Increased Hemoglobin A1c Threshold for Prediabetes Remarkably Improving the Agreement Between A1c and Oral Glucose Tolerance Test Criteria in Obese Population

ORIGINAL ARTICLE Increased Hemoglobin A1c Threshold for Prediabetes Remarkably Improving the Agreement Between A1c and Oral Glucose Tolerance Test Criteria in Obese Population Jie Li,* Hao Ma,* Lixin Na, Shuo Jiang, Lin Lv, Gang Li, Wei Zhang, Guanqiong Na, Ying Li, and Changhao Sun National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 150081 Harbin, China Context: It is unclear why the prevalence of diabetes and prediabetes, especially prediabetes, between diagnosed by oral glucose tolerance test (OGTT) and hemoglobin A1c (HbA1c) criteria, is substantially discordant. Objective: We aimed to evaluate the effects of obesity on the agreement between HbA1c and OGTT for diagnosing diabetes and prediabetes and identify the optimal HbA1c cutoff values in different body mass index (BMI) classifications. Design Setting and Participants: In a population-based, cross-sectional study in Harbin, China, 4325 individuals aged 20 –74 years without a prior diagnosed diabetes were involved in this study. Outcome: measure The performance and optimal cutoff points of HbA1c were assessed by receiver-operatingcharacteristiccurve.ThecontributionofBMItoHbA1cwasanalyzedbystructuralequationalmodel. Results: The agreement between HbA1c criteria and OGTT decreased with BMI gain (␬ ⫽ 0.359, 0.312, and 0.275 in a normal weight, overweight, and obese population, respectively). The structural equational model results showed that BMI was significantly associated with HbA1c in normal glucose tolerance and prediabetes subjects but not in diabetes subjects. At a specificity of 80% for prediabetes and 97.5% for diabetes, the optimal HbA1c cutoff points for prediabetes and diabetes were 5.6% and 6.4% in normal-weight, 5.7% and 6.5% in overweight, and 6.0% and 6.5% in an obese population. When the new HbA1c cutoff values were used, the agreement in obese subjects increased almost to the level in normal-weight subjects. Conclusions: The poor agreement between HbA1c and OGTT criteria in an obese population can be significantly improved through increasing the HbA1c threshold for prediabetes. (J Clin Endocrinol Metab 100: 1997–2005, 2015) n 2010, the American Diabetes Association (ADA) recommended the use of glycated hemoglobin (HbA1c) to diagnose diabetes and prediabetes (1). Although numerous cross-sectional and longitudinal studies indicate that HbA1c is correlated with risk of diabetes and diabetes- I related comorbidities (2– 4), it is worth noting that not only the of rate of hyperglycemia diagnosed by an oral glucose tolerance test (OGTT) and HbA1c criteria was different but also the overlap between glycemic classification as defined by OGTT and HbA1c criteria was limited ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received November 18, 2014. Accepted March 3, 2015. First Published Online March 9, 2015 * J.L. and H.M. contributed equally to this work. Abbreviations: ADA, American Diabetes Association; AUC, area under the curve; BMI, body mass index; BW, body weight; CI, confidence interval; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; 2h-glucose, 2-hour plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; MDA, methane dicarboxylic aldehyde; NGT, normal glucose tolerance; NPV, negative predictive value; OGTT, oral glucose tolerance test; PPV, positive predictive value; SEM, structural equation modeling; T-AOC, total antioxidative capacity; WC, waist circumference; WHO, World Health Organization. doi: 10.1210/jc.2014-4139 J Clin Endocrinol Metab, May 2015, 100(5):1997–2005 jcem.endojournals.org 1997 1998 Li et al Different HbA1c Cutoffs in BMI Classifications in Chinese (5, 6) and other populations (7–9). However, it is still unclear why the prevalence of diabetes and prediabetes between diagnosed by OGTT and HbA1c criteria is substantially discordant. HbA1c is the production of the glycation of hemoglobin. The concentration of HbA1c, which reflects the average blood glucose levels over the previous 3 months, depends on both prevailing glucose concentrations and the factors affecting the rate of glycation. It has been reported that oxidative stress is a key determiner of glycation rate and that the elevated oxidative stress is associated with increased HbA1c concentrations in nondiabetic subjects (10, 11). Furthermore, an in vitro study on human erythrocytes demonstrated that lipid peroxides directly affect glycated hemoglobin levels independently of glucose concentration (12). Therefore, oxidative stress may partly explain the discordance between HbA1c and blood glucose diagnosing diabetes and prediabetes. Obesity is a major public health issue in both developed and developing countries. The recently national survey showed that 31.4% of Chinese adults were overweight, 12.2% were obese, and 27.1% were centrally obese (13). It is reported that obesity per se can induce systemic oxidative stress (14) and is associated with increased glycation of hemoglobin independently of glucose levels (15, 16). Thus, HbA1c concentrations may be disproportionately elevate at a given glycemic level in obese subjects. In other words, HbA1c cannot reflect the real concentration of glucose in obese subjects. Diabetes is a disorder of glucose, not HbA1c, metabolism. It is necessary to clarify whether the diagnostic performance of HbA1c at the given cutoff point depends on the body mass index (BMI) of the target population. In this study, we aimed to evaluate whether obesity affected the performance of HbA1c in diagnosing diabetes and prediabetes against a standard OGTT, which was partly mediated by oxidative stress, and to identify the optimal HbA1c cutoffs in normal body weight (BW), overweight, and obese population in a large cross-sectional study in Harbin, China. Research Design and Methods Study population In this study, the participants were from a populationbased, cross-sectional diabetes survey that was conducted in Harbin, China, in 2008. A stratified, multistage, random cluster sampling design was used to recruit a representative sample of those in the general population who have lived in Harbin for at least 5 years. The details of the study design had been reported elsewhere (17). Briefly, a J Clin Endocrinol Metab, May 2015, 100(5):1997–2005 total of 8940 individuals aged 20 –74 years were invited to participate in the survey, and 8127 responded (90.9%). In this study, the inclusion criteria were as follows: 1) provided written informed consent, 2) without a prior diagnosed diabetes identified based on fasting plasma glucose (FPG) and 2-hour plasma glucose (2h-glucose) criteria or using medications that may affect glucose metabolism, 3) that FPG, OGTT, and HbA1c were measured on the same day, 4) no missing data for BMI and waist circumference (WC), 5) body weights were stable (⬍3 kg change over the past 3 mo), and 6) without anemia, live (...truncated)