Alexandra K. Lee

Identifying Trends in Undiagnosed Diabetes in U.S. Adults by Using a Confirmatory Definition: A Cross-sectional Study

Understanding the burden of undiagnosed diabetes is critical to the evaluation and monitoring of public health efforts related to diabetes screening and diagnosis. A common belief is that one quarter to one third of diabetes cases in the United States are undiagnosed (13). However, previous estimates of the proportion of total diabetes cases that are undiagnosed may be overestimated by epidemiologic studies that do not use confirmatory testing, in line with clinical diagnostic criteria (46). National estimates of undiagnosed diabetes from large epidemiologic cohorts typically have relied on a single measurement of fasting glucose, hemoglobin A1c (HbA1c), or 2-hour glucose level to identify cases of undiagnosed diabetes, potentially overstating its prevalence. Guidelines from the American Diabetes Association explicitly state that in the absence of a clear clinical diagnosis (overt symptoms of diabetes or hyperglycemic crisis), a second test, in a new blood sample, is required to confirm the diagnosis of diabetes (7). However, 2 different tests (for example, HbA1c and fasting glucose levels) frequently are done in the same sample, and the guidelines state that if the results of the 2 tests are above clinical thresholds, this also confirms the diagnosis (7). This confirmatory approach to diagnosing diabetes helps decrease false-positive results (8, 9). However, previous national estimates of the prevalence of undiagnosed diabetes did not use a confirmatory testing strategy. This is of particular concern, because earlier studies demonstrated high variability among the biochemical tests used to define diabetes (8), which may substantially inflate prevalence estimates. Thus, the objective of this study was to quantify the overall burden, trends, and risk factors of undiagnosed diabetes in the United States by using a combination of fasting glucose and HbA1c levels, a definition of undiagnosed diabetes consistent with clinical practice guidelines. Methods Study Population The NHANES (National Health and Nutrition Examination Survey) studies are cross-sectional, complex samples of the U.S. civilian noninstitutionalized population conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC). The present study included data from NHANES III (1988 to 1994) and the continuous NHANES (1999 to 2014), the results of which are released in 2-year cycles. The NCHS institutional review board approved protocols for the conduct of NHANES, and informed consent was obtained from all participants. To evaluate trends over time, we used data from NHANES III (n= 7385) and 4-year survey cycles from 1999 to 2014 (n= 17045). This study population was limited to nonpregnant adults aged 20 years and older who attended the fasting morning examination and excluded 54 eligible persons with missing fasting glucose or HbA1c values. Persons who self-reported insulin use but did not report a diabetes diagnosis also were excluded (n= 6). Measurement of HbA1c and Plasma Glucose Levels Hemoglobin A1c was measured in whole blood with instruments certified by the National Glycohemoglobin Standardization Program and standardized to the reference method used in the Diabetes Control and Complications Trial. Several changes were made to the HbA1c measurement methods during the 26-year survey data collection from 1988 to 2014. Details regarding each HbA1c measurement method are available from the NHANES documentation (10, 11). We calibrated HbA1c values to account for changes in laboratory methods from 1988 to 2014 (5). Uncalibrated HbA1c values have increased over successive NHANES surveys, even in young, healthy persons (12). These shifts have been attributed to changes in assay methods and have a substantial effect on population estimates. We used previously published methods to calibrate HbA1c values to a stable, standard distribution to align them over time, as documented in the supplement to our 2014 report (5). Plasma glucose concentrations were measured in specimens collected from participants who attended the morning fasting examination. Laboratory methods used to measure glucose levels also changed during the NHANES data collection period, and we applied regression equations recommended by the NCHS to align the plasma glucose values over time (5, 13, 14). Definitions of Diagnosed and Confirmed Undiagnosed Diabetes Diagnosed diabetes was defined as a self-reported physician diagnosis of diabetes (other than during pregnancy). Confirmed undiagnosed diabetes was defined as elevated levels of both fasting glucose (7.0 mmol/L [126 mg/dL]) and HbA1c (6.5%) measured in the same blood sample in a person without a previous diagnosis of diabetes. The term total diabetes is used here to refer to the combination of diagnosed and confirmed undiagnosed diabetes cases. In the main analyses, persons defined as not having diabetes included those with a single elevated fasting glucose or HbA1c value, but not both. We conducted sensitivity analyses comparing the prevalence of confirmed undiagnosed diabetes, defined as elevated levels of both fasting glucose and HbA1c, with 3 definitions of unconfirmed undiagnosed diabetes (a single elevated fasting glucose value, a single elevated HbA1c value, or either an elevated fasting glucose or an elevated HbA1c value). We also conducted sensitivity analyses comparing risk factor prevalence and associations in persons with unconfirmed undiagnosed diabetes, defined as a single elevated HbA1c or fasting glucose value (but not both), confirmed undiagnosed diabetes (elevation of both HbA1c and fasting glucose levels), or diagnosed diabetes. In this sensitivity analysis, the no-diabetes group comprised persons with levels of both fasting glucose and HbA1c below clinical thresholds (that is, an HbA1c level <6.5% and a fasting glucose level <7.0 mmol/L [<126 mg/dL]). Assessment of Demographics and Other Risk Factors All measurements were conducted by trained personnel using standardized protocols. Information on age, sex, race/ethnicity, family history of diabetes, smoking status, education, income, history of prediabetes, health insurance status, and access to care was self-reported. Hypertension was defined as systolic blood pressure of 140 mm Hg or greater, diastolic blood pressure of 90 mm Hg or greater, or current use of blood pressurelowering medication. High cholesterol was defined as a total cholesterol level of 240 mg/dL (6.2 mmol/L) or greater or current use of cholesterol-lowering medication. Body mass index (BMI) was calculated as weight in kilograms divided by height in square meters. Albumin and creatinine levels were measured in urine, and albuminuria was defined as an albumincreatinine ratio of 30 mg/g or greater. We also evaluated metformin use by using information from the prescription medication data files. Details on the interview questions are provided in Appendix Table 1. Appendix Table 1. NHANES 19992014 Questions* Statistical Analysis To evaluate trends over time, we calculated prevalence estimates and SEs from the 6-year cycle from NHANES III (1988 to 1994) and 4-year cycles of the continuous NHANES (1999 to 2002, 2003 to 2006, 2007 to 2010, and 2011 to 2014). We also obtained prevalence estimates and SEs for the combined survey period from 1999 to 2014. The NCHS analytic guidelines recommend combining survey cycles to obtain more reliable estimates. Analyses were weighted to provide nationally representative estimates of the general noninstitutionalized civilian adult population of the United States. Survey weights of NHANES account for the complex survey design (including oversampling), nonresponse, and poststratification. We obtained SEs by using the Taylor series (linearization) method following analytic procedures recommended by the NCHS (15, 16). Prevalence estimates from the different survey cycles were applied to U.S. Census population numbers to obtain estimates of the number of persons with diagnosed and confirmed undiagnosed diabetes in the United States. We used predictive margins from logistic regression to calculate the age-, sex-, and race-adjusted prevalence ratios (PRs) for risk factors for confirmed undiagnosed diabetes, combining the most current data from 1999 to 2014. Persons with missing risk factor data were excluded from those respective analyses; covariate data were missing in less than 3% of the eligible study sample, except for the variable of family incomepoverty ratio (8% missing). We generated a weighted scatter plot and calculated the weighted Spearman and Pearson correlations, overall percentage agreement, and percentage of positive agreement to show the concordance of fasting glucose and HbA1c levels in the overall study sample of persons without a diabetes diagnosis. Statistical analyses were conducted by using Stata SE, version 14.2 (StataCorp). We used svy commands in Stata to account for the complex survey design of NHANES. Hemoglobin A1c values were calibrated by using the equate package in R, version 2.15.1 (R Foundation for Statistical Computing) (5). Role of the Funding Source The funding source had no role in the design, conduct, or analysis of the study or the decision to submit the manuscript for publication. Results The prevalence of total diabetes in the United States for 1999 to 2014 was 9.3%. This estimate includes an 8.1% prevalence of diagnosed diabetes and a 1.2% prevalence of confirmed undiagnosed diabetes. The prevalence of total diabetes has increased substantially, from 5.5% in 1988 to 1994 (9.7 million adults) to 10.8% in 2011 to 2014 (25.5 million adults) (Table 1). Confirmed undiagnosed diabetes also has increased on an absolute scale (from 0.89% in 1988 to 1994 to 1.17% in 2011 to 2014) but has decreased as a proportion of total diabetes cases during this period. When a confirmatory definition is applied, the percentage of total diabetes cases in 1988 to 1994 that were undiagnosed is 16.3%; by 2

Risk factors for severe hypoglycemia in black and white adults with diabetes: The Atherosclerosis Risk in Communities (ARIC) Study

OBJECTIVE Severe hypoglycemia is a rare but important complication of type 2 diabetes. Few studies have examined the epidemiology of hypoglycemia in a community-based population. RESEARCH DESIGN AND METHODS We included 1,206 Atherosclerosis Risk in Communities (ARIC) Study participants with diagnosed diabetes (baseline: 1996–1998). Severe hypoglycemic events were identified through 2013 by ICD-9 codes from claims for hospitalizations, emergency department visits, and ambulance use. We used Cox regression to evaluate risk factors for severe hypoglycemia. RESULTS The mean age of participants was 64 years, 32% were black, and 54% were female. During a median follow-up period of 15.2 years, there were 185 severe hypoglycemic events. Important risk factors after multivariable adjustment were as follows: age (per 5 years: hazard ratio [HR] 1.24; 95% CI 1.07–1.43), black race (HR 1.39; 95% CI 1.02–1.88), diabetes medications (any insulin use vs. no medications: HR 3.00; 95% CI 1.71–5.28; oral medications only vs. no medications: HR 2.20; 95% CI 1.28–3.76), glycemic control (moderate vs. good: HR 1.78; 95% CI 1.11–2.83; poor vs. good: HR 2.62; 95% CI 1.67–4.10), macroalbuminuria (HR 1.95; 95% CI 1.23–3.07), and poor cognitive function (Digit Symbol Substitution Test z score: HR 1.57; 95% CI 1.33–1.84). In an analysis of nontraditional risk factors, low 1,5-anhydroglucitol, difficulty with activities of daily living, Medicaid insurance, and antidepressant use were positively associated with severe hypoglycemia after multivariate adjustment. CONCLUSIONS Poor glycemic control, glycemic variability as captured by 1,5-anhydroglucitol, kidney damage, and measures of cognitive and functional impairments were strongly associated with increased risk of severe hypoglycemia. These factors should be considered in hypoglycemia risk assessments when individualizing diabetes care for older adults.

The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes

OBJECTIVE There is suggestive evidence linking hypoglycemia with cardiovascular disease, but few data have been collected in a community-based setting. Information is lacking on individual cardiovascular outcomes and cause-specific mortality. RESEARCH DESIGN AND METHODS We conducted a prospective cohort analysis of 1,209 participants with diagnosed diabetes from the Atherosclerosis Risk in Communities (ARIC) study (analytic baseline, 1996–1998). Severe hypoglycemic episodes were identified using first position ICD-9 codes from hospitalizations, emergency department visits, and ambulance calls through 2013. Cardiovascular events and deaths were captured through 2013. We used adjusted Cox regression models with hypoglycemia as a time-varying exposure. RESULTS There were 195 participants with at least one severe hypoglycemic episode during a median fellow-up of 15.3 years. After severe hypoglycemia, the 3-year cumulative incidence of coronary heart disease was 10.8% and of mortality was 28.3%. After adjustment, severe hypoglycemia was associated with coronary heart disease (hazard ratio [HR] 2.02, 95% CI 1.27–3.20), all-cause mortality (HR 1.73, 95% CI 1.38–2.17), cardiovascular mortality (HR 1.64, 95% CI 1.15–2.34), and cancer mortality (HR 2.49, 95% CI 1.46–4.24). Hypoglycemia was not associated with stroke, heart failure, atrial fibrillation, or noncardiovascular and noncancer death. Results were robust within subgroups defined by age, sex, race, diabetes duration, and baseline cardiovascular risk. CONCLUSIONS Severe hypoglycemia is clearly indicative of declining health and is a potent marker of high absolute risk of cardiovascular events and mortality.

Enduring Consequences From the War on Drugs: How Policing Practices Impact HIV Risk Among People Who Inject Drugs in Baltimore City

ABSTRACT Background: Neighborhood-level characteristics, including police activity, are associated with HIV and Hepatitis C injection risk-behaviors among people who inject drugs (PWID). However, the pathways through which these neighborhood perceptions shape individual-level HIV risk behaviors are unclear. This study helps to explain perceived behaviors between perceived neighborhood police activity and HIV injection risk behavior (i.e., injection syringe/tool sharing in the previous 6 months). Methods: A sample of (n = 366) PWIDs who self-reported recent use were recruited using community-based outreach methods in Baltimore, Maryland. Neighborhood police perceptions were assessed by asking participants whether they would (1) be more likely to ask others to share injection tools in the context of heightened police activity and (2) be less likely to carry syringes with them due to fear of arrest. Poisson regression with robust variance was used to identify statistical relationships. Recent police encounters, frequency of heroin injection, and sociodemographic characteristics were controlled for in the model. Results: Neighborhood police perceptions shaped injection-risk behavior. Half of the sample (49%) reported an aversion of carrying personal syringes, due to fear of arrest. Those who agreed they would be more likely to ask others to share injection equipment in the context of heightened police activity were more likely to share syringes (21% vs. 3%, p <.01). Adjusted models showed that syringe sharing was independently associated with asking to borrow equipment in neighborhoods with perceived heightened police activity (aPR: 2.22, 95% confidence interval (CI): 1.7, 3.0). Conclusion: This study sheds light on how police perceptions may influence injection risk behavior. While these relationships require further elucidation, this study suggests that public health interventions aiming to reduce HIV risk would benefit from improving community-police relationships.

Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study

Importance The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. Objective To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. Design, Setting, and Participants The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed betweeen April 2017 and May 2018. Exposures Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Main Outcomes and Measures Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Results Of the 10 420 total participants (5878 women [56.4%] and 2794 black participants [26.8%]; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% CI, 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E &egr;4 genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), and incident stroke (HR, 3.38; 95% CI, 2.78-4.10) and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Conclusions and Relevance Potentially modifiable risk factors in midlife and the APOE &egr;4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.

Diabetes and Trajectories of Estimated Glomerular Filtration Rate: A Prospective Cohort Analysis of the Atherosclerosis Risk in Communities Study

OBJECTIVE To characterize long-term kidney disease trajectories in persons with and without diabetes in a general population. RESEARCH DESIGN AND METHODS We classified 15,517 participants in the community-based Atherosclerosis Risk in Communities (ARIC) study by diabetes status at baseline (1987–1989; no diabetes, undiagnosed diabetes, and diagnosed diabetes). We used linear mixed models with random intercepts and slopes to quantify estimated glomerular filtration rate (eGFR) trajectories at four visits over 26 years. RESULTS Adjusted mean eGFR decline over the full study period among participants without diabetes was −1.4 mL/min/1.73 m2/year (95% CI −1.5 to −1.4), with undiagnosed diabetes was −1.8 mL/min/1.73 m2/year (95% CI −2.0 to −1.7) (difference vs. no diabetes, P < 0.001), and with diagnosed diabetes was −2.5 mL/min/1.73 m2/year (95% CI −2.6 to −2.4) (difference vs. no diabetes, P < 0.001). Among participants with diagnosed diabetes, risk factors for steeper eGFR decline included African American race, APOL1 high-risk genotype, systolic blood pressure ≥140 mmHg, insulin use, and higher HbA1c. CONCLUSIONS Diabetes is an important risk factor for kidney function decline. Those with diagnosed diabetes declined almost twice as rapidly as those without diabetes. Among people with diagnosed diabetes, steeper declines were seen in those with modifiable risk factors, including hypertension and glycemic control, suggesting areas for continued targeting in kidney disease prevention.

Diagnostic Performance of 1,5-Anhydroglucitol Compared to 2-H Glucose in the Atherosclerosis Risk in Communities Study

To the Editor: Glucose measured 2 h after a 75-g carbohydrate challenge is considered gold standard for diabetes diagnosis but is a burdensome test. 1,5-anhydroglucitol (1,5-AG) is a biomarker of glucose excursions that is of growing interest and is sometimes used in diabetes care. Blood concentrations of 1,5-AG are decreased when blood glucose exceeds the renal threshold (approximately 160–180 mg/dL); thus, low plasma 1,5-AG reflects recent (1–2 weeks) glucose excursions. Some preliminary reports have suggested that 1,5-AG may be useful as a screening test for diabetes (1, 2). We evaluated the diagnostic performance of 1,5-AG compared to 2-h and fasting glucose in a community-based population. We conducted a cross-sectional analysis of 7813 participants without diagnosed diabetes at the fourth study visit (1996–1998) of the Atherosclerosis Risk in Communities study. Plasma glucose was analyzed with an enzymatic method on the Roche Hitachi 911 machine. 1,5-AG (GlycoMark®) was measured in 2015–2016 in stored plasma samples (collected at the same study visit in 1996–1998) with the Beckman AU480 Chemistry Analyzer (interassay coefficient of variation, 4.54%). We examined the performance of low 1,5-AG (<10 μg/mL) to detect increased 2-h glucose (≥200 mg/dL), fasting glucose (≥126 mg/dL), or both. We calculated clinical …

Acceptability and feasibility of a Peer Mentor program to train young Black men who have sex with men to promote HIV and STI home-testing to their social network members.

ABSTRACT Young Black men who have sex with men (YBMSM) experience persistently high rates of undiagnosed HIV and other sexually transmitted infections (STIs) and testing rates remain sub-optimal. Home-based testing (HBT) has been found to be acceptable among MSM and while awareness about HBT is relatively high, uptake has been low. Peer-based approaches have been shown to be effective in reducing HIV risk behavior, yet have not been used to increase utilization of HBT. The purpose of this study was to assess acceptability and feasibility of a program to train YBMSM as Peer Mentors to use and promote HIV and STI home-based testing and specimen collection to their social network members. Fifteen YBMSM ages 18–30 completed in-depth structured interviews and were asked to talk with their social network members about home-based testing. Participants reported acceptability of the Peer Mentor role and two-thirds had conversations with diverse social network members (e.g., male and female, sex partners, friends, family). Facilitators of peer outreach included the novelty of home-based testing, confidence about accuracy of the tests, and resources for linkage to care. Barriers included concerns about negative responses and disclosure of sexual identity/behavior. Results of this study suggest that YBMSM are willing and able to promote HBT to their social networks. This is a promising approach to increasing dissemination of HBT kits for both HIV and STI testing.

ISOLATED SYSTOLIC HYPERTENSION AND PULSE PRESSURE ARE ASSOCIATED WITH HIGH-SENSITIVITY CARDIAC TROPONIN-T AND NT-PRO BNP IN OLDER ADULTS

Background: We set out to test the prevalence of isolated systolic hypertension (ISH) and wide pulse pressure (PP), both proxies for vascular stiffness, among a modern cohort of older adults and to determine whether any association with high sensitivity cardiac troponin-T (hs-cTnT) and NT-pro BNP

Increases in Biomarkers of Hyperglycemia With Age in the Atherosclerosis Risk in Communities (ARIC) Study

The American Diabetes Association’s Standards of Medical Care in Diabetes—2017 states that age should be “taken into consideration” when diagnosing diabetes with HbA1c (1). Nonetheless, it is unclear how this recommendation might be implemented. Population studies demonstrate that HbA1c increases with age, which some experts have suggested may be due to nonglycemic factors like alterations in red cell turnover or hemoglobin glycation (2–4). However, prior studies lack concurrent comparisons across nonhemoglobin-related markers of hyperglycemia. We evaluated increases with age in fructosamine and glycated albumin—hemoglobin-independent measures of hyperglycemia—in comparison with HbA1c and fasting glucose in the community-based Atherosclerosis Risk in Communities (ARIC) study. We conducted serial cross-sectional analyses at visit 2 (1990–1992; n = 11,632) and visit 5 (2011–2013; n = 3,876), excluding individuals with diagnosed diabetes. We performed adjusted linear regression of z scores of each biomarker (standardized to visit 2) on age to allow head-to-head comparisons of the associations. Age was significantly correlated with all biomarkers of hyperglycemia at visit 2 (Fig. 1). In middle …