Maurice L. Sievers

LDL Cholesterol as a Strong Predictor of Coronary Heart Disease in Diabetic Individuals With Insulin Resistance and Low LDL The Strong Heart Study

Diabetes has been shown to increase the risk of coronary heart disease in all populations studied. However, there is a lack of information on the relative importance of diabetes-associated risk factors for cardiovascular disease (CVD), especially the role of lipid levels, because low density lipoprotein (LDL) cholesterol often is not elevated in diabetic individuals. The objective of this analysis was to evaluate CVD risk factors in a large cohort of diabetic individuals and to compare the importance of dyslipidemia (ie, elevated triglycerides and low levels of high density lipoprotein [HDL] cholesterol) and LDL cholesterol in determining CVD risk in diabetic individuals. The Strong Heart Study assesses coronary heart disease and its risk factors in American Indians in Arizona, Oklahoma, and South/North Dakota. The baseline clinical examinations (July 1989 to January 1992) consisted of a personal interview, physical examination, and drawing of blood samples for 4549 study participants (2034 with diabetes), 45 to 74 years of age. Follow-up averaged 4.8 years. Fatal and nonfatal CVD events were confirmed by standardized record review. Participants with diabetes, compared with those with normal glucose tolerance, had lower LDL cholesterol levels but significantly elevated triglyceride levels, lower HDL cholesterol levels, and smaller LDL particle size. Significant independent predictors of CVD in those with diabetes included age, albuminuria, LDL cholesterol, HDL cholesterol (inverse), fibrinogen, and percent body fat (inverse). A 10-mg/dL increase in LDL cholesterol was associated with a 12% increase in CVD risk. Thus, even at concentrations well below the National Cholesterol Education Program target of 130 mg/dL, LDL cholesterol is a strong independent predictor of coronary heart disease in individuals with diabetes, even when components of diabetic dyslipidemia are present. These results support recent recommendations for aggressive control of LDL cholesterol in diabetic individuals, with a target level of <100 mg/dL.

Incidence of end-stage renal disease in Type 2 (non-insulin-dependent) diabetes mellitus in pima indians

SummaryThe incidence of end-stage renal disease was determined in the Pima Indians of the Gila River Indian Community in Arizona, a population with a high prevalence of Type 2 (non-insulin-dependent) diabetes mellitus. Between 1975 and 1986, from a study population of 5059 subjects, end-stage renal disease occurred in 80 persons, 76 (95%) of whom had Type 2 diabetes. A review of the cases with end-stage renal disease indicated that among the diabetic subjects only two cases could be attributed to nondiabetic renal disease; all other cases were attributable to diabetic nephropathy. In diabetic Pima Indians the incidence rate of end-stage renal disease did not change during the study period, was similar in men and women, and was not effected by age at diagnosis of diabetes or by attained age, but did increase significantly with hypertension (p<0.05). The incidence of end-stage renal disease attributed to diabetic nephropathy increased from 0 cases/1000 person-years at 0–5 years to 40.8 cases/1000 person-years at ≥ 20 years duration of diabetes. In these subjects with Type 2 diabetes, the incidence rate of end-stage renal disease was similar to that in subjects with Type 1 (insulin-dependent) diabetes who were followed at the Joslin Clinic in Boston, Massachusetts when those with similar duration of diabetes were compared.

Individual Estimates of European Genetic Admixture Associated with Lower Body-Mass Index, Plasma Glucose, and Prevalence of Type 2 Diabetes in Pima Indians

Individual genetic admixture estimates (IA) from European Americans (EAs) were computed in 7,996 members of the Gila River Indian Community (Arizona). Parental populations for the analysis were European Americans and full-heritage Pima Indians. A logistic regression was performed on 7,796 persons, to assess association of IA with type 2 diabetes. The odds ratio, comparing diabetes risk in full-heritage EAs with full-heritage Pima Indians, was 0.329 (95% confidence interval [CI] 0.225-0.482). Proportional-hazards analysis was performed on 5,482 persons who were nondiabetic at their first examination and 1,215 subjects who developed diabetes during the study. The hazard risk ratio for IA was 0.455 (95% CI 0.301-0.688). Nondiabetic persons had significantly more European IA. In nondiabetic Pimans, multivariate linear regressions of quantitative predictors of type 2 diabetes mellitus, including fasting plasma glucose, 2-h post-load plasma glucose, and body-mass index, showed significant inverse relations with IA when controlled for sex and age. These results illustrate the ongoing evolution of populations by the mechanism of gene flow and its effect on disease risk in the groups with admixture. When the two parental populations differ in disease prevalence, higher or lower risk is associated with admixture, depending on the origin of the admixed alleles and the relative magnitude of the disease prevalence in the parental populations. These data also illustrate the strong genetic components in type 2 diabetes and are consistent with one susceptibility locus common to obesity and diabetes.

Determinants of end-stage renal disease in Pima Indians with Type 2 (non-insulin-dependent) diabetes mellitus and proteinuria

SummaryTo identify factors related to the development of end-stage renal disease after the onset of proteinuria, its incidence was determined in 364 Pima Indians aged 35 years or older with Type 2 (non-insulin-dependent) diabetes mellitus and proteinuria (protein-to-creatinine ratio ≥0.5 g/g). Of these 364 subjects, 95 (36 men, 59 women) developed end-stage renal disease. The cumulative incidence was 40% 10 years after and 61% 15 years after the onset of proteinuria. The incidence of end-stage renal disease was significantly related to the duration of diabetes, the duration of proteinuria, higher 2-h plasma glucose concentration, type of diabetes treatment, and the presence of retinopathy at the time of recognition of the proteinuria, but not to age, sex, or blood pressure. Duration of proteinuria influenced the risk of end-stage renal disease, contingent, however, upon the duration of diabetes at the onset of proteinuria. The higher cumulative incidence of end-stage renal disease 15 years after the onset of proteinuria in Pima Indians (61 %) than in Caucasians from Rochester, Minnesota (17%) may be attributable, in part, to the younger age of onset of Type 2 diabetes in Pima Indians than in Caucasians, to ethnic differences in susceptibility to renal disease, or to lower death rates among the Pima Indians from competing causes of death, such as coronary heart disease.

Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians

OBJECTIVE Markers of inflammation have recently been shown to be predictive of cardiovascular disease (CVD). Furthermore, the excess mortality in rheumatoid arthritis (RA), a disease characterized by chronic polyarthritis, is chiefly due to death from CVD. With this background, we studied the effect of inflammation, as reflected by the number of joints with soft tissue swelling, and rheumatoid factor (RF) seropositivity on CVD-related mortality. METHODS Mortality rates and rate ratios for all-cause and CVD-related deaths were computed in a longitudinal, population-based cohort of Pima Indians in Arizona from 1965 through 1994. Repeated health examinations were performed, involving systematic assessment of the features of RA, cardiovascular risk factors, serum titers of RF, as well as mortality. The cohort comprised 4,120 subjects (1,861 men, 2,259 women) who were examined an average of 3.5 times during a mean followup of 14 years. RESULTS During the followup period, 182 CVD-related deaths ocurred. The age- and sex-adjusted CVD-related mortality rates increased significantly with the presence of a higher number of joints with soft tissue swelling (Ptrend = 0.04), and were 2.07 (95% confidence interval [95% CI] 1.30-3.31) times as high in those subjects who had 2 or more swollen joints as in those who had none. There were no significant additional effects on CVD-related mortality when seropositivity for RF or a previous diagnosis of RA were considered. In age- and sex-adjusted proportional hazards analyses, which were controlled for possible confounders, the effect of swollen joints remained significant (mortality rate ratio 1.33, 95% CI 1.04-1.71 per category increase [no swollen joints, 1 swollen joint, at least 2 swollen joints]). CONCLUSION Joint swelling is a significant risk factor for CVD-related death, independent of other known risk factors including a diagnosis of RA. This finding supports the hypothesis that inflammatory mechanisms are important for the development of CVD.

Impact of NIDDM on Mortality and Causes of Death in Pima Indians

OBJECTIVE To compare overall and cause-specific death rates for diabetic and nondiabetic Pima Indians. RESEARCH DESIGN AND METHODS This community-based study determined overall and cause-specific death rates in persons with and without NIDDM in the Pima population. Underlying causes of death for the 10-yr period from 1975 to 1984 were derived from review of death certificates and medical records. Diabetes diagnoses were based on an ongoing diabetes study initiated by the National Institutes of Health in 1965. RESULTS Of the 512 deaths, 241 were in Pima Indians with NIDDM; 203 (84%) of the deaths in diabetic subjects were attributed to natural causes (46 diabetic nephropathy, 35 IHD, 29 infections, 20 malignant neoplasms, 20 alcoholic liver disease, 18 stroke, 35 other causes). For natural causes, the overall age-sex-adjusted death rate in diabetic subjects was 1.7 times (95% CI 1.4–2.2) that in nondiabetic subjects. Longer duration of diabetes was significantly related to mortality, an association that was stronger in women than in men. Rates of death from diabetic nephropathy, IHD, and infections (but not stroke) were each significantly related to longer diabetes duration. Together, diabetic nephropathy and IHD accounted for 90% of the excess death rate among diabetic, compared with nondiabetic, Pimas. CONCLUSIONS In Pima Indians, NIDDM has a significant adverse effect on death rates that is directly related to diabetes duration, especially for deaths from diabetic nephropathy, IHD, or infections. Among the Pima, diabetic nephropathy is the leading cause of death, and IHD ranks second—a variation from other populations (in which IHD ranks first), probably partly attributable to a much younger age of onset of diabetes among the Pima than in the U.S. white population.

Sequential Trends in Overall and Cause-Specific Mortality in Diabetic and Nondiabetic Pima Indians

OBJECTIVE To compare sequential trends in overall and cause-specific death rates for diabetic and nondiabetic Pima Indians. RESEARCH DESIGN AND METHODS Underlying causes of death in Pimas aged 15 years old were determined for the years 1975–1989 from review of death certificates and medical records. Overall and cause-specific death rates were compared for consecutive intervals. RESULTS The all-causes death rate, age- and sex-adjusted, did not change significantly between the first and second halves of the study for diabetic (death rate ratio [DRR] = 0.99, 95% CI 0.70–1.4) or nondiabetic Pimas (DRR = 0.92, 95% CI 0.74–1.1). Among diabetic Pimas, however, the death rate for diabetic nephropathy declined from 2.7 to 1.5/1,000 person-years (DRR = 0.55, 95% CI 0.33–0.93), with ischemic heart disease (IHD) replacing diabetic nephropathy as the leading cause in the second half (DRR = 1.5, 95% CI 0.91–2.6). For diabetic and nondiabetic Pimas combined, the death rate in three consecutive 5-year periods declined progressively for alcoholic liver disease (P = 0.024) and external causes of death (P = 0.016), the largest component of which was automobile accidents. CONCLUSIONS The decrease in death rate for diabetic nephropathy may be a result of greater access to and improvements in renal replacement therapy. Because of shared risk factors, however, the IHD death rate increased and largely offset the decrease in diabetic nephropathy deaths. The decline in deaths from alcoholic liver disease and from automobile accidents parallels the national trend.

Adverse mortality experience of a southwestern American Indian community: overall death rates and underlying causes of death in Pima Indians

As part of an ongoing epidemiologic study, the death rate and causes of death during 1975 through 1984 were determined in Pima Indians who resided in the Gila River Indian Community (GRIC) in 1965 and later. Death certificates were available for 677 of the 681 deaths. In 78% of the deaths, the underlying cause recorded on the death certificate agreed with the cause determined after review of all available relevant records. The age- and sex-adjusted average annual death rate for the GRIC population (1639/100,000) was 1.9 times (95% CI 1.7-2.0) the 1980 rate for the U.S. all races (878/100,000). In Pima males, whose death rate was substantially higher than that of Pima females, the age-adjusted death rate was 2.3 times that in U.S. males, all races. Moreover among males 25-34 years of age, the Pima death rate was 6.6 times that for the U.S. all races. Diseases of the heart and malignant neoplasms caused 59% of U.S. deaths in 1980, but only 19% of GRIC deaths. By contrast, the age- and sex-adjusted mortality rate in the GRIC Pima was 5.9 times the rate of the U.S. all races for accidents, 6.5 times for cirrhosis, 7.4 times for homicide, 4.3 times for suicide, and 11.9 times for diabetes. Tuberculosis and coccidioidomycosis were important causes of death in the Pima, for whom infectious diseases was the tenth leading cause of death. The findings indicate that programs to improve the adverse mortality experience of the GRIC population should emphasize factors related to fatal accidents, alcoholic cirrhosis, homicide, suicide, diabetes mellitus, and infectious diseases. Young Pimas, especially the males, should be the primary focus of such preventive efforts. These findings and recommendations probably apply to many Native American populations.

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.

Serum Cholesterol and Mortality Rates in a Native American Population With Low Cholesterol Concentrations: A U-Shaped Association

BACKGROUND Low serum cholesterol concentrations are associated with high death rates from cancer, trauma, and infectious diseases, but the meaning of these associations remains controversial. The present report evaluates whether low cholesterol is likely to be a causal factor for mortality from all causes or from specific causes. METHODS AND RESULTS Among 4553 Pima Indians > or =20 years old, a population with low serum cholesterol (median, 4.50 mmol/L), 1077 deaths occurred during a mean follow-up of 12.8 years. Trauma was the most common cause. The relationship between serum cholesterol measured at 2-year intervals and age- and sex-standardized mortality rates was U-shaped. Cholesterol was related positively to mortality from cardiovascular diseases and diabetes (including nephropathy) and negatively to mortality from cancer and alcohol-related diseases. The relationship was U-shaped for mortality from infectious diseases, and cholesterol was not related to mortality from trauma. Change in cholesterol from one examination to the next was positively related to mortality from diabetes. In proportional-hazards models adjusted for potential confounders, the relationship between baseline cholesterol and mortality was U-shaped for all causes and diabetes and positive for cardiovascular diseases. Other relationships were nonsignificant. Among 3358 subjects followed > or =5 years, the relationship was significant and positive only for mortality from cardiovascular diseases. CONCLUSIONS Despite a high exposure risk for Pima Indians, if low cholesterol level is a causal factor, the relationships between low serum cholesterol and high mortality rates probably result from diseases lowering cholesterol rather than from a low cholesterol causing the diseases.