Bethany Warren

Comparative prognostic performance of definitions of prediabetes: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study.

Background There is a lack of consensus across international organizations regarding definitions of prediabetes. Associations with complications can inform the comparative value of different prediabetes definitions. Methods We conducted a prospective cohort study of 10,844 Atherosclerosis Risk in Communities (ARIC) study participants without diagnosed diabetes who attended visit 2 (1990–92) and 7,194 who attended visit 4 (1996–98). Fasting glucose and HbA1c were measured at visit 2 and fasting glucose and 2-hour glucose were measured at visit 4. We compared prediabetes definitions based on fasting glucose (American Diabetes Association [ADA] 5.6–6.9 mmol/L and World Health Organization [WHO] 6.1–6.9 mmol/L), HbA1c (ADA 39–46 mmol/mol and International Expert Committee [IEC] 42–46 mmol/mol), and 2-hour glucose (ADA/WHO 7.8–11.0 mmol/L). Findings ADA fasting glucose-defined prediabetes (prevalence 37.9%) was the most sensitive for major clinical outcomes, while ADA and IEC HbA1c and WHO fasting glucose-based definitions (prevalence 18.7%, 9.0%, 11.2%, respectively) were more specific. After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and demonstrated better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality compared to fasting glucose (modestly larger C-statistics, all p<0.05). For example, the C-statistic for incident chronic kidney disease was 0.636 for ADA fasting glucose categories and 0.640 for ADA HbA1c clinical categories (difference −0.005, 95%CI −0.008, −0.001). Additionally, ADA HbA1c-defined prediabetes also demonstrated significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared to glucose-based definitions. Comparing ADA and WHO fasting glucose and ADA/WHO 2-hour did not reveal statistically significant differences in risk discrimination for chronic kidney disease, cardiovascular, or mortality outcomes. Interpretation Our results suggest that HbA1c-defined prediabetes definitions were more specific and provided modest improvements in risk discrimination for clinical complications. ADA fasting glucose was a more sensitive definition overall.

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.

Establishment of Community-Based Reference Intervals for Fructosamine, Glycated Albumin, and 1,5-Anhydroglucitol

BACKGROUND There is growing interest in fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) as alternative measures of hyperglycemia, particularly for use in settings where traditional measures (glucose and HbA1c) are problematic or where intermediate (2-4 weeks) glycemic control is of interest. However, reference intervals for these alternative biomarkers are not established. METHODS We measured fructosamine, glycated albumin, and 1,5-AG in a community-based sample of US black and white adults who participated in the Atherosclerosis Risk in Communities (ARIC) Study. We calculated reference intervals, evaluated demographic differences, and derived cutoffs aligned with current diagnostic cutpoints for HbA1c and fasting glucose. RESULTS In a healthy reference population of 1799 individuals (mean age, 55 years; 51% women; 15% black), the 2.5 and 97.5 percentiles, respectively, were 194.8 and 258.0 μmol/L for fructosamine, 10.7% and 15.1% for glycated albumin, and 8.4 and 28.7 μg/mL for 1,5-AG. Distributions differed by race, sex, and body mass index. Equivalent concentrations of fructosamine and glycated albumin corresponding to an HbA1c of 6.5% (96.5 percentile) were 270.2 μmol/L and 15.6%, respectively. Equivalent concentrations of fructosamine and glycated albumin corresponding to a fasting glucose of 126 mg/dL (93.9 percentile) were 261.7 μmol/L and 15.0%, respectively. CONCLUSIONS The reference intervals for these biomarkers should inform their clinical use. Diagnostic cutpoint equivalents for fructosamine and glycated albumin could be useful to identify persons with hyperglycemia in settings where fasting glucose or HbA1c are not available or where the interpretation of these traditional measures is problematic.

Performance of non-traditional hyperglycemia biomarkers by chronic kidney disease status in older adults with diabetes: Results from the Atherosclerosis Risk in Communities Study

In people with chronic kidney disease (CKD), HbA1c may be a problematic measure of glycemic control. Glycated albumin and fructosamine have been proposed as better markers of hyperglycemia in CKD. In the present study we investigated associations of HbA1c, glycated albumin, and fructosamine with fasting glucose by CKD categories.

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 …

Prediabetes definitions and clinical outcomes – Authors' reply

94 www.thelancet.com/diabetes-endocrinology Vol 5 February 2017 Authors’ reply We appreciate Luís Maurício T R Lima’s thoughts about the potential use of the homoeostasis model assessmentinsulin resistance (HOMA-IR), an index for estimating insulin resistance, in future studies. Although HOMA-IR has been investigated in the Atherosclerosis Risk in Communities (ARIC) study and other cohort studies and is modestly associated with cardiovascular outcomes, it is not recommended as a tool for identifi cation of individuals with prediabetes. HOMA-IR has poor reproducibility (high coefficient of variation) and has no consensus cutoff points, limiting its clinical utility. The focus of our study was on comparison of prediabetes defi nitions from existing clinical guidelines to better understand the prognostic implications of these different definitions. Future studies could be done to determine whether HOMA-IR or related measures could add information to traditional definitions of prediabetes for the prediction of clinical outcomes. We also thank Yuli Huang and Meijun Li for their interest in our study. We agree with their observations, especial ly that prediabetes provides an opportunity for lifestyle intervention. Weight loss, physical activity, and other interventions are likely to have the greatest benefit early in the disease process. Furthermore, results from randomised trials of glucose-lowering interventions in high-risk individuals with longstanding diabetes have not shown major benefits in cardiovascular risk reduction. A concern is that interventions in people with longstanding diabetes are too little, too late, emphasising the need to prevent diabetes in the first place. We also agree with Huang and Li that the definitions of prediabetes based on HbA1c are more specifi c than glucosebased defi nitions and will identify a smaller, but higher-risk, group. The fi ndings from our study underscore the inherent trade-offs and inform the comparative performance of the diff erent prediabetes defi nitions. The existence of five separate definitions of prediabetes in clinical use is problematic. Disagreement regarding how best to define prediabetes can complicate treatment decisions, medical insurance coverage, and referrals for weight loss and nutritional counselling, and ultimately hamper diabetes prevention eff orts. We believe that a consensus approach about how to define prediabetes is urgently needed to address these issues.

DEVELOPMENT AND VALIDATION OF PREDICTION MODELS WITH NON-TRADITIONAL MARKERS FOR 10-YEAR RISK OF ISCHEMIC LEG AMPUTATION AMONG PERSONS WITH DIABETES: THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY

Background: The ability of non-traditional markers for predicting ischemic leg amputation in diabetes is unknown. Methods: In 3321 ARIC participants with diabetes (45-73 y during 1987-98), we identified traditional factors contributing to ischemic leg amputation (ICD code of leg amputation [84.1x]

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 …