1. Cardiac Autonomic Neuropathy in Type 2 Diabetes: Predicting Cardiac Risk Margaret M. McCarthy 1 Lawrence Young 2 Silvio Inzucchi 2 Janice Davey 2 Frans J Th Wackers 2 Deborah A. Chyun 1 1 New York University College of Nursing 2 Yale University School of Medicine Council for the Advancement of Nursing Science September 13, 2012

2. Background Individuals with diabetes mellitus (DM) at increased risk of morbidity and mortality associated with coronary artery disease (CAD) One quarter have clinically unrecognized disease Asymptomatic nature presents unique challenges in primary/secondary prevention as routine screening not advocated Current risk calculators have not performed well –Not account for gender difference and glycemic status

3. Background (2) Knowledge of additional risk factors, particularly those related to long-term glucose control might assist in identifying high-risk patients Cardiac autonomic neuropathy (CAN) hypothesized to contribute to silent ischemia and adverse outcomes –Underutilized in the clinical setting –Possible role in identifying high-risk –Need to capture DM-specific predictors

4. Purpose Determine the association of CAN measures with CAD events (cardiac death, acute coronary syndromes, heart failure, and revascularization) Examine gender differences in relation to CAD events Identify sociodemographic, T2DM-related and CAD risk factors associated with CAN

5. Methods Secondary analysis of data from a multi-site trial, the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Study Randomized screening trial Silent ischemia Prevalence Predictors 5 year outcomes of events

6. Subjects and Setting Men and women (N=1119) Age 50 to 75 History of T2DM No previous diagnosis of CAD Followed over 5 years from 14 sites across the United States and Canada Follow-up phone calls every 6 months All CAD events adjudicated

7. Measures Baseline assessment Sociodemographic Diabetes-related Cardiac risk factors Testing for CAN Cardiac events collected every 6 months

8. Measures of CAN Assessed using standard heart rate (HR) and blood pressure (BP) based Ewing tests –HR during deep breathing (HRDB):6 breaths/ min –Valsalva ratio (VR):forced expiration at 40mmHg –Standing HR (R30:15):15 th and 30 th beats –Standing BP and handgrip BP obtained Power Spectral Analysis (PSA) Heart Rate Variability (HRV) –Low (LF) and high frequency (HF); LF:HF

9. Data Analysis SAS 9.2 Spearman Correlation Chi-square and t-tests Logistic Regression Cox Proportional Hazards

10. Results Subject characteristics Cardiac events over 5 years Factors associated with and predictive of cardiac events Measures of CAN Gender differences Clinical factors predictive of CAN

11. Subject Characteristics Mean age: 61 ± 6.6 years Women: 46% (n=519) Race/ethnicity: 17% (n=190) Black T2DM duration: 8.5 ± 7.0 years HbA1c: 7.1 ± 1.5 % Insulin use: 23% (n=260) Resting heart rate (beats/min): 70 ± 10

12. Cardiac Events over 5 Years 8.4% (n=94) had cardiac events Cardiac death Acute coronary syndrome Heart failure Revascularization

13. CAN Measures and Events

14. Predictors of Cardiac Events in All Subjects

15. + Lowest quartile of Valsalva is < 1.37 with Anscore or 1.17 without

16. Factors Associated with Cardiac Events FactorNo EventEventP-value Duration of T2DM--years (mean ± sd) Men Women 8.2 ± 6.8 8.0 ± 6.6 12.3 ± 7.8 13.0 ± 8.0 <.001 Peripheral numbness-- no. (%) Men Women 170 (31%) 173 (36%) 31 (52%) 17 (50%).002.009 Highest quartile resting pulse pressure* Men Women 109 (20%) 131 (27%) 22 (37%) (17 (50%).003.004 Insulin use Men Women 110 (20%) 123 (25%) 20 (33%) 7 (21%).02.53 * > 60.3 mmHg

17. Factors Associated with Cardiac Events FactorNo EventEventP-value MEN (N=600) N=540N=60 HbA1c % (mean ± sd) Women 7.0 ± 1.52 7.1 ± 1.51 7.5 ± 1.49 7.2 ± 1.55.004.58 Waist-to-hip ratio (mean ± sd) Women.94 ±.09.89 ±.79.97 ±.08.91 ±.84.002.28 Abnormal VR—no. (%) Women 89 (16%) 89 (18%) 20 (33%) 10 (34%).001.11 WOMEN (N=519) N=485N=34 Family History of Heart Disease Men 98 (20%) 90 (17%) 13 (38%) 13 (22%).08.33 Black Race Men 19 (4%) 65 (12%) 1 (3%) 5 (8%).10.69 No Physical Activity at Baseline Men 120 (25%) 129 (24%) 13 (38%) 19 (32%).08.18

18. Factors Predicting Cardiac Events FactorHR95% CIP-value Duration of T2DM (per year) Men Women 1.04 1.10 1.00-1.07 1.06-1.15.02 <.0001 HbA1c (per 1% increase) Men Women 1.20 1.30 1.04-1.34 0.99-1.68.009.05 Highest quartile resting pulse pressure* Men Women 1.80 3.02 1.01-3.05 1.50-6.07.046.002 * > 60.3 mmHg

19. Factors Predicting Cardiac Events FactorHR95% CIP-value Men Peripheral Numbness2.01.20-3.30.009 Waist-to-hip ratio1.040.99-1.07.05 Abnormal VR2.031.20-3.50.01 Women Black race0.310.09-1.03.05 Insulin use0.340.12-0.89.03 Family history of heart disease2.301.11-4.72.02

20. Factors Predicting Abnormal VR (Lowest quartile) FactorOR95% CIP-value Black Race0.530.33-0.85.009 Insulin Use1.451.02-2.10.04 Clinical Proteinuria 3.201.71-6.00.0003 Pulse Pressure1.021.003-1.03.01 Use of ACE- inhibitor 1.441.05-1.96.02 Use of Beta- blocker 1.420.88-2.28.15

21. Conclusions Baseline characteristics predictive of cardiac events in total sample Some differences in factors predictive of cardiac events in men and women Factors associated with abnormal VR

22. Limitations Limited by previously collected data Factors collected at baseline only Use of 2 different measurements for HR- based tests Relatively small sample size when men and women examined individually

23. Strengths Large cohort study with 5 years of follow- up Comprehensive assessment of diabetes- related factors Extensive testing of autonomic function Sample representative of contemporary diabetes care

24. Implications CAN consistently shown to be associated with adverse outcomes CAN preventable complication of T2DM Elevated BP also important contributor to cardiac risk in T2DM Identify high-risk individuals for both CAN and cardiac events using common clinical characteristics –Gender differences

25. Thank you

26. Comparisons PSA- HRV

27. Comparison Automated and Holter-Obtained Readings

29. Cardiac Autonomic Neuropathy Damage to autonomic nerves innervating heart and blood vessels Abnormalities –Resting tachycardia –Orthostatic hypotension –Exercise Intolerance Heart rate testing –Heart rate during deep breathing –Valsalva ratio –Heart rate after standing

30. Pulse Pressure Resting pulse pressure: Resting systolic and diastolic pressure taken 3x and averaged to obtain resting pulse pressure SBP-DBP=PP

31. abstract Cardiac Autonomic Neuropathy in Type 2 Diabetes: Predicting Cardiac Risk Aim: The role of cardiac autonomic neuropathy (CAN) has not been clearly established in the risk of cardiac disease in patients with type 2 diabetes (T2DM). The aim of this secondary data analysis of the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study was to examine the diabetes and cardiac factors associated with CAN and its role in predicting cardiac events in older adults with T2DM. Gender differences in the CAN predictors of cardiac risk were also examined. Method: In the DIAD study, older patients with T2DM (n=1119) without a baseline diagnosis of coronary artery disease (CAD) were followed over five years. Diabetes and cardiac risk factors, as well as CAN measures were assessed at baseline; cardiac events were assessed every 6 months. Results: Diabetes and cardiac factors associated with abnormal valsalva ratio (VR) included: diabetes duration (p=.001); insulin use (p=.008); microalbumin (p<.0001); serum creatinine (p=.05); retinopathy (p=.006); erectile dysfunction (p=.03); HDL (p=.04);lipid (p=.009) and hypertension (p=.001) treatment; systolic BP (p=.004) ; and resting heart rate (p=.0007). Over 5 years of follow-up, 94 (8.4%) subjects experienced a cardiac event. CAN factors predictive of an event included: highest pulse pressure (HR=2.04; p=.001) and lowest VR (HR=1.58; p=.04). In analyzing men alone, lowest VR was even higher risk (HR=2.03; p=.01); in women only, highest pulse pressure was a higher risk (HR=3.02; p=.002). Conclusions: Results highlight factors that may allow healthcare providers to identify asymptomatic patients with T2DM who are more likely to have CAN and are at risk for symptomatic cardiac disease.

32. Background and Significance Cardiovascular Disease Deaths Prevalence of Type 2 Diabetes (T2DM) Role of Cardiac Autonomic Neuropathy

33. T2DM Age ≥ 20 years: 25.6 million (11.3%) Age ≥ 65 years: 10.9 million (26.9%) T2DM = 90-95% Leading cause of: Kidney failure Non-traumatic lower limb amputations New cases blindness Annual cost: $174 billion Diabetic Neuropathies 2011 Diabetes Fact Sheet (CDC) % CDC 2011

34. Cardiovascular Disease Deaths in Diabetes CDC 2010

35. Cardiac Autonomic Neuropathy (CAN) Damage to autonomic nerves to heart & blood vessels Abnormalities –Resting tachycardia –Orthostatic hypotension –Exercise intolerance Associated with silent ischemia, cardiomyopathy Predictor –All cause and cardiovascular mortality