Relationship of Glycated Albumin to Outcomes in DCCT/EDIC

Abstract and Introduction

Abstract

The association of chronic glycemia, measured by HbA_1c, with long-term complications of type 1 diabetes has been well established in the Diabetes Control and Complications Trial (DCCT) and other studies. The role of intermediate-term and acute glycemia and of glucose variability on microvascular and cardiovascular disease (CVD) is less clear. In order to examine the interrelationships among long-term, intermediate-term, and acute measures of glucose and its daily variability, we compared HbA_1c, glycated albumin (GA), and seven-point glucose profile concentrations measured longitudinally in a case-cohort subpopulation of the DCCT. HbA_1c and GA were closely correlated with each other and with the mean blood glucose (MBG) calculated from the seven-point profile. The associations of glucose variability and postprandial concentrations with HbA_1c and GA were relatively weak and were further attenuated when MBG was included in multivariate models. In the case-cohort analyses, HbA_1c and GA had similar associations with retinopathy and nephropathy, which were strengthened when both measures were considered together. Only HbA_1c was significantly associated with CVD. The demonstrated interrelationships among different measures of glycemia will need to be considered in future analyses of their roles in the development of long-term complications of type 1 diabetes.

Introduction

The Diabetes Control and Complications Trial (DCCT) showed that intensive therapy aimed at near-normal levels of HbA_1c substantially reduced the risk of microvascular complications, and that mean HbA_1c was the principal determinant of risk of complications. Moreover, the difference in risk between the intensive and conventional treatment groups was virtually completely explained by the difference in levels of HbA_1c during the DCCT. The reductions in risk of microvascular complications with intensive therapy persisted during the Epidemiology of Diabetes Interventions and Complications (EDIC) observational follow-up study despite negligible differences in HbA_1c since the end of the DCCT—a phenomenon named "metabolic memory". Extended follow-up of the DCCT cohort also revealed a major effect of intensive therapy and lower levels of HbA_1c on cardiovascular outcomes, with a 58% reduction in fatal and nonfatal myocardial infarctions and stroke. The DCCT results have been used to set targets for diabetes management based on desired levels of HbA_1c.

HbA_1c, the result of the nonenzymatic glycation of hemoglobin, reflects average glycemia over the preceding 8–12 weeks. Whether average glycemia as reflected by HbA_1c is the major glycemic determinant of complications and whether other measures of glycemia contribute, and to what extent, are unknown. Glycemic variability, potentially through an independent effect on oxidative stress, has been suggested to be an additional mediator of complications, but studies have not been consistent in supporting this hypothesis. Other measures of shorter-term glycemia, such as fructosamine or glycated albumin (GA), have also been associated with long-term complications. In addition, GA has been suggested to be a better index of glucose variability than HbA_1c. For evaluation of the contributions of different indices of glycemia to the risk of developing complications, understanding the relationships among them is necessary.

During the DCCT, HbA_1c and quarterly seven-point daily glucose profiles were obtained from its 1,441 subjects, and outcomes were assessed systematically over an average of 6.5 years. The results herein are based on a substudy of 497 subjects in whom shorter-term glycemia (GA) was measured annually from frozen specimens. We describe the association between HbA_1c and GA levels and their relationships with mean blood glucose (MBG), pre- and postprandial glucose concentrations, and measures of within-profile glucose variation—all derived from the seven-point profile. We then evaluate whether and to what extent GA levels contribute to the risk relationship between HbA_1c and retinopathy, nephropathy, and cardiovascular disease (CVD) events. Analyses relating glucose variation to clinical outcomes will be the focus of a future study based on all 1,441 subjects in the cohort.