Heart Rate and Heart Rate Variability Changes Are Not Related to Future Cardiovascular Disease and Death in People With and Without Dysglycemia: A Downfall of Risk Markers? The Whitehall II Cohort Study

OBJECTIVEHigher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants’ baseline glycemic state.RESEARCH DESIGN AND METHODSIn this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested.RESULTSAt baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non–CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm–higher baseline HR level was associated with an 11.4% higher rate of all-cause mortality (95% CI 1.0–22.9%; P = 0.032). Glycemic state did not modify associations.CONCLUSIONSChanges in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia.     

Predictive properties of impaired glucose tolerance for cardiovascular risk are not explained by the development of overt diabetes during follow-up

OBJECTIVE: To evaluate the relationship of impaired glucose tolerance (IGT) at baseline to coronary heart disease (CHD) incidence, and cardiovascular disease (CVD) and total mortality at follow-up, and to analyze whether the relationship is independent of the subsequent development of diabetes during follow-up. RESEARCH DESIGN AND METHODS: A baseline screening survey for diabetes was performed in 1987 using a 2-h 75-g oral glucose tolerance test. A total of 1234 men and 1386 women aged 45-64 years, who were free of diabetes at baseline, were followed up for 10 years. During the follow-up, 153 subjects had an incident CHD event, 224 died, and 100 deaths were due to cardiovascular causes. Multivariate adjusted (adjusted for age, sex, waist-to-hip ratio, systolic blood pressure, cholesterol, HDL cholesterol, and smoking) hazard ratio (HR) was estimated using Cox regression analysis. RESULTS: In subjects who had IGT at baseline and who did not progress to diabetes during the follow-up, the multivariate adjusted HR (95% CI) was 1.49 (0.95-2.34) for CHD incidence, 2.34 (1.42-3.85) for CVD mortality, and 1.65 (1.13-2.40) for all-cause mortality. CONCLUSIONS: Baseline IGT was an independent risk predictor for cardiovascular morbidity and mortality and for total mortality, which was not confounded by the subsequent development of overt diabetes.     

Metabolic syndrome as a predictor of all-cause and cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

OBJECTIVE: The aim of this study was to assess in an 11-year survival follow-up of a population-based cohort of type 2 diabetes the predictive role of World Health Organization-defined metabolic syndrome, independent of conventional cardiovascular risk factors. RESEARCH DESIGN AND METHODS: During the follow-up (1991-2001), 1,565 patients were regularly examined with centralized measurements of HbA(1c). The independent role of the metabolic syndrome as a predictor of all-cause and cardiovascular mortality was assessed with multivariate Cox proportional hazards modeling. RESULTS: At baseline, the prevalence of the metabolic syndrome was 75.6% (95% CI 73.6-77.9). Results are based on 685 deaths (520 with the metabolic syndrome and 165 without it) in 10,890.2 person-years of observations. With respect to subjects without the metabolic syndrome, those with the metabolic syndrome had a similar hazard ratio (HR) of cardiovascular mortality after adjustment for age, sex, smoking, total cholesterol level, and coronary heart disease. In contrast, relative to subjects with diabetes only, the HR of subjects with only one component of the syndrome was 2.92 (1.16-7.33), independent of other risk factors. CONCLUSIONS: We found that 1) the prevalence of the metabolic syndrome in a population-based cohort of type 2 diabetes is high (75.6%); 2) the metabolic syndrome is not a predictor of 11-year all-cause and cardiovascular mortality; and 3) more than twofold higher cardiovascular risk, independent of conventional risk factors, is evident in diabetic subjects with only one component of the syndrome compared with those with diabetes only. Categorizing type 2 diabetic subjects as having or not having the metabolic syndrome does not provide further prediction compared with the knowledge of its single components.     

New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study

OBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes. RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality. RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95% CI 1.7-10.8]), and did not increase over time. CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.     

Associations of Type 2 Diabetes Onset Age With Cardiovascular Disease and Mortality: The Kailuan Study

OBJECTIVEWe aimed to explore the associations between type 2 diabetes onset age and cardiovascular disease (CVD) and all-cause mortality in the Chinese population.RESEARCH DESIGN AND METHODSThis study included 101,080 participants free of prevalent diabetes and CVD at baseline from the Kailuan Study. All participants were monitored biennially until 31 December 2017. During follow-up, 11,384 participants were diagnosed as having type 2 diabetes. For each case subject, one control subject was randomly selected, matched for age (± 1 years) and sex. The final analysis comprised 10,777 case-control pairs. Weighted Cox regression models were used to evaluate the average hazard ratios (AHRs) and 95% CIs of incident CVD and all-cause mortality among patients with new-onset type 2 diabetes versus control subjects across age-groups.ResultsDuring a median follow-up of 5.57 years, 1,794 incident events (907 CVD events, of which there were 725 strokes and 887 deaths) occurred. After adjustment for potential confounders, participants with type 2 diabetes diagnosed at age <45 years had the highest relative risks of CVD and all-cause mortality relative to the matched control subjects, with AHRs of 3.21 (95% CI 1.18–8.72) for CVD, 2.99 (95% CI 1.01–9.17) for stroke, and 4.79 (95% CI 1.95–11.76) for all-cause mortality. The risks gradually attenuated with each decade increase in type 2 diabetes onset age.CONCLUSIONSThe relative risks of CVD and all-cause mortality differed across type 2 diabetes onset age-groups, and the associations were more evident in younger-onset type 2 diabetes.     

Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study

OBJECTIVE: To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations. RESEARCH DESIGN AND METHODS: This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15-60 years, who were examined for retinopathy by taking two-field 45 degrees fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6-8 years after baseline examination according to a standardized protocol. RESULTS: After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HRs) of all-cause mortality were 1.45 (95% CI 0.71-2.96) and 4.16 (1.96-8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15-2.60) and 2.05 (1.22-3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance. CONCLUSIONS: This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved.     

Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women

OBJECTIVE: To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences. RESEARCH DESIGN AND METHODS: Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality. RESULTS: Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98-1.83), 1.30 (0.86-1.96), and 1.18 (0.74-1.89), respectively, for background retinopathy and 3.05 (1.70-5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38-7.30), and 4.98 (2.06-12.06), respectively, for proliferative retinopathy. CONCLUSIONS: Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.     

Heart Rate–Corrected QT Interval Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Diabetes Heart Study

OBJECTIVE

Heart rate–corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.

RESEARCH DESIGN AND METHODS

We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.

RESULTS

At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03–1.36]) and 29% increased risk for CVD mortality (1.29 [1.05–1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95–3.15]; CVD mortality 2.86 [1.35–6.08]).

CONCLUSIONS

Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.     

Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy

OBJECTIVE: Cardiac autonomic neuropathy (CAN) has been associated with a poor prognosis in patients with diabetes. Because CAN is common in patients with diabetic nephropathy, we evaluated the predictive value of CAN in type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy and a matched group of 191 patients with long-standing type 1 diabetes and normoalbuminuria were followed for 10.1 years (range 0.0-10.3 years). At baseline, CAN was assessed by heart rate variation (HRV) during deep breathing. HRV was evaluated as a predictor of the primary end point: cardiovascular morbidity and mortality. As secondary end points, all-cause mortality and the influence of HRV on progression of diabetic nephropathy (decline in glomerular filtration rate [GFR]) was evaluated. RESULTS: During the follow-up, 79 patients (40%) with nephropathy reached the combined primary end point vs. 19 patients (10%) with normoalbuminuria (log-rank test, P < 0.0001). The unadjusted hazard ratio (HR) for reaching the primary end point when having an abnormal HRV (< or =10 bpm) measured at baseline compared with a normal HRV was 7.7 (range 1.9-31.5; P = 0.004) in patients with nephropathy. Similarly in the normoalbuminuric patients, the unadjusted HR was 4.4 (1.4-13.6; P = 0.009). In patients with nephropathy, abnormal HRV was significantly associated with fatal and nonfatal cardiovascular disease after adjustment for cardiovascular risk factors. The adjusted HR for reaching the primary end point in a patient with nephropathy and an abnormal HRV was 6.4 (1.5-26.3, P = 0.010), as compared with a normal HRV. The unadjusted HR for dying when having an abnormal HRV compared with a normal HRV was 3.3 (95% CI 1.0-10.7; P = 0.043) in patients with diabetic nephropathy. After adjustment for confounding factors, the impact of HRV on all-cause mortality in patients with nephropathy was no longer significant (P = 0.293). There was no relationship between abnormal HRV and rate of decline in GFR. CONCLUSIONS: HRV is an independent risk factor for cardiovascular morbidity and mortality in type 1 diabetic patients with nephropathy.     

Impact of incident diabetes and incident nonfatal cardiovascular disease on 18-year mortality: the multiple risk factor intervention trial experience

OBJECTIVE: To report long-term risks for total, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality associated with incident diabetes (using current diagnostic criteria) and with incident nonfatal CVD (NF-CVD). RESEARCH DESIGN AND METHODS: A total of 11645 participants without diabetes or CVD at baseline from the Multiple Risk Factor Intervention Trial who survived to the end of the trial were grouped by during-trial incident diabetes and/or NF-CVD events: neither diabetes nor NF-CVD, diabetes only, NF-CVD only, or both diabetes and NF-CVD. Incident diabetes was defined by use of hypoglycemic agents or fasting glucose >or=126 mg/dl at any time over the 6 trial years. Proportional hazards models tested group differences in mortality over 18 post-trial years. RESULTS: Among 3859 total deaths were 1846 from CVD and 1277 from CHD, with death rates per 10000 person-years of 203, 97, and 67, respectively. Multivariate-adjusted hazard ratios (HRs) for total mortality were 2.75 (P < 0.0001) for those with NF-CVD and diabetes both, 1.92 (P < 0.0001) for those with NF-CVD only, and 1.49 (P < 0.0001) for those with diabetes only, relative to neither diabetes nor NF-CVD. NF-CVD was associated with a higher hazard of death than diabetes for total (HR 1.29, P = 0.0004), CVD (HR 1.76, P < 0.0001), and CHD (HR 1.88, P < 0.0001) mortality. Only the subgroup of participants on hypoglycemic agents showed an equivalent risk of total mortality relative to participants with NF-CVD (HR 0.93, P = 0.54). CONCLUSIONS: Current diabetes diagnostic criteria conferred significantly increased total, CVD, and CHD mortality risks independent of the impact of NF-CVD. NF-CVD was more strongly predictive of mortality.     

Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes

BACKGROUND: The causes and mechanisms of increased mortality of patients with diabetic nephropathy are unclear, and its natural history is poorly understood. Aim: To evaluate risk factors for mortality in type 2 diabetic patients with nephropathy. DESIGN: Retrospective study of clinical and biochemical parameters in diabetic nephropathic patients and controls sampled from a secondary care register. METHODS: We studied 170 type 2 diabetic patients (from 1987 to 1995) with nephropathy (proteinuria >0.5 g/24 h) and 170 non-nephropathic patients. Follow-up was until death or December 1997. Details of demographics, clinical and treatment history were obtained from medical records. RESULTS: Mean follow-up was 5.3 years. Of the patients with nephropathy at baseline, 63 (37%) died compared with 14 (8%) non-nephropathic patients (chi(2)=53.8, p<0.0001). Age- and sex-adjusted all-cause mortality rates were 8.1 (6.4, 9.8) and 1.4 (0.5, 2.2) deaths per 100 person-years, respectively (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular causes (rate ratio 5.4). Mortality was directly proportional to degree of proteinuria: 0.5-2 g/24 h, 4.6 (2.9-7.1); >2 g/24 h, 9.9 (7.3-13.5) per 100 patient-years. A 36% (5-78%) excess risk of mortality was observed for each log unit increase in proteinuria. Multivariate Cox regression analyses confirmed a five-fold excess risk for all-cause and cardiovascular mortality in patients with nephropathy compared with those without. This was independent of other risk factors including baseline age [5% (1-8%)/year], creatinine [2.5 (1.12-5.6)/10 micromol/l] and glycaemic control (HbA(1c)) [15% (1-31%) per 1% rise]. CONCLUSIONS: Proteinuria is a potentially preventable and reversible risk factor associated with high mortality in type 2 diabetic patients. Prevention of the development of overt nephropathy and improvement in diabetes control may reduce mortality in these patients.     

All-cause and cardiovascular mortality among diabetic participants in the San Antonio Heart Study: evidence against the "Hispanic Paradox"

OBJECTIVE: The observation that Hispanics have lower all-cause and cardiovascular mortality, despite increased diabetes and obesity, lower socioeconomic status (SES), and barriers to health care, has been termed the "Hispanic Paradox." We examined the relationship between ethnicity and all-cause and cardiovascular mortality in Mexican Americans (MAs) and non-Hispanic whites (NHWs) with diabetes. RESEARCH DESIGN AND METHODS: In the San Antonio Heart Study, a prospective cohort, we compared the mortality in 554 U.S.-born MAs, 95 Mexico-born MAs, and 178 NHW participants with diabetes aged 25-72 years. Over an average of 10.4 years, 188 deaths occurred: 115 from cardiovascular disease (CVD) [death certificate ICD-9 codes 401-414 or 420-447 (excluding 427.5)]. Because of potential differences between migrants and nonmigrants, hazard ratios (HRs) were calculated comparing U.S.-born MAs and Mexico-born MAs with NHWs. RESULTS: The age- and sex-adjusted HR for all-cause mortality comparing U.S.-born MAs with NHWs was 1.66 (95% CI 1.15-2.40), while comparing Mexico-born MAs with NHWs was 1.14 (95% CI 0.63-2.06). Cardiovascular mortality HRs were 1.66 (95% CI 1.04-2.65) and 0.89 (95% CI 0.40-2.01), respectively. After adjusting for possible confounders, such as fasting glucose and diabetes duration, the hazard of all-cause and cardiovascular mortality (although not statistically significant) appeared higher in U.S.-born MAs than in the other two groups. CONCLUSIONS: We found it important to differentiate MAs by birthplace. Among diabetic participants, contrary to the prediction of the "Hispanic Paradox," compared with NHWs, U.S.-born MAs were at greater risk of all-cause and cardiovascular mortality, while Mexico-born MAs appeared to be at similar risk.     

Proinsulin concentration is an independent predictor of all-cause and cardiovascular mortality: an 11-year follow-up of the Hoorn Study

OBJECTIVE: High proinsulin concentration may be a better predictor for cardiovascular disease (CVD) mortality than insulin concentration. Previous observations may have been confounded by glucose tolerance status or lack of precision because of high intraindividual variability. We investigated the longitudinal relation of means of duplicate measurements of insulin and proinsulin with all-cause and CVD mortality in a population-based cohort taking glucose tolerance status into account. RESEARCH DESIGN AND METHODS: Fasting and post-75-g glucose-load (2-h) glucose, insulin, and proinsulin values were determined in duplicate on separate days in 277 participants with normal glucose metabolism, 208 participants with impaired glucose metabolism, and 119 newly detected patients with type 2 diabetes of the Hoorn Study. Insulin resistance and beta-cell function were estimated by homeostasis model assessment (HOMA-IR and HOMA-B, respectively), and the fasting proinsulin-to-insulin ratio was calculated. Subjects were followed with respect to mortality until January 2003. RESULTS: Fasting proinsulin levels were significantly associated with all-cause and CVD mortality. The hazard ratios (HRs) per increase in interquartile range adjusted for age and sex were 1.21 (95% CI 1.04-1.42) for all-cause mortality and 1.33 (1.06-1.66) for CVD mortality. Adjustment for glucose tolerance status and HOMA-IR did not substantially change the associations. CONCLUSIONS: Fasting proinsulin was associated with all-cause and CVD mortality, independent of glucose tolerance status and insulin resistance and largely independent of other CVD risk factors. Proinsulin might play a role in the relationship between insulin resistance and CVD.     

High risk of cardiovascular disease in patients with type 1 diabetes in the U.K.: a cohort study using the general practice research database

OBJECTIVE: To estimate the absolute and relative risk of cardiovascular disease (CVD) in patients with type 1 diabetes in the U.K. RESEARCH DESIGN AND METHODS: Subjects with type 1 diabetes (n = 7,479) and five age- and sex-matched subjects without diabetes (n = 38,116) and free of CVD at baseline were selected from the General Practice Research Database (GPRD), a large primary care database representative of the U.K. population. Incident major CVD events, comprising myocardial infarction, acute coronary heart disease death, coronary revascularizations, or stroke, were captured for the period 1992-1999. RESULTS: The hazard ratio (HR) for major CVD was 3.6 (95% CI 2.9-4.5) in type 1 diabetic men compared with those without diabetes and 7.7 (5.5-10.7) in women. Increased HRs were found for acute coronary events (3.0 and 7.6 in type 1 diabetic men and women, respectively, versus nondiabetic subjects), coronary revascularizations (5.0 in men, 16.8 in women), and for stroke (3.7 in men, 4.8 in women). Type 1 diabetic men aged 45-55 years had an absolute CVD risk similar to that of men in the general population 10-15 years older, with an even greater difference in women. CONCLUSIONS: Despite advances in care, these data show that absolute and relative risks of CVD remain extremely high in patients with type 1 diabetes. Women with type 1 diabetes continue to experience greater relative risks of CVD than men compared with those without diabetes.     

Maximal Exercise Electrocardiographic Responses and Coronary Heart Disease Mortality Among Men With Metabolic Syndrome

OBJECTIVE: To examine the association between abnormal exercise electrocardiographic (E-ECG) test results and mortality (all-cause and that resulting from coronary heart disease [CHD] or cardiovascular disease [CVD]) in a large population of asymptomatic men with metabolic syndrome (MetS).PATIENTS AND METHODS: A total of 9191 men (mean age, 46.9 years) met the criteria of having MetS. All completed a maximal E-ECG treadmill test (May 14, 1979, through April 9, 2001) and were without a previous CVD event or diabetes at baseline. Main outcomes were all-cause mortality, mortality due to CHD, and mortality due to CVD. Cox regression analysis was used to quantify the mortality risk according to E-ECG responses.RESULTS: During a follow-up of 14 years, 633 deaths (242 CVD and 150 CHD) were identified. Mortality rates and hazard ratios (HRs) across E-ECG responses were the following: for all-cause mortality: HR, 1.36; 95% confidence interval (CI), 1.09-1.70 for equivocal responses and HR, 1.41; 95% CI, 1.12-1.77 for abnormal responses (P_trend<.001); for mortality due to CVD: HR, 1.29; 95% CI, 0.88-1.88 for equivocal responses and HR, 2.04; 95% CI, 1.46-2.84 for abnormal responses (P_trend<.001); and for mortality due to CHD: HR, 1.62; 95% CI, 1.02-2.56 for equivocal responses and HR, 2.45; 95% CI, 1.62-3.69 for abnormal responses (P_trend<.001). A positive gradient for CHD, CVD, and all-cause mortality rates across E-ECG categories within 3, 4, or 5 MetS components was observed (P<.001 for all).CONCLUSION: Among men with MetS, an abnormal E-ECG response was associated with higher risk of all-cause, CVD, and CHD mortality. These findings underscore the importance of E-ECG tests to identify men with MetS who are at risk of dying.ACLS = Aerobics Center Longitudinal Study; CHD = coronary heart disease; CI = confidence interval; CRF = cardiorespiratory fitness; CVD = cardiovascular disease; DM = diabetes mellitus; ECG = electrocardiography; E-ECG = exercise ECG; HR = hazard ratio; MET = metabolic equivalent; MetS = metabolic syndrome; NDI = National Death Index; SRI = stress-recovery indexMetabolic syndrome (MetS) is a clustering of cardiovascular disease (CVD) risk factors,¹ including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance,² that currently affects nearly 25% of Americans and is a growing concern because of increasing rates of obesity and hypertension.³ Because many of the components of MetS are associated with an increased risk of CVD and death, a noninvasive diagnosis of subclinical CVD in patients with MetS is important and may optimize secondary preventive interventions in this high-risk population.We showed earlier that abnormal exercise electrocardiographic (E-ECG) results during maximal exercise testing was associated with an elevated risk of incident coronary heart disease (CHD), CVD, and all-cause mortality in 2854 men with diabetes mellitus (DM).⁴ Thus, although DM is considered a CHD risk equivalent, important additional information for risk stratification can be obtained from exercise testing. We also showed that exercise testing can be used to identify women with impaired fasting glucose, a predecessor to DM and MetS, who are at high risk of all-cause mortality.⁵ Callaham et al⁶ studied 1747 US veterans with DM and showed that exercise-induced ST-segment depression was associated with more CVD events during a mean follow-up of 2 years than was observed in participants without ST-segment depression. In a study of 45 patients with exercise-induced silent ischemia, Weiner et al⁷ reported that patients with DM had worse outcomes in terms of CVD events than persons without DM.Currently, no known studies have evaluated the association between abnormal E-ECG responses and all-cause, CHD, and CVD mortality risk in men with MetS. Although sparse, some studies have examined the association between E-ECG responses and CHD risk in men with components of MetS. Ekelund et al⁸ reported that positive findings on E-ECG was an independent predictor of CVD events in men with hypercholesterolemia. Laukkanen et al⁹ reported that exercise-induced ischemia was associated with a higher risk of adverse outcomes in persons at high risk of CHD. Bigi et al¹⁰ suggested that the stress-recovery index (SRI) predicts all-cause mortality in persons with hypertension.Therefore, our study primarily aimed to evaluate the association between abnormal E-ECG test results and mortality (all-cause and that due to CHD or CVD) in a large population of asymptomatic men with MetS. We showed earlier that a maximal E-ECG test performed in asymptomatic men free of CVD can predict future risk of CHD death,¹¹ and that an abnormal test result was a more powerful predictor of risk in those with DM than those without the diagnosis.⁴ The current study will expand this earlier report and focus on men with MetS.     

Diabetes and the risk of infection-related mortality in the U.S

OBJECTIVE--To determine whether diabetes predicts infection-related mortality and to clarify the extent to which this relationship is mediated by comorbid conditions that may themselves increase risk of infection. RESEARCH DESIGN AND METHODS--We performed a retrospective cohort study using the Second National Health and Nutrition Examination Survey Mortality Study of 9,208 adults aged 30-74 years in 1976-1980. We defined demographic variables, diabetes, cardiovascular disease (CVD), and smoking by self-report; BMI, blood pressure, and serum cholesterol from baseline examination; and cause-specific mortality from death certificates. RESULTS--Over 12-16 years of follow-up, 36 infection-related deaths occurred among 533 adults with diabetes vs. 265 deaths in 8,675 adults without diabetes (4.7 vs. 1.5 per 1,000 person-years, P < 0.001). Diabetes (RR 2.0, 95% CI 1.2-3.2) and congestive heart failure (2.8, 1.6-5.1) were independent predictors of infection-related mortality after simultaneous adjustment for age, sex, race, poverty status, smoking, BMI, and hypertension. After subdividing infection-related deaths into those with (n = 145) and without (n = 156) concurrent cardiovascular diagnoses at the time of death, diabetic adults were at risk for infection-related death with CVD (3.0, 1.8-5.0) but not without CVD (1.0, 0.5-2.2). CONCLUSIONS--These nationally representative data suggest that diabetic adults are at greater risk for infection-related mortality, and the excess risk may be mediated by CVD.     

HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study

OBJECTIVE: To evaluate whether homeostasis model assessment-estimated insulin resistance (HOMA-IR) is an independent predictor of cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Conventional CVD risk factors (sex, age, smoking, plasma lipids, blood pressure, and metabolic control) and insulin resistance (estimated by HOMA) were evaluated at baseline in 1,326 patients with type 2 diabetes examined within the Verona Diabetes Complications Study. At baseline and after a mean follow-up of 4.5 years, CVD was assessed by medical history, physical examination, electrocardiography, and echo-Doppler of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were carefully scrutinized to identify cardiovascular deaths. In statistical analyses, CVD was an aggregate end point including both fatal and nonfatal coronary, cerebrovascular, and peripheral vascular disease as well as ischemic electrocardiographic abnormalities and vascular lesions identified by echo-Doppler. RESULTS: At baseline, 441 subjects were coded positive for CVD (prevalent cases). Incident cases numbered 126. Multiple logistic regression analyses showed that, along with sex, age, smoking, HDL/total cholesterol ratio, and hypertension, HOMA-IR was an independent predictor of both prevalent and incident CVD. A 1-unit increase in (log)HOMA-IR value was associated with an odds ratio for prevalent CVD at baseline of 1.31 (95% CI 1.10-1.56, P = 0.002) and for incident CVD during follow-up of 1.56 (95% CI 1.14-2.12, P < 0.001). CONCLUSIONS: HOMA-IR is an independent predictor of CVD in type 2 diabetes. The improvement of insulin resistance might have beneficial effects not only on glucose control but also on CVD in patients with type 2 diabetes.     

Cardiometabolic risk in impaired fasting glucose and impaired glucose tolerance: the Atherosclerosis Risk in Communities Study

OBJECTIVE: We compared and contrasted cardiovascular disease (CVD) risk factors, subclinical manifestations of CVD, incident coronary heart disease (CHD), and all-cause mortality by categories of impaired glucose regulation in nondiabetic individuals. RESEARCH DESIGN AND METHODS: The study included 6,888 participants aged 52-75 years who had no history of diabetes or CVD. All-cause mortality and incident CHD were ascertained over a median of 6.3 years of follow-up. RESULTS: Agreement between fasting and postchallenge glucose impairment was poor: 3,048 subjects (44%) had neither impaired fasting glucose (IFG) nor impaired glucose tolerance (IGT), 1,690 (25%) had isolated IFG, 1,000 (14%) had isolated IGT, and 1,149 (17%) had both IFG and IGT. After adjustment for age, sex, race, and center, subjects with isolated IFG were more likely to smoke, consume alcohol, and had higher mean BMI, waist circumference, LDL cholesterol, and fasting insulin and lower HDL cholesterol than those with isolated IGT, while subjects with isolated IGT had higher mean triglycerides, systolic blood pressure, and white cell counts. Measures of subclinical CVD and rates of all-cause mortality and incident CHD were similar in isolated IFG and isolated IGT. CONCLUSIONS: Neither isolated IFG nor isolated IGT was associated with a more adverse CVD risk profile.     

Mortality Among Low-Income African Americans and Whites With Diabetes

OBJECTIVE

To estimate mortality rates and risk factors for mortality in a low-socioeconomic status (SES) population of African Americans and whites with diabetes.

RESEARCH DESIGN AND METHODS

We determined mortality among African Americans and whites aged 40–79 years with (n = 12,498) and without (n = 49,914) diabetes at entry into a cohort of participants recruited from government-funded community health centers. Multivariable Cox analysis was used to estimate mortality hazard ratios (HRs) (95% CI) among those with versus those without diabetes and among those with diabetes according to patient characteristics.

RESULTS

During follow-up (mean 5.9 years), 13.5% of those with and 7.3% of those without diabetes died. All-cause mortality risk was higher among those with versus without diabetes for both African Americans (HR 1.84 [95% CI 1.71–1.99]) and whites (1.80 [1.58–2.04]), although among those with diabetes, mortality was lower among African Americans than whites (0.78 [0.69–0.87]). Mortality risk increased with duration of diabetes and was greater among patients on insulin therapy and reporting histories of cardiovascular disease (CVD), hypertension, and stroke. The HRs associated with these multiple risk factors tended to be similar by sex and race, with the exception of a differentially higher impact of prevalent CVD on mortality among African Americans (interaction P value = 0.03), despite a lower baseline prevalence of CVD.

CONCLUSIONS

In this population with similarly low SES and access to health care, strong and generally similar predictors of mortality were identified for African Americans and whites with diabetes, with African Americans at a moderately but significantly lower mortality risk.Population studies have consistently shown increased all-cause mortality among individuals with type 2 diabetes (1–4). Several reports have also shown that the impact of diabetes on mortality varies by socioeconomic status (SES) (5–7), race (8–10), and/or sex (4,11). However, scant literature exists on the mortality experience of diabetic patients within low-SES populations in the U.S. and whether within these vulnerable populations mortality varies by sex or race. We have previously reported that the prevalence of diabetes is only slightly higher among African Americans than whites once SES and other risk factors are accounted for (12). We now describe mortality patterns and risk factors for mortality by sex and race in a large, low-SES population of southern U.S. African Americans and whites with type 2 diabetes.     

Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. 27

OBJECTIVE: Diabetes is a leading cause of morbidity and mortality. The purpose of this study is to assess the associations between diabetes complications and mortality in the Early Treatment Diabetic Retinopathy Study (ETDRS). RESEARCH DESIGN AND METHODS: We examined demographic, clinical, and laboratory characteristics of the 3,711 subjects enrolled in the ETDRS, a randomized controlled clinical trial designed to evaluate the role of laser photocoagulation and aspirin therapy for diabetic retinopathy. The outcome assessed was all-cause mortality. Multivariable Cox proportional hazards regression was used to assess associations between diabetes complications and mortality for type 1 and type 2 diabetes separately. RESULTS: The 5-year estimates of all-cause mortality were 5.5 and 18.9% for patients with type 1 and type 2 diabetes, respectively. In patients with type 1 diabetes, amputation (hazard ratio [HR] 5.08 [95% CI 2.06-12.54]) and poor visual acuity (1.74 [1.10-2.75]) remained significantly associated with mortality, after adjusting for other diabetes complications and baseline characteristics. In patients with type 2 diabetes, macrovascular disease and worsening levels of nephropathy, neuropathy, retinopathy, and visual acuity are associated with progressively increasing risks of mortality, after controlling for other baseline risk factors. CONCLUSIONS: Amputation is the strongest predictor for mortality in patients with type 1 diabetes. All complications independently predict mortality in patients with type 2 diabetes. There is an increased risk for mortality as the degree of each complication worsens. Additional studies are needed to investigate the effectiveness of tertiary prevention to decrease mortality in these patients.