Autonomic dysfunction independently predicts poor cardiovascular outcomes in asymptomatic individuals with type 2 diabetes in the DIAD study.

OBJECTIVE: The primary aim of this secondary analysis was to determine whether cardiac autonomic neuropathy independently predicted adverse cardiac outcomes in asymptomatic individuals with type 2 diabetes. Additional aims include the determination of the correlation of standard autonomic testing measures and power spectral analysis of heart rate variability, and the association of diabetes-related and cardiac risk factors with cardiac autonomic neuropathy measures. METHODS: Cardiac autonomic neuropathy was assessed at the study entry into the Detection of Ischemia in Asymptomatic Diabetics study, using autonomic heart rate and blood pressure testing, and power spectral analysis of heart rate variability. All participants were prospectively followed for the composite clinical outcome of cardiac death, acute coronary syndromes, heart failure, or coronary revascularization. RESULTS: Over 5 years of follow-up, 94 of 1119 (8.4%) subjects developed symptomatic cardiac disease. In unadjusted bivariate analyses, abnormalities in several cardiac autonomic neuropathy tests, including lower Valsalva and Standing Heart Rate Ratios, higher resting Heart Rate, greater systolic blood pressure decrease on standing, and lower low-frequency power, were predictive of symptomatic disease. Independent predictors of poor cardiac outcome were a lower Valsalva Heart Rate Ratio, non-Black ethnicity, longer diabetes duration, higher glycated hemoglobin (HbA1c), insulin use, reported numbness in the extremities, higher pulse pressure, family history of coronary artery disease, and higher waist-to-hip ratio. Clinical factors independently associated with a lower Valsalva Heart Rate Ratio were insulin use, clinical proteinuria, higher pulse pressure, use of angiotensin-converting enzyme inhibitor and non-Black ethnicity. CONCLUSION: Cardiac autonomic neuropathy predicted adverse cardiac outcomes in asymptomatic type 2 diabetes without known cardiac disease. Clinical variables may help to identify patients who might have cardiac autonomic neuropathy and warrant consideration for autonomic testing.

Gender-based divergence of cardiovascular outcomes in asymptomatic patients with type 2 diabetes: results from the DIAD study.

Gender differences in cardiovascular outcomes were compared in asymptomatic men and women with type 2 diabetes (T2DM) in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Of 1123 participants, 290 men and 271 women were randomised to screening with stress myocardial perfusion imaging (MPI); 311 men and 251 women were randomised to no screening. Follow-up was 4.8±0.9 years for the occurrence of cardiac events (CE; cardiac death or non-fatal myocardial infarction). The frequency of abnormal screening was similar in men (24%) and women (19%), (p=0.2), although women trended to have smaller MPI abnormalities. CE rates were lower in women than men (1.7% vs. 3.8%, p=0.04). No CEs occurred in 17 high-risk (UKPDS risk engine) women, whereas 14 (11.2%) occurred in 125 high-risk men. Asymptomatic women with T2DM have significantly better cardiac outcomes than their male counterparts and represent a subgroup for which screening for coronary artery disease does not appear warranted.

Five-year outcomes in high-risk participants in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study: a post hoc analysis.

OBJECTIVE: To estimate baseline cardiovascular risk of 1,123 participants in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study and to assess cardiac event rates and the effect of screening on outcomes in these higher-risk participants. RESEARCH DESIGN AND METHODS: Baseline cardiovascular risk was assessed using four established methods: Framingham score, UK Prospective Diabetes Study (UKPDS) risk engine, criteria of the French-Speaking Association for the Study of Diabetes and Metabolic Diseases, and the presence or absence of metabolic syndrome. Cardiac events (cardiac death or nonfatal myocardial infarction) were assessed during the 4.8-year follow-up in participants with intermediate/high cardiovascular risk. RESULTS: By various risk-stratification approaches, 53-75% of participants were defined as having intermediate or high cardiovascular risk. The prevalence of inducible ischemia on screening in these individuals ranged from 21 to 24%, similar to lower-risk participants (19-23%). Cardiac event rates were greater in intermediate-/high-risk versus low-risk groups, but this was only significant for the UKPDS risk engine (4.2 vs. 1.2%, P = 0.002). The annual cardiac event rate was <1% in all risk groups, except in the high-risk UKPDS group (∼2% per year). In intermediate-/high-risk participants randomized to screening versus no screening, 4.8-year cardiac event rates were similar (2.5-4.8% vs. 3.1-3.7%). CONCLUSIONS: A substantial portion of the DIAD population was defined as having intermediate/high baseline cardiovascular risk. Nevertheless, their annual cardiac event rate was low and not altered by routine screening for inducible ischemia.

Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial.

CONTEXT: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PATIENTS: 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: Cardiac death or nonfatal myocardial infarction (MI). RESULTS: 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. CONCLUSION: 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.

Resolution of asymptomatic myocardial ischemia in patients with type 2 diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study.

OBJECTIVE: The purpose of this study was to assess whether the prevalence of inducible myocardial ischemia increases over time in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants enrolled in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study underwent repeat adenosine-stress myocardial perfusion imaging 3 years after initial evaluation. Patients with intervening cardiac events or revascularization and those who were unable or unwilling to repeat stress imaging were excluded. RESULTS: Of the initial 522 DIAD patients, 358 had repeat stress imaging (DIAD-2), of whom 71 (20%) had ischemia at enrollment (DIAD-1). Of 287 patients with normal DIAD-1 studies, 259 (90%) remained normal in DIAD-2, whereas 28 (10%) developed new ischemia in DIAD-2. Of the 71 patients with abnormal DIAD-1 studies, 56 (79%) demonstrated resolution of ischemia, whereas 15 (21%) remained abnormal. During this 3-year interval, medical treatment was intensified, with more patients using statins, aspirin, and ACE inhibitors than at baseline. Patients with resolution of ischemia had significantly greater increases in these medications than patients who developed new ischemia (P = 0.04). CONCLUSIONS: Thus, the majority of asymptomatic patients with type 2 diabetes demonstrated resolution of ischemia upon repeat stress imaging after 3 years. This resolution was associated with more intensive treatment of cardiovascular risk factors.

Glucose and cardiac risk factor control in individuals with type 2 diabetes: implications for patients and providers.

PURPOSE: The purpose of this descriptive study was to describe attainment of glucose and coronary heart disease (CHD) risk factor goals and to identify factors that were associated with successful goal achievement. METHODS: A cross-sectional survey enrolled 110 subjects with type 2 diabetes undergoing screening for asymptomatic myocardial ischemia. RESULTS: Many participants had HbA1c levels > or =7% (45%), and 46% to 79% were not meeting goals for CHD risk reduction. Individual factors of age, gender, and anxiety; the illness-related factor of lipid-lowering therapy; and the family-related factor of living alone were independently associated with 1 of the 7 outcomes under study. Illness-related factors of a longer duration of diabetes were strongly associated with glucose and blood pressure control, insulin use with glucose control and waist circumference, and antihypertensive use with blood pressure, triglycerides, and body mass index. Family-related factors of higher income were significantly associated with poorer glucose control and higher body mass index, while higher levels of perceived support by family and friends were associated with a lower risk of not meeting lipid goals. However, individual factors, represented by several aspects of personal model beliefs (exercising regularly, testing glucose, and checking one's feet) and physical activity, were consistently related to lipid and weight control. CONCLUSIONS: A variety of factors were associated with control of blood glucose and CHD risk factors, suggesting that a one-size-fits-all approach to multiple risk factor reduction efforts may not result in goal attainment.

Value of peripheral vascular endothelial function in the detection of relative myocardial ischemia in asymptomatic type 2 diabetic patients who underwent myocardial perfusion imaging.

BACKGROUND: Endothelial dysfunction precedes overt atherosclerosis and is present in patients with type 2 diabetes mellitus (T2DM). Myocardial perfusion imaging (MPI) is an effective method of detection of coronary artery disease (CAD); however, the relationship between endothelial function and MPI in asymptomatic patients with T2DM has not been examined. METHODS AND RESULTS: This study used a subset of the population from the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIV) were measured by use of brachial artery ultrasonography in 75 asymptomatic patients with T2DM (56 men; mean age, 58.6 +/- 6.4 years; mean duration of diabetes, 8.4 +/- 7.5 years) who underwent adenosine MPI. Of the patients, 15 (20%) had evidence of relative ischemia (MPI(+)) whereas 60 (80%) had a normal study (MPI(-)). Both EDV (3.5% +/- 3.7% vs 4.5% +/- 6.6%, P = not significant) and EIV (15.1% +/- 7.5% vs 16.8% +/- 8.4%, P = not significant) were similar in the 2 groups. On the basis of a receiver-operator analysis, an EDV response of 8% was selected as a cut point, with a negative predictive value of 93% (13/14 subjects with EDV >or=8% were MPI(-)). CONCLUSIONS: Endothelial function in asymptomatic patients with T2DM is not associated with the presence of relative myocardial ischemia by MPI; however, an EDV of 8% or greater has a high negative predictive value for the exclusion of CAD.

The impact of screening for asymptomatic myocardial ischemia in individuals with type 2 diabetes.

Little is known about factors that contribute to either emotional or behavior outcomes following screening for coronary artery disease (CAD). The purpose of this prospective study was to explore these outcomes, along with potentially contributing factors in individuals enrolled in a screening trial for asymptomatic CAD. Included were 47 subjects with type 2 diabetes. Data were collected at study baseline and 3 and 6 months following entry by self-administered questionnaires and telephone follow-up. Emotional outcomes (quality of life and anxiety) tended to improve in those who underwent more aggressive screening with myocardial perfusion imaging, as well as in those who discussed the results of laboratory tests with their providers. Lower levels of diabetes competence and higher levels of controlled motivation for diet were associated with poorer emotional outcomes. Improvements in CAD risk factor behaviors were not observed.

The association of psychological factors, physical activity, neuropathy, and quality of life in type 2 diabetes.

The objective of this study was to determine the relationship of sociodemographics; diabetes-related factors, including diabetes-related microvascular complications; cardiac risk factors; and psychological factors with quality of life (QOL). Participants enrolled at three sites in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study were invited to participate in this ancillary study. Questionnaires assessing psychological factors were completed by participants, and the remainder of the data was obtained as part of the DIAD study. Many participants had elevated levels of anxiety (n = 91; 82%), depressive symptoms (n = 16; 14%), anger (n = 38; 34%), and hostility (n = 17; 17%). Results of multivariate analyses conducted for each of the eight domains on the Medical Outcomes Study Short Form-36 and two Diabetes Quality of Life domains demonstrated that in the majority of models (42% to 68% of the variance explained), female sex, peripheral or autonomic neuropathy, physical inactivity, higher body mass index, and the presence of depressive symptoms and anxiety were associated with poorer QOL (p = .0001). These findings demonstrate that anxiety, depressive symptoms, and neuropathy are prevalent in older adults with type 2 diabetes. In addition, potentially important correlations were demonstrated between psychological factors, neuropathy, body mass index, and physical inactivity.

Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study.

OBJECTIVE: To assess the prevalence and clinical predictors of silent myocardial ischemia in asymptomatic patients with type 2 diabetes and to test the effectiveness of current American Diabetes Association screening guidelines. RESEARCH DESIGN AND METHODS: In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 1,123 patients with type 2 diabetes, aged 50-75 years, with no known or suspected coronary artery disease, were randomly assigned to either stress testing and 5-year clinical follow-up or to follow-up only. The prevalence of ischemia in 522 patients randomized to stress testing was assessed by adenosine technetium-99m sestamibi single-photon emission-computed tomography myocardial perfusion imaging. RESULTS: A total of 113 patients (22%) had silent ischemia, including 83 with regional myocardial perfusion abnormalities and 30 with normal perfusion but other abnormalities (i.e., adenosine-induced ST-segment depression, ventricular dilation, or rest ventricular dysfunction). Moderate or large perfusion defects were present in 33 patients. The strongest predictors for abnormal tests were abnormal Valsalva (odds ratio [OR] 5.6), male sex (2.5), and diabetes duration (5.2). Other traditional cardiac risk factors or inflammatory and prothrombotic markers were not predictive. Ischemic adenosine-induced ST-segment depression with normal perfusion (n = 21) was associated with women (OR 3.4). Selecting only patients who met American Diabetes Association guidelines would have failed to identify 41% of patients with silent ischemia. CONCLUSIONS: Silent myocardial ischemia occurs in greater than one in five asymptomatic patients with type 2 diabetes. Traditional and emerging cardiac risk factors were not associated with abnormal stress tests, although cardiac autonomic dysfunction was a strong predictor of ischemia.

Brachial artery reactivity in asymptomatic patients with type 2 diabetes mellitus and microalbuminuria (from the Detection of Ischemia in Asymptomatic Diabetics-brachial artery reactivity study).

Microalbuminuria is a novel atherosclerotic risk factor in patients with type 2 diabetes mellitus (DM) and predicts future cardiovascular events. Endothelial dysfunction and systemic inflammation have been proposed as common links between microalbuminuria and cardiovascular disease. However, no study has assessed the relation between microalbuminuria and vascular dysfunction as measured by brachial artery reactivity (BAR) in DM. We evaluated 143 patients (85 men; mean age 60.0 +/- 6.7 years) with DM (mean duration 8.2 +/- 7.4 years) enrolled in the Detection of Ischemia in Asymptomatic Diabetics study. Subjects were categorized as those with microalbuminuria (ratio of urinary albumin to creatinine 30 to 299 microg/mg creatinine, n = 28) and those with normoalbuminuria (ratio of urinary albumin to creatinine 0 to 29.9 microg/mg creatinine, n = 115). High-resolution ultrasound BAR testing was used to measure endothelium-dependent and endothelium-independent vasodilations. C-reactive protein was measured as a marker of systemic inflammation. Patients with microalbuminuria and normoalbuminuria had similar baseline characteristics, with the exception that those with microalbuminuria had a longer duration of DM (p = 0.03). Endothelium-dependent vasodilation at 1 minute (p = 0.01) and endothelium-independent vasodilation at 3 minutes (p = 0.007) were significantly less in patients with microalbuminuria. In addition, 96% of patients with microalbuminuria and 76% of those with normoalbuminuria had impaired endothelium-dependent vasodilation (<8%, p = 0.01). Microalbuminuria was an independent predictor of endothelium-dependent vasodilation in the entire cohort (p = 0.045) and after excluding patients on hormone replacement therapy (p = 0.01). Levels of C-reactive protein were significantly higher in patients with microalbuminuria than in those with normoalbuminuria (p = 0.02). We conclude that in DM the presence of microalbuminuria is associated with impaired endothelium-dependent and endothelium-independent vasodilations of the brachial artery and a higher degree of systemic inflammation. In addition, microalbuminuria is an independent predictor of endothelial dysfunction in asymptomatic patients with DM, especially in the absence of hormone replacement therapy.