Joseph V. Selby

Population Trends in the Incidence and Outcomes of Acute Myocardial Infarction

BACKGROUND Few studies have characterized recent population trends in the incidence and outcomes of myocardial infarction. METHODS We identified patients 30 years of age or older in a large, diverse, community-based population who were hospitalized for incident myocardial infarction between 1999 and 2008. Age- and sex-adjusted incidence rates were calculated for myocardial infarction overall and separately for ST-segment elevation and non-ST-segment elevation myocardial infarction. Patient characteristics, outpatient medications, and cardiac biomarker levels during hospitalization were identified from health plan databases, and 30-day mortality was ascertained from administrative databases, state death data, and Social Security Administration files. RESULTS We identified 46,086 hospitalizations for myocardial infarctions during 18,691,131 person-years of follow-up from 1999 to 2008. The age- and sex-adjusted incidence of myocardial infarction increased from 274 cases per 100,000 person-years in 1999 to 287 cases per 100,000 person-years in 2000, and it decreased each year thereafter, to 208 cases per 100,000 person-years in 2008, representing a 24% relative decrease over the study period. The age- and sex-adjusted incidence of ST-segment elevation myocardial infarction decreased throughout the study period (from 133 cases per 100,000 person-years in 1999 to 50 cases per 100,000 person-years in 2008, P<0.001 for linear trend). Thirty-day mortality was significantly lower in 2008 than in 1999 (adjusted odds ratio, 0.76; 95% confidence interval, 0.65 to 0.89). CONCLUSIONS Within a large community-based population, the incidence of myocardial infarction decreased significantly after 2000, and the incidence of ST-segment elevation myocardial infarction decreased markedly after 1999. Reductions in short-term case fatality rates for myocardial infarction appear to be driven, in part, by a decrease in the incidence of ST-segment elevation myocardial infarction and a lower rate of death after non-ST-segment elevation myocardial infarction.

Midlife cardiovascular risk factors and risk of dementia in late life

Objective: To evaluate if midlife cardiovascular risk factors are associated with risk of late-life dementia in a large, diverse cohort. Method: The authors conducted a retrospective cohort study of 8,845 participants of a health maintenance organization who underwent health evaluations from 1964 to 1973 when they were between the ages of 40 and 44. Midlife cardiovascular risk factors included total cholesterol, diabetes, hypertension, and smoking. Diagnoses of dementia were ascertained by medical records from January 1994 to April 2003. Results: The authors identified 721 participants (8.2%) with dementia. Smoking, hypertension, high cholesterol, and diabetes at midlife were each associated with a 20 to 40% increase in risk of dementia (fully adjusted Cox proportional hazards model: HR 1.24, 95% CI 1.04 to 1.48 for hypertension, HR 1.26, 95% CI 1.08 to 1.47 for smoking, HR 1.42, 95% CI 1.22 to 1.66 for high cholesterol, and HR 1.46, 95% CI 1.19 to 1.79 for diabetes). A composite cardiovascular risk score was created using all four risk factors and was associated with dementia in a dose-dependent fashion. Compared with participants having no risk factors, the risk for dementia increased from 1.27 for having one risk factor to 2.37 for having all four risk factors (fully adjusted model: HR 2.37, 95% CI 1.10 to 5.10). Conclusion: The presence of multiple cardiovascular risk factors at midlife substantially increases risk of late-life dementia in a dose dependent manner.

Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus

CONTEXT Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes. OBJECTIVE To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years. DESIGN, SETTING, AND PATIENTS A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California. MAIN OUTCOME MEASURE Hypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease. RESULTS At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55). CONCLUSIONS Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown.

Risk of Bladder Cancer Among Diabetic Patients Treated With Pioglitazone: Interim report of a longitudinal cohort study

OBJECTIVE Some preclinical in vivo studies and limited human data suggest a possible increased risk of bladder cancer with pioglitazone therapy. This is an interim report of an ongoing cohort study examining the association between pioglitazone therapy and the risk of bladder cancer in patients with diabetes. RESEARCH DESIGN AND METHODS This study includes 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≥40 years of age between 1997 and 2002. Those with prior bladder cancer were excluded. Ever use of each diabetes medication (defined as two or more prescriptions within 6 months) was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared pioglitazone use with nonpioglitazone use adjusted for age, sex, race/ethnicity, diabetes medications, A1C, heart failure, household income, renal function, other bladder conditions, and smoking. RESULTS The group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9–1.5]), with similar results in men and women (test for interaction P = 0.8). However, in the a priori category of >24 months of therapy, there was an increased risk (1.4 [1.03–2.0]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage. CONCLUSIONS In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.

The Insulin Resistance Atherosclerosis Study (IRAS). Objectives, design, and recruitment results

The Insulin Resistance Atherosclerosis Study (IRAS) is the first epidemiologic study designed to assess the relationships between insulin resistance, insulinemia, glycemia, other components of the insulin resistance syndrome, and prevalent cardiovascular disease (CVD) in a large multiethnic cohort. Over 1600 men and women were recruited from four geographic areas to represent a range of glucose tolerance (normal, impaired, and diabetic) and ethnicity (hispanic, non-Hispanic white, and African-American). Insulin resistance was assessed directly using the frequently sampled intravenous glucose tolerance test with minimal model analysis. Intimal-medial carotid artery wall thickness, an indicator of atherosclerosis, was measured using B-mode ultrasonography. Prevalent CVD was assessed by questionnaire and resting electrocardiography. This report describes the design of the study and provides the recruitment results. Forthcoming cross-sectional analyses will help to disentangle the association between insulin resistance and CVD, apart from the concomitant hyperinsulinemia and related CVD risk factors.

Increased Insulin Resistance and Insulin Secretion in Nondiabetic African-Americans and Hispanics Compared With Non-Hispanic Whites: The Insulin Resistance Atherosclerosis Study

The etiology of NIDDM is still controversial, with both insulin resistance and decreased insulin secretion postulated as potential important factors. African-Americans and Hispanics have a two- to threefold excess risk of developing NIDDM compared with non-Hispanic whites. Yet little is known concerning the prevalence of insulin resistance and secretion defects in minorities, especially in African-Americans in population-based studies. Fasting and 2-h post–glucose load glucose and insulin levels, insulin-mediated glucose disposal (insulin sensitivity index) (SI), glucose effectiveness (SG), and first-phase insulin response (acute insulin response [AIR]) were determined in nondiabetic African-Americans (n = 288), Hispanics (n = 363), and non-Hispanic whites (n = 435) as part of the Insulin Resistance Atherosclerosis Study. Subjects received a standard 2-h oral glucose tolerance test on the first day and an insulin-modified frequently sampled intravenous glucose tolerance test on the second day. African-Americans and Hispanics were more obese than non-Hispanic whites. Both African-Americans and Hispanics had higher fasting and 2-h insulin concentrations and AIR but lower SI than non-Hispanic whites. No ethnic difference was observed in SG. After further adjustments for obesity, body fat distribution, and behavioral factors, African-Americans continued to have higher fasting and 2-h insulin levels and AIR, but lower SI, than non-Hispanic whites. In contrast, after adjustment for these covariates, no significant ethnic differences in SI or fasting insulin levels were observed between Hispanics and non-Hispanic whites. Hispanics continued to havehigher 2-h insulin levels and AIRs than those in non-Hispanic whites. In this report, the association between SI and upper body adiposity (waist-to-hip ratio) was similar in each ethnic group. Both nondiabetic African-Americans and Hispanics have increased insulin resistance and higher AIR than nondiabetic non-Hispanic whites, suggesting that greater insulin resistance may be in large part responsible for the higher prevalence of NIDDM in these minority groups. However, in Hispanics, the greater insulin resistance may be due to greater adiposity and other behavioral factors.

Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins.

SummaryConcordance for Type 2 (non-insulin-dependent) diabetes was determined in 250 monozygotic and 264 dizygotic white male twin pairs who participated in the National Heart, Lung, and Blood Institute Twin Study. These twins were born between 1917 and 1927 and were identified from military records without regard to disease status. We examined surviving members of the cohort twice — at mean ages of 47 and 57 years — and obtained 1-h post-load glucose tests and medication histories. Diagnostic criteria for Type 2 diabetes included a glucose value≥13.9 mmol/l or current use of antidiabetic medication; possible Type 1 (insulin-dependent) diabetic twins were excluded. A strong genetic predisposition to Type 2 diabetes was suggested by 3 lines of evidence from the second examination: (1) 58% of monozygotic co-twins of diabetic twins were themselves diabetic compared with an expected prevalence of 10%; (2) only 1 of 15 originally disease-discordant, monozygotic twin pairs remained discordant for diabetes; and (3) 65% of non-diabetic monozygotic co-twins of diabetic twins had elevated glucose values. Because concordance for diabetes was less than 100% for twins aged 52–65 years and because twins varied in age at onset of disease, non-genetic factors may also influence diabetes development. Among the 19 monozygotic twins pairs discordant for diabetes, diabetic twins did not differ from their non-diabetic co-twins in obesity, diet, alcohol consumption, or education. However, compared with unrelated nondiabetic twins of the same ages, non-diabetic co-twins of diabetic twins gained more weight as adults (p<0.02) and had higher glucose levels (p<0.03).

Lower-Extremity Amputation in People With Diabetes: Epidemiology and Prevention

The age-adjusted rate of lower-extremity amputation (LEA) in the diabetic population is ∼15 times that of the nondiabetic population. Over 50,000 LEAs were performed on individuals with diabetes in the United States in 1985. Among individuals with diabetes, peripheral neuropathy and peripheral vascular disease (PVD) are major predisposing factors for LEA. Lack of adequate foot care and infection are additional risk factors. Several large clinical centers have experienced a 44–85% reduction in the rate of amputations among individuals with diabetes after the implementation of improved foot-careprograms. Programs to reduce amputations among people with diabetes in primarycare settings should identify those at high risk; clinically evaluate individuals to determine specific risk status; ensure appropriate preventive therapy, treatment for foot problems, and follow-up; provide patient education;and, when necessary, refer patients to specialists, including health-care professionals for diagnostic and therapeutic interventions and shoe fitters for proper footwear. Programs should monitor and evaluate their activities andoutcomes. Many issues related to the etiology and prevention of LEAs requirefurther research.

Excess costs of medical care for patients with diabetes in a managed care population

OBJECTIVE To estimate the excess costs of medical care for patients with diabetes in a managed care population and to determine the proportion of costs spent on treating the complications of diabetes. RESEARCH DESIGN AND METHODS A comparison of 1-year (1994) costs of medical care in the 85,209 members of the diabetes registry of Kaiser Permanente, Northern California, and in 85,209 age- and sex-matched nondiabetic control subjects. Costs were obtained from automated program databases. Costs specifically related to treating acute and long-term complications of diabetes were identified, and the excess costs attributable to each complication in individuals with diabetes were calculated. RESULTS Excess expenditures in individuals with diabetes totaled

LDL subclass phenotypes and the insulin resistance syndrome in women.

282.7 million, or