestamibi 3 Years Hypothesis: In patients with Type 2 diabetes, the prevalence of myocardial ischemia increases over time. Wackers et al. Diabetes Care 30:2892, 2007

27 The DIAD 2 Cohort 358 (68%) Repeat SPECT 164 (32%) No Repeat SPECT Cardiac Events: death (10), MI (2), revasc (15) New co-morbidity (10) Refusal (87) Lost to follow-up (17) New Orleans area (21) Non-interpretable SPECT (2) Wackers et al. Diabetes Care 30:2892, 2007

Baseline Characteristics Original Cohort (n=522) Repeat SPECT (n=358) No

HbA1C Retinopathy Neuropathy Erect. Dysf. 60.0 yrs 53 % 15 % 5.8 yrs 6.

3 yrs 7.0 % 20 % 38 % 58 %.67.25.001.36.005.001.03.

28 Baseline Characteristics Original Cohort (n=522) Repeat SPECT (n=358) No Repeat SPECT (n=164) p Age Male Afro-American Diabetes Dur. HbA1C Retinopathy Neuropathy Erect. Dysf yrs 53 % 15 % 5.8 yrs 6.8 % 14 % 31 % 48 % % 10 % 5.7 yrs % 28% 44% 60.1 yrs 49 % 26 % 6.3 yrs 7.0 % 20 % 38 % 58 % ADENO SPECT Normal Abnormal Mod/Large Def. 78 % 22 % 6 % 80% 20% 4.5% 74 % 26 % 10 % Wackers et al. Diabetes Care 30:2892, 2007

29 Index Screening DIAD Repeat Screening DIAD Abnormal 71 (20%) Abnormal 43 (12%) Normal 287 (80%) Normal 315 (88%) n = 358 Patients with Events, Revascularization Excluded n = 358 p = Wackers et al. Diabetes Care 30:2892, 2007

Index Screening DIAD-1 2000-2002 Normal 56 (79%) Resolution of Ischemia Repeat Screening

Normal 259 (90%) Normal 315 (88%) n = 358 Patients with Events, Revascularization

30 Index Screening DIAD Normal 56 (79%) Resolution of Ischemia Repeat Screening DIAD Abnormal 71 (20%) Abnormal 15 (21%) Abnormal 43 (12%) Normal 287 (80%) Normal 259 (90%) Normal 315 (88%) n = 358 Patients with Events, Revascularization Excluded Wackers et al. Diabetes Care 30:2892, 2007 Abnormal 28 (10%) New Ischemia n = 358 p = 0.008

31 Exposure to 3 Medications Combined 100 p = 0.04 (ACE + Statin + ASA) 80 Total Time Exposure (drug months) months 55 months 20 0 Resolution Ischemia New Ischemia Wackers et al. Diabetes Care 30:2892, 2007

32 DIAD 2 Hypothesis: In patients with Type 2 diabetes, the prevalence of myocardial ischemia increases over time.

33 DIAD 2 Lesson: In the context of modern medical therapy, myocardial perfusion defects can and often do resolve in patients with T2DM.

34 DIAD 3 5-year clinical follow-up Hypothesis: Randomization to screening would improve clinical outcomes by identifying disease early.

35 Young LH et al. JAMA 301:1547, 2009 DIAD-3: 5 Year Follow-Up Primary End Point: Cardiac Death + Non-fatal MI Event Rate: 3 % (0.6% / yr) Cardiac Death: 15* Pts (1.4 %) Non-fatal Acute MI: 17 Pts (1.5 %) [Total deaths: 33 Pts (3.9%)]

36 Cardiac Death and Non-Fatal MI: Screening Group Young LH et al. JAMA 301:1547, 2009

37 Major Cardiac Event Predictors Male Gender Peripheral Vascular Disease LDL-C per 10 mg/dl incr Serum Cr (per 1 mg/dl ) Abnl HR response to standing Mod-Large MPI Defects Non-Perfusion Abnormalities HR* (95% CI) 2.6 ( ) 3.2 ( ) 1.16 ( ) 1.6 ( ) 3.6 ( ) 6.2 ( ) 4.8 ( ) P *Cox Logistic Regression Young LH et al. JAMA 301:1547, 2009

38 Cardiac Death and Non-Fatal MI Screening vs. No Screening Young LH et al. JAMA 301:1547, 2009

39 All End Points at 5 Years Screening No Screening n = 558 n = 561 P Cardiac Death 8 (1.4%) 7 (1.2%) NS Myocardial Infarction 7 (1.2%) 10 (1.8%) NS Unstable Angina 4 (0.7%) 3 (0.5%) NS Heart Failure 7 (1.2%) 7 (1.2%) NS Stroke 10 (1.8%) 5 (0.9%) NS Young LH et al. JAMA 301:1547, 2009

40 DIAD 3 Hypothesis: Randomization to screening would improve clinical outcomes by identifying disease early.

41 DIAD 3 Lesson: Although screening does identify a higher-risk cohort of patients, indiscriminate screening has no clinical advantages to routine care.

Are DIAD Patients a Representative Cohort?

to participate in research Self-referred No Symptoms

42 Are DIAD Patients a Representative Cohort? Middle-aged: 61+7 yrs DM Duration: 8+7 yrs BMI: 31+6 Insulin: 22%, Orals: 63% > 2 Risk Factors 60% No Activity at all: 34% Unable to Exercise: 50% Willing to participate in research Self-referred No Symptoms Normal Rest ECG HbA1c % Young LH et al. JAMA 301:1547, 2009

43 Outcomes by High-Risk Designation Framingham Risk Score Intermediate/High Risk No Screening (422) Screening (418) p HR(95% CI) Primary CE 15 (3.6%) 13 (3.1%) ( ) Secondary CE 13 (3.1%) 17 (4.1%) ( ) UKPDS Risk Engine Intermediate/High Risk No Screening (289) Screening (291) p HR(95% CI) Primary CE 11 (3.7%) 14 (4.8%) ( ) Secondary CE 11 (3.7%) 12 (4.1%) ( ) ALFEDIAM / SFC High-Risk No Screening (361) Screening (352) p HR(95% CI) Primary CE 11 (3.1%) 13 (3.7%) ( ) Secondary CE 12 (3.3%) 18 (5.1%) ( ) Metabolic Syndrome No Screening (361) Screening (352) p HR(95% CI) Primary CE 14 (3.5%) 10 (2.5%) ( ) Secondary CE 12 (3.0%) 15 (3.8%) ( ) Bansal et al. Diabetes Care 34:203, 2011

44 Screening for CAD in Diabetes 1. Screening T2DM patients for silent ischemia with nuclear stress testing will detect a significant proportion (~1 in 5) of patients with CAD (with ~1 in 16 having major abnormalities.) 2. Ischemia appears to resolve in a significant number of patients. (? Whether aggressive risk factor modification is responsible.) 3. Although stress testing does identifiy those at the highest risk for events - in the context of modern practice - routine screening for CAD does NOT appear to favorably alter the outcome rates.

45 Screening for CAD in Diabetes 4. The overall outcome rates in DIAD were extremely favorable (0.6% / year)! 5. The DIAD population was not, at first glance, a low-risk group. Post-hoc stratified analysis still finds no benefit to screening even the highest risk individuals. 6. While there may be some benefits to screening for some patients, routine screening should not be recommended at this time.

46 CAD Screening: What We Don t Know Is there a high-risk cohort that would benefit from routine CAD screening (e.g. identified by novel markers)? Should patients be pre-screened with another modality (e.g. coronary CT), with more intensive screening for those with high coronary calcium scores? Would the DIAD results be different if angiography/ revascularization were pre-specified in those with major abnormalities? What about younger patients with T1DM?

Gender Differences in Physical Inactivity and Cardiac Events in Men and Women with Type 2 Diabetes

Gender Differences in Physical Inactivity and Cardiac Events in Men and Women with Type 2 Diabetes Margaret M. McCarthy 1 Lawrence Young 2 Silvio Inzucchi 2 Janice Davey 2 Frans J Th Wackers 2 Deborah