This dissertation focuses on the utility of nontraditional biomarkers of hyperglycemia (fructosamine, glycated albumin, and 1,5-anhydroglucitol [1,5-AG]) for research and clinical purposes. We have undertaken several studies in the Atherosclerosis Risk in Communities (ARIC) Study to assess the following: the short-term variability of these biomarkers, racial comparisons of associations with long-term microvascular and macrovascular complications, and their ability to improve performance of risk prediction in the setting of diabetes.The first chapter is a review of the utility of nontraditional biomarkers of hyperglycemia for diagnosis, prognosis, and management of diabetes. There has been growing interest in the use of fructosamine, glycated albumin, and 1,5-AG in clinical practice but their epidemiology is relatively uncharacterized. We evaluated the recent literature and summarized findings in regard to associations of these biomarkers with complications; use of these biomarkers for monitoring of glycemic control, diabetes screening, and diagnosis, and in special populations; and discussed limitations of current studies, as well as potential avenues of interest for further study.The second chapter is a repeatability study that we conducted using a subset of participants who attended the fifth examination of the ARIC Study (from 2011 to 2013) and a second examination approximately 6 weeks after the first. We quantified the short-term variability of both traditional and nontraditional biomarkers of hyperglycemia in persons with and without diagnosed diabetes, and compared results across biomarkers in the persons who had blood collected at both of these examinations. The within-person coefficient of variation was highest for fasting glucose (9.6% and 5.3% in persons with and without diabetes, respectively) and lowest for hemoglobin A1c (HbA1c) (2.0% and 1.5%, respectively); and was intermediate between fasting glucose and HbA1c for fructosamine (3.7% and 3.4%, respectively), glycated albumin (3.8% and 2.7%, respectively), and 1,5-AG (5.7% and 2.9%, respectively). For each biomarker, the within-person coefficient of variation was greater in persons with diagnosed diabetes as compared to those without diagnosed diabetes. HbA1c and nontraditional biomarkers of hyperglycemia tracked well over six weeks and they had lower within-person variability than fasting glucose.The third chapter is a prospective study that compares in whites and blacks the association of traditional and nontraditional biomarkers of hyperglycemia with incident cardiovascular disease (CVD) and end-stage renal disease (ESRD) over ~20 years of follow-up. Previous studies have reported racial differences in HbA1c, which has spurred recent debate over the use of HbA1c as a diagnostic test. We found that levels of hyperglycemia and incidence rates of CVD and ESRD were higher in blacks than whites. However, the relative associations of HbA1c and nontraditional biomarkers of hyperglycemia were similar in whites and blacks (all p-values for interaction >0.15). Our findings support the use of similar cut-points for HbA1c in whites and blacks. The fourth chapter examines the association of large changes or sustained elevations in hs-CRP over a six-year time period with incident diabetes, cardiovascular events, and mortality over a median of 14 years of follow-up. CRP is a non-specific biomarker of inflammation, which has been associated with diabetes. Although the pathway by which inflammation may be involved in the development of insulin resistance and diabetes is not entirely clear, hs-CRP may be a good indicator of diabetes risk. We found that the more proximal measure of hs-CRP was associated with incident diabetes, regardless of hs-CRP measured six years earlier. Compared to persons with sustained low or moderate hs-CRP, those with increased or sustained elevated hs-CRP had an increased risk of incident diabetes (HRs [95% CIs]: 1.56 [1.38, 1.76] and 1.39 [1.25, 1.56], respectively). Persons with sustained elevations in hs-CRP were at the highest risk of CVD and mortality. Compared to persons with sustained low or moderate hs-CRP, those with sustained elevated hs-CRP had an increased risk of CVD events and mortality (HRs ranged from 1.51 to 1.70 and all had P<0.05).The fifth chapter presents a risk prediction model for 10-year risk of a combined endpoint of major complications (CVD, CKD, or lower extremity hospitalizations) in persons with diagnosed diabetes, considering death due to another cause as a competing risk. We developed a risk prediction model using traditional demographic and clinical variables, and then tested the addition of 13 biomarkers of hyperglycemia, cardiac function, kidney function, liver function, and inflammation. The addition of HbA1c, beta-2 microglobulin, N-terminal probrain natriuretic peptide, and high-sensitivity cardiac troponin T improved model discrimination (c-statistic 0.679 vs. 0.716, P<0.001). In conclusion, we determined that the epidemiology of fructosamine, glycated albumin, and 1,5-AG is relatively uncharacterized, and that few prospective studies have been sufficiently conducted to address the utility of these biomarkers for diabetes diagnosis, prognosis, and management. This dissertation addressed some of these gaps in the literature. We found that nontraditional biomarkers of hyperglycemia had good six-week reliability, especially compared to fasting glucose, in persons with and without diabetes. The similar diagnostic and prognostic value of HbA1c and nontraditional biomarkers of hyperglycemia in whites and blacks suggests similar cut-points for HbA1c across race. Furthermore, biomarkers of hyperglycemia, cardiac damage, kidney function, liver function, and inflammation may improve risk prediction of diabetes and its complications. The most recent measurement of hs-CRP was the best indicator of future diabetes risk. However, two measurements of hs-CRP were better than one at identifying persons at highest risk of cardiovascular outcomes and death. Combinations of biomarkers may help improve risk stratification and identify high-risk persons to target for intensive therapy. In particular, fructosamine, glycated albumin, and 1,5-AG may be important as adjuncts or alternatives to fasting glucose and HbA1c.
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The Epidemiology of Nontraditional Biomarkers of Hyperglycemia and their Prognostic Value
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