Falsely high glycated haemoglobin [HbA1C] because of haemoglobin OSU‐Christiansborg

Glycated haemoglobin (HbA1c) is routinely used to assess the degree of glycaemic control in diabetic patients. We report a case of a 73 year old diabetic woman who had an elevated HbA1c of 13.4%. She was on maximum oral hypoglycaemic agents and was commenced on insulin. However, her HbA1c continued to remain high at 20.4%. Subsequent tests revealed that she had a haemoglobin variant, Haemoglobin Osu‐Christiansborg, causing the falsely high glycated haemoglobin.     

糖化血红蛋白用于筛查糖尿病的意义

目的比较并评价空腹血糖（FPG）和糖化血红蛋白（HbA1c）在筛查DM中的应用价值。方法上海地区研究对象2298名,为明确DM诊断而就诊者和DM高危人群接受DM筛查者,男956名,女1342名,年龄52±13岁,行OGTT并测定HbA1C;以其工作特征曲线（ROC）评价FPG和HbA。C在筛查DM中的敏感性和特异性。结果（1）按照1999年WHO的DM诊断标准,本研究人群糖耐量正常（NGT）、空腹血糖受损（IFG）、糖耐量受损（IGT）、IGT合并IFG和DM者分别为830、110、380、183、795例。其中DM患病率为34．6％。（2）依据ROC判断,与DM状态相关的FPG最佳临界点为6．1mmol／L,敏感性和特异性均为81．5％,曲线下面积为0．899（95％CI0．885～0．914）,阳性似然比4．18,阴性似然比0．23;与DM状态相关的HbA1c最佳临界点为6．1％,敏感性和特异性均为81．0％,曲线下面积为0．890（95％CI0．876-0．904）,阳性似然比4．26,阴性似然比0．23;如应用FPG≥6．1mmol／L或HbA1c≥6．1％筛查DM,敏感性和特异性分别为96．5％和65．2％,阳性似然比2．77,阴性似然比0．05。结论FPG和HbA1C在筛查DM中具有相似的价值,二者均有相似的特异性和敏感性以及阳性似然比和阴性似然比。为了最大限度的筛查出DM患者,建议对于6．1mmol／L≤FPG〈7．0mmol／L或HbA1c≥6．1％的患者行OGTT检查以明确有无DM。     

The relationship between birth weight and maternal glycated haemoglobin (HbA1c) concentration in pregnancies complicated by Type 1 diabetes.

AIM: To examine the relationships between maternal HbA1c concentration at different time points and birth weight in pregnancies complicated by pre-existing Type 1 diabetes. METHODS: A comprehensive audit dataset was collected prospectively on all deliveries in Scotland to women with pre-existing Type 1 diabetes occurring between 1 April 1998 and 31 March 1999. Data items included HbA1c concentrations prior to conception and in each of the three trimesters of pregnancy, and birth weight. Relationships between standardized birth weight and HbA1c concentrations at each of the four time points were examined using correlation analysis. RESULTS: Standardized birth weight (Z scores) could be calculated for 203 of 208 singleton liveborn infants. HbA1c concentrations, standardized to correct for assay differences among hospitals, at different time points were available for between 134 (pre-pregnancy) and 192 (third trimester) cases. Standardized birth weight, relative to a reference population, showed a unimodal distribution, shifted to the right (mean, +1.57 sd). There was a significant negative correlation between pre-pregnancy HbA1c and birth weight (Spearman's R, -0.208; P = 0.016). There were no statistically significant correlations for other time points. CONCLUSIONS: Standardized birth weight scores of the infants of diabetic mothers are higher than those of a reference population. There is no simple relationship between maternal glycaemic status and birth weight, but there appears to be a paradoxical inverse relationship between pre-pregnancy glycaemic control and standardized birth weight.     

Diagnostic value of glycated haemoglobin (HbA1c) for the early detection of diabetes in high‐risk subjects

Objective The aim of this study was to assess the validity of fasting plasma glucose (FPG) and/or glycated haemoglobin (HbA_1c) as screening tests for the early detection of diabetes in high‐risk subjects. Methods A total of 392 subjects (149 male and 243 female) with risk factors for diabetes were included. All subjects underwent a 75‐g oral glucose tolerance test and HbA_1c measurement. Receiver operating characteristic curve analysis was used to examine the sensitivity and specificity of FPG and HbA_1c for detecting diabetes, which was defined as a FPG ≥ 7.0 mmol/l or a post‐challenge 2‐h plasma glucose ≥ 11.1 mmol/l. Results The prevalence of newly diagnosed diabetes was 22.4% (n = 88). The current guideline of FPG ≥ 7.0 mmol/l for diabetes screening detected only 55.7% of diabetic subjects. The optimal cut‐off points of HbA_1c and FPG for the diagnosis of diabetes were 6.1% (sensitivity 81.8%, specificity 84.9%) and 6.1 mmol/l (sensitivity 85.2%, specificity 88.5%), respectively. The screening model using FPG ≥ 6.1 mmol/l and/or HbA_1c ≥ 6.1% had sensitivities of 71.6–95.5% and specificities of 77.6–95.7% for detecting undiagnosed diabetes. Conclusions The current American Diabetes Association diagnostic criteria, based only on FPG, are relatively insensitive in the detection of diabetes in high‐risk subjects. The simultaneous measurement of FPG and HbA_1c might be a more sensitive screening tool for identifying high‐risk individuals with diabetes at an early stage.     

Falsely low HbA1c value due to a rare variant of hemoglobin J-Baltimore

HbA1c values are heavily relied on to assess glycemic control. Hemoglobin variants may interfere with measurements of HbA1c resulting in falsely low values. We present the first report of a rare variant of Hb in a patient with type 2 diabetes, which lead to a falsely low HbA1c.     

Effect of once‐weekly dulaglutide on glycated haemoglobin (HbA1c) and fasting blood glucose in patient subpopulations by gender,duration of diabetes and baseline HbA1c

Aims

To evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD‐1 to ‐6 and ‐8 clinical trials).

Methods

Change in HbA1c was analysed by gender, duration of diabetes (<5, ≥5 years and <10, ≥10 years), and baseline HbA1c (<8.5%, ≥8.5%) in pooled and individual studies. Changes from baseline in weight, hypoglycaemia and gastrointestinal adverse events were evaluated for individual trials.

Results

In the pooled analysis of patients treated with dulaglutide 1.5 mg at 6 months, the reductions in HbA1c from baseline were similar across gender (men: least squares [LS] mean ?1.26% [95% confidence interval {CI} ?1.36, ?1.16]; women: LS mean ?1.33% [95% CI ?1.43, ?1.24]) and among duration of diabetes subgroups (<5 years: LS mean ?1.32% [95% CI ?1.43, ?1.22]; ≥5 and <10 years: LS mean ?1.33% [95% CI ?1.43, ?1.22]; ≥10 years: ?1.24% [95% CI ?1.35, ?1.14]). Patients with baseline HbA1c ≥8.5% had greater HbA1c reductions than patients with baseline HbA1c <8.5%, (≥8.5%: LS mean ?1.86% [95% CI ?1.97, ?1.75]; <8.5%: LS mean ?1.02% [95% CI ?1.12, ?0.93]). Reductions in fasting blood glucose (FBG) were consistent with HbA1c changes. Similar results were observed with dulaglutide 0.75 mg. In general, body weight changes were similar among duration of diabetes and in baseline HbA1c subgroups, respectively; women had a numerically greater weight loss or less weight gain than men with both dulaglutide doses. There was no clinically meaningful difference in hypoglycaemia trends by gender or duration of diabetes. Hypoglycaemia incidence and rate were generally lower in patients with baseline HbA1c ≥8.5% than in those with <8.5%, except for the AWARD‐4 study (combination with mealtime insulin).

Conclusions

Across the AWARD studies, dulaglutide demonstrated significant improvements in glycaemic control irrespective of gender, duration of diabetes, or baseline HbA1c, with greater HbA1c and FBG reductions in patients with a higher baseline HbA1c. Dulaglutide was well tolerated, with a safety profile similar to other glucagon‐like peptide‐1 receptor agonists.     

Hemoglobin variants and determination of glycated hemoglobin (HbA1c)

Measurement of glycated hemoglobin in diabetic patients is an established procedure for evaluating long-term control of diabetes. The Diabetes Control and Complications Trial (DCCT), as well as the United Kingdom Prospective Diabetes Study (UKPDS), confirmed the direct relationship between the degree of glycemic control as estimated by glycohemoglobin (GHb) determinations and the development and progression of long-term complications in diabetic patients. Samples with known interferences of HbA(1c) determination as hemoglobinopathies are specifically excluded from certification testing and there are no guidelines or requirements for comparability of samples containing hemoglobin (Hb) variants. This paper reviews the interference of Hb variants on determination methods of glycated hemoglobin as they result in false HbA(1c) results.     

Radioimmunoassay for the determination of glycated haemoglobin

Summary A competitive radioimmunoassay for the quantitative determination of glycated haemoglobin was developed. The antiserum, obtained by immunizing guinea pigs with reduced glycated human albumin, was capable of identifying and quantitating the glucitollysine residues of glycated Hb after reduction with sodium borohydride. To simplify the sample preparation we introduced trichloroacetic acid precipitation to remove unreacted sodium borohydride instead of using dialysis or gel filtration. Using this procedure, our radioimmunoassay became relatively simple and provided satisfactory within- and between-run (1.3–2.8% and 1.9–5.4% coefficient of variation, respectively). The radioimmunoassay method was compared to the measurement of HbA _1c by high performance liquid chromatography which is the most widely used method for quantitating glycated Hb. For this purpose glycated Hb was measured in normal glucose tolerance, impaired glucose tolerance, and diabetes mellitus groups based on WHO criteria. Both assays were able to discriminate between the normal and diabetic groups. In addition, while the determination of glycated Hb by the radioimmunoassay method was able to clearly discriminate between the normal and impaired glucose tolerance groups, the determination of HbA _1c by the high performance liquid chromatography method failed to discriminate between these two groups. Moreover, 15 of the 20 impaired glucose tolerance patients exceeded the upper normal range (mean normal values + 2 SD) in radioimmunoassay. But all 20 patients with impaired glucose tolerance were within the upper normal range in HbA _1c values.These results demonstrate that the measurement of glycated Hb by radioimmunoassay is more sensitive than the measurement of HbA _1c by high performance liquid chromatography since it can discriminate between the normal and impaired glucose tolerance groups.     

Epidemiological features of glycated haemoglobin A1c-distribution in a healthy population

Summary HbA_1c was measured in 3240 healthy non-diabetic adult individuals in a working population. There was no difference in HbA_1c between sexes. The distribution of HbA_1c was approximately normal with a slight difference between mean and median values at all ages in both sexes. HbA_1c increased with deterioration of glucose tolerance and with all the known risk factors for diabetes (age, obesity, family history of diabetes, history of a large newborn delivery); age but not body mass index appeared as a factor influencing HbA_1c independently. In women, HbA_1c levels rose particularly at the age of menopause but the use of oral contraceptives or oestrogens made no difference. In both sexes, HbA_1c was higher in smokers than in non-smokers. No consistent seasonal variation was observed. Haematologic factors had a negligible influence on HbA_1c level. HbA_1c was more highly correlated with fasting plasma glucose than with 2 h-plasma/glucose (r=0.20 vs 0.11). In a stepwise multiple regression analysis, age followed by fasting plasma glucose were the only two significant factors associated with the level of HbA_1c. These data indicate that HbA_1c is influenced only by factors closely linked to diabetes.     

Glycated haemoglobin (HbA1c): today and tomorrow

The assay of glycated haemoglobin (HbA1c) is a gold standard in bioanalysis, and is essential to ensure the optimal care of diabetic patients. Accordingly, the principal scientific societies in diabetology and clinical chemistry have made efforts to standardize this assay in order to select and validate certain analytical methods and achieve consistency in the results obtained therewith. However, clinicians have to be aware of the caution required when interpreting HbA1c assay results owing to modified lifetime and (or) abnormal synthesis of haemoglobin. Although this biological examination has now become an essential part of diabetes monitoring, its status as a screening tool is still controversial, even after 30 years of debate. Other uses of HbA1c assay are currently being assessed in cardiology (coronary syndromes), vascular diseases (arteriopathy), nephrology (renal insufficiency), haematology (anaemia) and oncology (factors of predisposition).     

Performance of glycated haemoglobin (HbA1c) as a screening test for diabetes and impaired glucose tolerance (IGT) in a high risk population—The Brazilian Xavante Indians

AimsTo examine the properties of HbA1c to detect diabetes and IGT in adult Brazilian Xavante Indians, a high risk population for diabetes.MethodsThe survey was carried out between October 2010 and January 2012 and based on a 75 g oral glucose tolerance test (OGTT). Basal and 2 h capillary glycaemia were measured by HemoCue Glucose 201+; HbA1c using an automated high-performance liquid chromatography analyzer (Tosoh G7).Results630 individuals aged ≥20 years were examined and 80 had a previous diagnosis of diabetes. Sensitivity, specificity and accuracy for HbA1c ≥ 6.5% (≥48 mmol/mol) were 71.3%, 90.5% and 87.2%. The areas under the ROC curve (AUC) was 0.88 (95%CI: 0.83–0.93). To identify IGT, HbA1c values between 5.7% and 6.4% (39–47 mmol/mol) presented sensitivity, specificity and accuracy of 87.2%, 24.7% and 51.4%, with an AUC of 0.62 (95%CI: 0.57–0.67).ConclusionsThe ADA/WHO proposed cut-off of 6.5% (48 mmol/mol) for HbA1c was adequate to detect diabetes among the Xavante. However, the performance of the ADA proposed cut-off points for pre-diabetes, when used to detect IGT was inadequate and should not be recommended.     

The ratio of glycated albumin to glycated haemoglobin correlates with insulin secretory function

Objective Although glycated haemoglobin (A1c) levels are similar among patients with type 2 diabetes, the glycated albumin (GA)/A1c ratio varies considerably. On the basis of the hypothesis that endogenous insulin secretion might be correlated with the GA/A1c ratio, we investigated whether insulin secretory function or insulin resistance has different effects on the GA/A1c ratio in patients with type 2 diabetes using the standardized liquid meal test. Design A clinical, retrospective study. Patients and measurements A total of 758 patients with type 2 diabetes ingested a standardized liquid meal (i.e. 500 kcal, 17·5 g fat, 68·5 g carbohydrate and 17·5 g protein). The subjects were divided into two groups: those with GA/A1c ratio <2·5 (n = 414) and those with GA/A1c ratio ≥2·5 (n = 344). We compared the A1c and GA levels, and the GA/A1c ratio and evaluated the relationships between the glycaemic indices and other parameters. Effects of β‐cell function [homeostasis model assessment (HOMA‐β), insulinogenic index (IGI)] and insulin resistance (HOMA‐IR) on the GA/A1c ratio were also examined. Results The GA/A1c ratio was significantly correlated with HOMA‐β, IGI and body mass index (BMI) but not with HOMA‐IR. Furthermore, after adjusting for age, gender, BMI, haemoglobin and albumin levels, the GA/A1c ratio was still inversely correlated with both HOMA‐β and IGI. Conclusions The GA/A1c ratio is significantly correlated with insulin secretory function but not with insulin resistance.     

The use of glycated haemoglobin (HbA1C) in determining glycemic control (and relevance of BMI) in diabetic patients in Ahmadu Bello University Teaching Hospital Zaria,Nigeria

This study was carried out to specifically investigate the local HbA1_C level and determine extent of (if any) variation from the WHO (World Health Organization) recommended threshold for the diagnosis of diabetes and prediabetes using blood glucose as a benchmark. In addition, we also looked to see what role BMI (Body Mass Index) plays among subjects used for the study.152 subjects were used for the study: 101 diabetic subjects and 51 non-diabetic control subjects. 5 mL of blood sample was collected from each of the subjects after about 8–10 h of overnight fasting. 3–4 mL of the sample was centrifuged and the serum analysed for glucose. The remaining 1–2 ml was transferred into EDTA bottles and analysed immediately for glycated haemoglobin (HbA1_C). The BMI (kg/m²) was calculated by dividing the weight in kilograms (kg) by the square of the height in metres (m²).For the BMI, no significant difference was observed between the diabetic subjects (mean = 25.75 kg/m²) and the non-diabetic control subjects (mean = 25.09 kg/m²). Thirty-seven (37) of the diabetic subjects and twenty-three (23) of the non-diabetic subjects had HbA1_C levels (mean = 6.96% and 6.29% respectively) that would imply either prediabetes or diabetes but were actually normal going by their fasting blood glucose (FBG) levels. A new chart for the interconversions between FBG and HbA1c and for predicting their expected values from each other was realized, drawn up and recommended for consideration in the management of diabetic patients along with the WHO recommended chart.There are a lot of normal individuals with HbA1c level that does not conform to (or that are simply higher than) what is regarded as the threshold for the onset of diabetes or prediabetes. Generally, the local (Nigerian) glycated haemoglobin (HbA1c) level can therefore be said to be distinctly higher for a given blood glucose range and should be taken as such in the management of diabetes in this environment. Being overweight or obese is not prerequisite to the development of diabetes or abnormal glycated haemoglobin level.     

Interventions in primary care to improve cardiovascular risk factors and glycated haemoglobin (HbA1c) levels in patients with diabetes: a systematic review

Most patients with diabetes are treated in primary care (PC). We performed a systematic review to assess the effect of single and combined interventions on cardiovascular risk factors (CVRFs) and glycated haemoglobin (HbA1c) levels in patients with diabetes in PC settings. We searched the MEDLINE database from January 1990 to October 2008. According to the Cochrane Effective Practice and Organization of Care Group (EPOC) criteria, (cluster-)randomized control studies and controlled before-and-after studies were selected and reviewed. Identified interventions were classified according to a modified EPOC intervention taxonomy. We included 68 studies. Forty-five studies evaluated the effect of any intervention on HbA1c. Seventeen studies presented a significant improvement in HbA1c. Nine out of 27 studies evaluating CVRFs [cholesterol, blood pressure (BP)] and HbA1c showed a significant improvement in at least two of these factors. Audit and feedback on performance, clinical decision support systems, multi-professional teams and patient education seemed to be successful strategies. The increasing evidence regarding the treatment of persons with chronic illnesses, summarized in the Chronic Care Model (CCM), is not reflected in most recent studies about diabetes treatment in PC. Most interventions still seem only partly adapted to the CCM. The methodological quality of many studies is still poor and often the pivotal outcomes, CVRFs and HbA1c, are not appropriately addressed. As a consequence, the potential of PC in the care of patients with diabetes may still be underestimated.     

Glycaemic efficacy of an expanded dose range of dulaglutide according to baseline glycated haemoglobin (HbA1c) subgroup: Post hoc analysis of AWARD-11

The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide 3.0 and 4.5 mg compared to dulaglutide 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. This post hoc analysis examined the change from baseline in glycated haemoglobin (HbA1c) and proportions of patients achieving HbA1c <7% at weeks 36 and 52 with dulaglutide 1.5 mg, 3.0 mg or 4.5 mg across clinically relevant baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%). Mean reductions in HbA1c were observed across all baseline HbA1c subgroups at 36 weeks (range of HbA1c change: 1.5 mg: −1.0% to −2.2%; 3.0 mg: −1.2% to −2.5%; and 4.5 mg: −1.2% to −3.2%). More patients randomized to 3.0 mg or 4.5 mg (vs. 1.5 mg) achieved HbA1c <7% at 36 weeks regardless of baseline HbA1c; the difference in proportions was greater at higher baseline HbA1c (P-interaction = 0.096). Similar patterns in glycaemic improvement and proportions achieving HbA1c <7% were observed at 52 weeks. Hypoglycaemia and gastrointestinal adverse events were similar among the HbA1c subgroups. Glycaemic control was improved with dulaglutide dose escalation from 1.5 mg to 3.0 mg or 4.5 mg across baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%).