Serum lipids and mortality in an American Indian population: A longitudinal study.

BACKGROUND: In Caucasians, lower triglycerides (TG), total or LDL cholesterol and high HDL cholesterol are generally associated with lower mortality. However, low cholesterol is associated with higher mortality in some Asian populations. This study examines the relationship between serum lipids and mortality in American Indians. METHODS: 2125 American Indians aged ≥40years were examined biennially between 1993 and 2007. Vital status was determined through 2011. Mortality rates, adjusted for age, sex and diabetes, were calculated using Poisson regression. RESULTS: The median baseline age was 46years and 61% were women. Over a median follow-up of 10.1years, 522 deaths occurred. Relationships between baseline lipids, except for HDL cholesterol, and all-cause mortality were negative and linear in persons without diabetes and U-shaped in persons with diabetes. For HDL cholesterol, the relationship was U-shaped in the total cohort. Cardiovascular mortality was positively associated with total, LDL and non-HDL cholesterol whereas lower lipid concentrations were adversely associated with mortality from liver disease or external causes, except for HDL cholesterol, where associations were positive. CONCLUSION: The common belief that low cholesterol and TG are beneficial for health is not universally observed; evidence suggests increased mortality at both ends of the cholesterol and TG distributions.

Higher energy expenditure in humans predicts natural mortality.

CONTEXT: Higher metabolic rates increase free radical formation, which may accelerate aging and lead to early mortality. OBJECTIVE: Our objective was to determine whether higher metabolic rates measured by two different methods predict early natural mortality in humans. DESIGN: Nondiabetic healthy Pima Indian volunteers (n = 652) were admitted to an inpatient unit for approximately 7 d as part of a longitudinal study of obesity and diabetes risk factors. Vital status of study participants was determined through December 31, 2006. Twenty-four-hour energy expenditure (24EE) was measured in 508 individuals, resting metabolic rate (RMR) was measured in 384 individuals, and 240 underwent both measurements on separate days. Data for 24EE were collected in a respiratory chamber between 1985 and 2006 with a mean (SD) follow-up time of 11.1 (6.5) yr and for RMR using an open-circuit respiratory hood system between 1982 and 2006 with a mean follow-up time of 15.4 (6.3) yr. Cox regression models were used to test the effect of EE on natural mortality, controlled for age, sex, and body weight. RESULTS: In both groups, 27 natural deaths occurred during the study period. For each 100-kcal/24 h increase in EE, the risk of natural mortality increased by 1.29 (95% confidence interval = 1.00-1.66; P < 0.05) in the 24EE group and by 1.25 (95% confidence interval = 1.01-1.55; P < 0.05) in the RMR group, after adjustment for age, sex, and body weight in proportional hazard analyses. CONCLUSIONS: Higher metabolic rates as reflected by 24EE or RMR predict early natural mortality, indicating that higher energy turnover may accelerate aging in humans.

Effect of intrauterine diabetes exposure on the incidence of end-stage renal disease in young adults with type 2 diabetes.

OBJECTIVE: We examined the effect of intrauterine diabetes exposure (IDE) on the incidence of diabetic end-stage renal disease (ESRD) in Pima Indians with type 2 diabetes. RESEARCH DESIGN AND METHODS: Individuals were followed from their first diabetic examination until December 2006, death, ESRD, or age of 45 years. RESULTS: Among the 1,850 diabetic participants, 102 had IDE. ESRD developed in 57, 5 of whom had IDE. Cumulative incidence of ESRD by age 45 was 19.3% in participants with IDE and 5.1% in those without; the age- and sex-adjusted incidence rate ratio was 4.12 (95% CI 1.54-11.02). After additional adjustment for age at diabetes onset, ESRD incidence was similar in the two groups (incidence rate ratio 1.38, 95% CI 0.45-4.24). CONCLUSIONS: IDE increases the age- and sex-adjusted incidence of ESRD fourfold in young adults with type 2 diabetes, mediated primarily by the earlier onset of type 2 diabetes in those with IDE.

Childhood obesity, other cardiovascular risk factors, and premature death.

BACKGROUND: The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood. METHODS: In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O'odham Indian heritage. RESULTS: There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24). CONCLUSIONS: Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes.

The separate and joint effects of prolonged QT interval and heart rate on mortality.

OBJECTIVES: Understanding why prolonged Bazett-corrected QT interval (QTc) is a risk factor for mortality is difficult, because QTc is positively correlated with heart rate. To optimally distinguish the effects of QT interval and heart rate on mortality, QT interval and heart rate were modeled separately and jointly in Pima Indians. METHODS: The effects of QT and heart rate on all-cause and cause-specific mortality were assessed in the overall study population and according to the presence or absence of diabetes using multivariable time-dependent proportional hazards models. RESULTS: Among 1488 nondiabetic and 990 diabetic subjects > or =25 years old, 81 nondiabetic and 149 diabetic subjects died during a median follow-up of 7.3 years. When included in the same regression model, QT and heart rate each predicted all-cause mortality [hazard ratios per standard deviation (SD) (95% confidence interval)=1.31 (1.10-1.57) and 1.57 (1.32-1.87) respectively]. In nondiabetic subjects, hazard ratios for all-cause mortality were 1.54 (1.19-1.99) for QT and 1.86 (1.46-2.37) for heart rate. In diabetic subjects, hazard ratios for all-cause mortality were lower, 1.27 (1.00-1.62) for QT and 1.41 (1.12-1.78) for heart rate. In the overall study population, neither QT nor heart rate significantly predicted cardiovascular disease (CVD) mortality [hazard ratios=1.13 (0.77-1.64) and 1.46 (0.98-2.19)] when adjusted for each other. Heart rate unadjusted for QT, however, predicted CVD mortality [hazard ratio=1.34 (1.00-1.79)] in a separate model. CONCLUSIONS: QT prolongation and high heart rate both predict all-cause mortality in Pima Indians, but heart rate was consistently the stronger predictor of the two.

Plasma glucose regulation and mortality in pima Indians.

OBJECTIVE: To evaluate whether impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are associated with increased risk of mortality and prevalent ischemic heart disease (IHD) and to analyze if the increased risk of death is dependent on subsequent development of diabetes in Pima Indians. RESEARCH DESIGN AND METHODS: A total of 2,993 Pima Indians aged >or=35 years were included. Prevalent IHD, defined by major ischemic electrocardiogram changes, was evaluated according to the following glucose/diabetes categories: normal glucose regulation (NGR), IFG and/or IGT, and diabetic groups by duration. During a median follow-up of 10.4 years, 780 subjects died from natural causes and 156 of these died from IHD. Mortality was analyzed according to the same glucose/diabetes categories at baseline and then as time-dependent variables. RESULTS: Only subjects with diabetes >or=15 years of duration have a higher prevalence of IHD (odds ratio 1.9 [95% CI 1.4-2.5]) relative to NGR. In baseline and time-dependent models, age- and sex-adjusted death rates from natural causes and from IHD were similar among the nondiabetic groups. Among diabetic subjects, natural mortality was higher in those with >or=15 years diabetes duration (death rate ratio [DRR] relative to NGR = 2.6 [95% CI 2.1-3.3]). IHD mortality was higher in subjects with long diabetes duration (DRR for diabetes 10-15 years = 3.8 [1.5-9.5]; DRR for diabetes >or=15 years = 8.6 [3.8-19.4]) in the time-dependent model. CONCLUSIONS: Natural and IHD mortality are not increased in Pima Indians with IFG and/or IGT. Only after the onset of diabetes do the rates of these events increase relative to NGR.

Homocysteine and vitamin B(12) concentrations and mortality rates in type 2 diabetes.

OBJECTIVE: To assess the role of homocysteine as a risk factor for mortality in diabetic subjects. METHODS: Homocysteine, vitamin B(12), and folate concentrations were measured in stored sera of 396 diabetic Pima Indians aged > or = 40 years when examined between 1982 and 1985. Vital status was assessed through 2001. RESULTS AND CONCLUSIONS: Over a median follow-up of 15.7 years, there were 221 deaths-76 were due to cardiovascular disease (CVD), 36 to diabetes/nephropathy and 34 to infections. Homocysteine was positively associated with mortality from all causes (hazard rate ratio (HRR) for highest versus lowest tertile of homocysteine = 1.70, 95% confidence interval (CI) 1.18-2.46), from diabetes/nephropathy (HRR = 2.39, 95% CI 0.94-6.11) and from infectious diseases (HRR = 3.39, 95% CI 1.19-9.70), but not from CVD (HRR = 1.16, 95% CI 0.62-2.17) after adjustment for age, sex and diabetes duration. Homocysteine correlated with serum creatinine (r = 0.50), and the relationships with mortality rates were not significant after adjustment for creatinine. Vitamin B(12) was positively associated with all-cause mortality (HRR for 100 pg/mL difference adjusted for age, sex and diabetes duration = 1.15, 95% CI 1.08-1.22) and death from diabetes/nephropathy (HRR = 1.27, 95% CI 1.10-1.46). The association between homocysteine and mortality in type 2 diabetes is not causal, but is confounded by renal disease in Pima Indians.

Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians.

CONTEXT: The long-term outcome of persons with youth-onset type 2 diabetes mellitus has not been well described. OBJECTIVE: To compare incidence of diabetic end-stage renal disease (ESRD) and mortality in Pima Indians with youth- and older-onset type 2 diabetes mellitus. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal population-based study conducted between 1965 and 2002 in Pima Indians from the state of Arizona. Participants were divided into 2 groups: (1) youth-onset type 2 diabetes mellitus (onset <20 years of age) and (2) older-onset type 2 diabetes mellitus (onset > or =20 - <55 years of age). Events and person-years of follow-up were stratified in a time-dependent fashion by decades of age. End-stage renal disease was defined as dialysis attributed to diabetic nephropathy or death from diabetic nephropathy. MAIN OUTCOME MEASURES: Incidence rate of diabetic ESRD and mortality between 25 and 55 years of age, according to age at onset of type 2 diabetes mellitus. RESULTS: Among the 1856 diabetic participants, 96 had youth-onset type 2 diabetes mellitus. The age-sex-adjusted incidence of diabetic ESRD was 25.0 cases per 1000 person-years (95% confidence interval [CI], 6.7-43.1) in youth-onset diabetes mellitus and 5.4 cases per 1000 person-years (95% CI, 4.4-6.4) in older-onset diabetes mellitus (incidence rate ratio, 4.6; 95% CI, 2.2-9.8). Age-specific incidence rates were higher in participants with youth-onset diabetes mellitus at all ages. Between 25 and 55 years of age, the age-sex-adjusted death rate from natural causes was 15.4 deaths per 1000 person-years (95% CI, 0.2-30.5) in participants with youth-onset diabetes mellitus and 7.3 deaths per 1000 person-years (95% CI, 5.9-8.7) in individuals with older-onset diabetes mellitus (death rate ratio, 2.1; 95% CI, 0.8-5.7). Compared with nondiabetic participants, the death rate was 3.0 times as high in individuals with youth-onset diabetes mellitus (95% CI, 1.1-8.0) and 1.4 times as high in individuals with older-onset diabetes mellitus (95% CI, 1.1-1.8). In a subset of 1386 participants with complete data for all covariates who were observed from the onset of diabetes mellitus, the age at onset of diabetes mellitus was not associated with the incidence of ESRD (hazard ratio, 1.0; 95% CI, 0.9-1.2) after adjusting for sex, mean arterial pressure, body mass index (calculated as weight in kilograms divided by height in meters squared), plasma glucose concentration, smoking, hypoglycemic medicines, and blood pressure medicines in a Cox proportional-hazards model. CONCLUSIONS: Early-onset type 2 diabetes mellitus is associated with substantially increased incidence of ESRD and mortality in middle age. The longer duration of diabetes mellitus by middle age in individuals diagnosed younger than age 20 years largely accounts for these outcomes.

Electrocardiographic abnormalities predict deaths from cardiovascular disease and ischemic heart disease in Pima Indians with type 2 diabetes.

BACKGROUND: The association between electrocardiographic (ECG) abnormalities and deaths from cardiovascular diseases (CVD) and ischemic heart disease (IHD) has been reported in the general population, but there is little information regarding persons with type 2 diabetes. METHODS: Minor and major ECG abnormalities were identified and classified according to the Minnesota Code in a longitudinal study of 1605 Pima Indians aged > or =35 years with type 2 diabetes. Underlying causes of death were determined by review of all available clinical records, autopsy reports, medical examiners' findings, and death certificates. RESULTS: During a median follow-up of 14.1 years (range 0.1 to 33.8 years), there were 190 CVD deaths, 135 (71.1%) of which were attributable to IHD. The age-adjusted CVD death rates in men with none, minor, and major ischemic ECG abnormalities were 7.3, 12.2 and 27.8, and in women, 4.3, 4.8 and 12.5 per 1000 person-years, respectively. After adjustment for other co-variables in a multiple proportional hazards model, subjects with minor and major ischemic abnormalities on ECG had 1.22 (95% CI, 0.76-1.97) and 1.83 (95% CI, 1.21-2.76) times the CVD death rate, and 1.32 (95% CI, 0.70-2.50) and 2.12 (95% CI, 1.26-3.57) times the IHD death rate of those with no ischemic ECG abnormalities, respectively. CONCLUSIONS: The CVD and IHD death rates were higher in men and in subjects with major ischemic ECG abnormalities. Major ischemic abnormalities on ECG predicted death after accounting for other cardiovascular risk factors, including proteinuria.

Trends in heart disease death rates in diabetic and nondiabetic Pima Indians.

BACKGROUND: Secular trends over 34 years (1965-1998) in overall and cause-specific mortality were examined in 4,623 Pima Indians >or=35 years old. METHODS: The underlying and contributing causes of the 1,363 deaths were determined from a review of all available clinical records; 540 of the deaths occurred in the 2,528 nondiabetic participants and 823 in the 2,095 participants who had diabetes during all or part of the study period. Age/sex-adjusted death rates were calculated across four 8.5-year time intervals. RESULTS: In the nondiabetic participants, the rate of death from natural causes declined gradually over time (20.4, 17.3, 17.3, and 16.0 deaths per 1,000 persons/year; P=.11); deaths from ischemic heart disease (IHD) were uncommon (n=22), and the rate did not change appreciably, remaining as the fifth leading natural cause of death. In the diabetic participants, the rate of death from natural causes was unchanged over time, but the rate of death from IHD (n=141) increased nearly twofold (3.3, 4.2, 6.4, and 6.4 deaths per 1,000 persons/year; P<.01), becoming the leading cause of death in the third and fourth time intervals. CONCLUSIONS: The rate of death from IHD remained stable in nondiabetic Pima Indians but increased among those with diabetes. This finding suggests that, in the absence of diabetes, the underlying susceptibility to IHD in this population has not changed.

Predominant effect of kidney disease on mortality in Pima Indians with or without type 2 diabetes.

BACKGROUND: We examined the effect of kidney disease (KD) on mortality in nondiabetic and diabetic Pima Indians aged > or = 45 years old. METHODS: Deaths and person-years of follow-up were stratified in a time-dependent fashion into categories of (1) no proteinuria and normal serum creatinine (SCr); (2) proteinuria and normal SCr; (3) high SCr [SCr > or = 133 micromol/L (1.5 mg/dL) in men, > or = 124 micromol/L (1.4 mg/dL) in women] but not on renal replacement therapy (RRT); or (4) RRT. RESULTS: Among 1993 subjects, 55.8% had type 2 diabetes at baseline. Overall death rates increased with declining kidney function in both the nondiabetic and diabetic subjects (P < 0.0001). Death rates were similar in nondiabetic and diabetic subjects with comparable levels of kidney function, although the number of deaths among nondiabetic subjects with advanced KD was small. Infections and malignancy were the leading causes of death in nondiabetic subjects with KD. Among diabetic subjects, overall mortality increased with diabetes duration (P = 0.0001) and was highest in those on RRT (P < 0.0001). High SCr was associated with higher death rates from cardiovascular disease (CVD), diabetic nephropathy (DN), infections, and malignancy. CONCLUSION: Death rates increased comparably with worsening kidney function in both nondiabetic and diabetic subjects and were similar in nondiabetic and diabetic subjects without KD. KD was associated with excess mortality from DN, CVD, infections, and malignancy in diabetic subjects, and from infections in those without diabetes.

Periodontal disease and mortality in type 2 diabetes.

OBJECTIVE: Periodontal disease may contribute to the increased mortality associated with diabetes. RESEARCH DESIGN AND METHODS: In a prospective longitudinal study of 628 subjects aged > or =35 years, we examined the effect of periodontal disease on overall and cardiovascular disease mortality in Pima Indians with type 2 diabetes. Periodontal abnormality was classified as no or mild, moderate, and severe, based on panoramic radiographs and clinical dental examinations. RESULTS: During a median follow-up of 11 years (range 0.3-16), 204 subjects died. The age- and sex-adjusted death rates for all natural causes expressed as the number of deaths per 1,000 person-years of follow-up were 3.7 (95% CI 0.7-6.6) for no or mild periodontal disease, 19.6 (10.7-28.5) for moderate periodontal disease, and 28.4 (22.3-34.6) for severe periodontal disease. Periodontal disease predicted deaths from ischemic heart disease (IHD) (P trend = 0.04) and diabetic nephropathy (P trend < 0.01). Death rates from other causes were not associated with periodontal disease. After adjustment for age, sex, duration of diabetes, HbA1c, macroalbuminuria, BMI, serum cholesterol concentration, hypertension, electrocardiographic abnormalities, and current smoking in a proportional hazards model, subjects with severe periodontal disease had 3.2 times the risk (95% CI 1.1-9.3) of cardiorenal mortality (IHD and diabetic nephropathy combined) compared with the reference group (no or mild periodontal disease and moderate periodontal disease combined). CONCLUSIONS: Periodontal disease is a strong predictor of mortality from IHD and diabetic nephropathy in Pima Indians with type 2 diabetes. The effect of periodontal disease is in addition to the effects of traditional risk factors for these diseases.

An explanation for the increase in heart disease mortality rates in diabetic Pima Indians: effect of renal replacement therapy.

OBJECTIVE: Diabetic nephropathy (DN) became the leading cause of death in diabetic Pima Indians in the 1970s, but was superseded by ischemic heart disease (IHD) in the 1980s. This study tests the hypothesis that the rise in the IHD death rate between 1965 and 1998 is attributable to access to renal replacement therapy (RRT). RESEARCH DESIGN AND METHODS: Underlying causes of death were determined among 2,095 diabetic Pima Indians > or = 35 years old during four 8.5-year time intervals. To assess the effect of access to RRT on IHD death rates, trends were reexamined after subjects receiving RRT were classified as if they had died of DN. RESULTS: During a median follow-up of 11.1 years (range 0.01-34), 818 subjects died. The age- and sex-adjusted DN death rate decreased over the 34-year study (P = 0.05), whereas the IHD death rate increased from 3.3 deaths/1,000 person-years (95% CI 1.4-5.2) to 6.3 deaths/1,000 person-years (95% CI 4.5-8.0; P = 0.03). After 151 subjects on RRT were reclassified as if they had died of DN, the death rate for DN increased from 4.8 deaths/1,000 person-years (95% CI 2.6-7) to 11.3 deaths/1,000 person-years (95% CI 9-13.6; P = 0.0007), whereas the increase in the IHD death rate disappeared (P = 0.57). CONCLUSIONS: The incidence rate of renal failure attributable to diabetes has increased rapidly over the past 34 years in Pima Indians. IHD has emerged as the leading cause of death due largely to the availability of RRT and to changes in the pattern of death among those with DN.