High-normal HbA1c is a strong predictor of type 2 diabetes in the general population

OBJECTIVE

Glycosylated hemoglobin (HbA_1c) recently has been recommended for the diagnosis of diabetes by the American Diabetes Association, but its value in the prediction of type 2 diabetes is poorly understood. In this study we evaluated how high-normal HbA_1c levels predict type 2 diabetes.

RESEARCH DESIGN AND METHODS

We measured HbA_1c in 919 Caucasian subjects, aged 40–79 years, and recorded new cases of type 2 diabetes in the following 15 years. Diabetes was diagnosed with HbA_1c.

RESULTS

Subjects were stratified according to baseline HbA_1c (<5.0, 5.00–5.49 [reference], 5.50–5.99, and 6.00–6.49%). Sex- and age-adjusted hazard ratios (95% CI) for type 2 diabetes were 1.11 (0.30–4.41), 1.00, 3.79 (1.79–8.06), and 12.50 (5.51–28.34), respectively. Results did not change after adjusting for several putative confounding factors and were confirmed when models with updated variables were used.

CONCLUSIONS

HbA_1c is an independent risk factor for type 2 diabetes. Subjects with high-normal levels of HbA_1c deserve particular attention because they have a strong risk of developing diabetes.Glycosylated hemoglobin (HbA_1c) was proposed as a reliable tool for diagnosing diabetes and identifying subjects at increased risk of type 2 diabetes (1). In 2010, the American Diabetes Association (ADA) pointed out that prevention strategies should be particularly intensive in subjects with high-normal HbA_1c because they have the greatest risk (2), but this recommendation was based more on common sense than literature data. In fact, only few studies (3,4) showed an elevated risk of type 2 diabetes in subjects with high-normal HbA_1c. Moreover, in these studies type 2 diabetes was self-reported during telephone interviews. To support ADA recommendations, we evaluated diabetes risk in the 6.00–6.49% category of HbA_1c, with a more robust approach based on laboratory measurement of glycemic parameters.     

老年2型糖尿病糖化血红蛋白与血糖波动的相关性分析

目的：研究老年2型糖尿病患者动态血糖波动与糖化血红蛋白(HbA1 c)之间的相关性。方法84例老年2型糖尿病患者均于入院后行动态血糖监测,并测定 HbA1 c 水平,按 HbA1 c 水平分为3组,Ⅰ组(HbA1 c≤7.0%)20例、Ⅱ组(7.0%10%)25例,分析动态血糖波动与 HbA1 c 的相关性,探讨夜间低血糖与睡前血糖的关系。结果3组患者空腹血糖、餐后2小时血糖、低血糖比例Ⅱ组与Ⅰ组比较有统计学意义(P <0.05),Ⅲ组与Ⅱ组比较有统计学意义(P <0.05);3组平均血糖(MBG)、空腹平均血糖(MFBG)、早餐后2 h 平均血糖、中餐后2 h 平均血糖、晚餐后2 h 平均血糖与 HbA1 c 均呈正相关(P 均<0.01);平均血糖波动幅度、有效血糖波动次数、日间血糖平均绝对差随着 HbA1 c 的增高也逐渐升高。多元线性回归分析显示 HbA1 c 与血糖呈显著正相关(P <0.01)。夜间低血糖发生率16.8%,其中,睡前血糖最低值(7.2±3.4)mmol/L。结论老年2型糖尿病患者 HbA1 c 与动态血糖水平显著相关,HbA1 c 与 MBG 相关性最好,睡前血糖在7.2mmol/L 以下,夜间低血糖发生率高。     

Immediate feedback of HbA1c levels improves glycemic control in type 1 and insulin-treated type 2 diabetic patients.

OBJECTIVE: Accurate and reliable HbA1c results can be obtained at the time of the office visit by using benchtop analyzers. We tested the hypothesis that immediately available HbA1c results could improve glycemic control by changing physician or patient behavior or both. RESEARCH DESIGN AND METHODS: A randomized controlled trial was conducted in 201 type 1 and insulin-treated type 2 diabetic patients attending an academic diabetes center. HbA1c levels, changes in insulin therapy, and use of health care resources were assessed during a 12-month follow-up period. RESULTS: HbA1c levels decreased significantly at 6 and 12 months in the immediate assay group (-0.57 +/- 1.44 and -0.40 +/- 1.65%, respectively; P < 0.01) but did not change in the control group (-0.11 +/- 0.79 and -0.19 +/- 1.16%, respectively; NS). The changes were similar for both type 1 and type 2 diabetic patients. There were no differences in the rates of hypoglycemic events or use of health care resources. CONCLUSIONS: In the setting of a controlled randomized trial, the immediate feedback of HbA1c results at the time of patient encounters resulted in a significant improvement of glycemic control at 6-month follow-up and persisted for the 12-month study. The introduction of this assay was positively received by both patients and physicians.     

The relationship between HbA1c level, symptoms and self-rated health in type 2 diabetic patients

Objective

Improving glycaemic control is generally supposed to reduce symptoms experienced by type 2 diabetic patients, but the relationships between glycated haemoglobin (HbA_1c), diabetes-related symptoms, and self-rated health (SRH) are unclarified. This study explored the relationships between these aspects of diabetes control.

Design

A cross-sectional study one year after diagnosis of type 2 diabetes.

Subjects

A population-based sample of 606 type 2 diabetic patients, median age 65.6 years at diagnosis, regularly reviewed in primary care.

Main outcome measures

The relationships between HbA_1c, diabetes-related symptoms, and SRH.

Results

The patients’ median HbA_1c was 7.8 (reference interval: 5.4–7.4 % at the time of the study). 270 (45.2%) reported diabetes-related symptoms within the past 14 days. SRH was associated with symptom score (γ = 0.30, p < 0.001) and HbA_1c (γ = 0.17, p = 0.038) after correction for covariates. The relation between HbA_1c and symptom score was explained by SRH together with other confounders, e.g. hypertension (γ = 0.02, p = 0.40). The relation between the symptom fatigue and SRH was not explained by symptom score and significantly modified the direct association between symptom score and SRH.

Conclusions

Symptom relief may not occur even when HbA_1c level is at its lowest average level in the natural history of diabetes, and symptoms and SRH are closely linked. Monitoring symptoms in the clinical encounter to extend information on disease severity, as measured e.g. by HbA_1c, may help general practitioners and patients to understand the possible impact of treatments and of disease manifestations in order to obtain optimum disease control.Key Words: Family practice, glycosylated haemoglobin A, health status, signs and symptoms, type 2 diabetes mellitusTo reduce complications, lowering of HbA1c is a primary objective in diabetes care.

• Many patients experience diabetes-related symptoms in spite of acceptable glycaemic control.
• These symptoms are closely related to poor SRH while the association with HbA_1c is weak.

Patients with type 2 diabetes mellitus (T2DM) are commonly treated in general practice where treatment typically aims to improve glycaemic control in order to prevent complications [1], reduce symptom burden, and improve perceived health [2]. Moreover, the experience of obtaining these goals may improve patients’ motivation for treatment adherence, e.g. lifestyle changes and medication [3,4].Poor glycaemic control is related to symptoms such as frequent urination, genital itching, and unintended weight loss [5,6]. The association between glycated haemoglobin (HbA_1c) levels and specific symptoms is not necessarily close [7,8] except among dysregulated patients, e.g. at the time of diagnosis [5] or in patients with longstanding diabetes [2,6]. Despite the central role of symptom amelioration in treatment, few studies have looked into the relation between HbA_1c level and symptoms when HbA_1c is supposed to be at its lowest average level in the natural history of diabetes [7,9].General practitioners (GPs) and patients may evaluate the patient''s health differently [10]. The association between the patient''s HbA_1c level and perceived health is weak [2], or non-existent [1,11]. The patients’ perceived health gauged by a single question, known as perceived health, self-assessed health, or self-rated health (SRH), has been shown to vary with other factors than HbA_1c such as symptoms [12,13], sociodemographic factors [14], comorbidities [14–16], and functional ability [12,14]. Recent research has shown that SRH predicts which patients have a higher risk of diabetic complications even after accounting for established risk factors such as HbA_1c, but this predictive value may be mediated by presence of symptoms which were not accounted for [16]. Yet the relationships between HbA_1c and symptoms, both of which are important treatment targets, and SRH, which is a motivational factor for treatment adherence [2,3], are unclarified. A better insight into these relationships may help GPs to tailor treatments such as to maintain or improve patients’ health, which may include motivating the patient for treatment adherence.In a population-based sample of patients with T2DM seen in general practice one year after diabetes diagnosis we examined the relationships between HbA_1c, symptoms, and SRH primarily to see whether high HbA_1c levels are associated with many symptoms and low SRH ratings, and whether many symptoms are associated with low SRH ratings.     

Biological variation in HbA1c predicts risk of retinopathy and nephropathy in type 1 diabetes

OBJECTIVE: We hypothesized that biological variation in HbA(1c), distinct from variation attributable to mean blood glucose (MBG), would predict risk for microvascular complications in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: A longitudinal multiple regression model was developed from MBG and HbA(1c) measured in the 1,441 DCCT participants at quarterly visits. A hemoglobin glycation index (HGI = observed HbA(1c) - predicted HbA(1c)) was calculated for each visit to assess biological variation based on the directional deviation of observed HbA(1c) from that predicted by MBG in the model. The population was subdivided by thirds into high-, moderate-, and low-HGI groups based on mean participant HGI during the study. Cox proportional hazard analysis compared risk for development or progression of retinopathy and nephropathy between HGI groups controlled for MBG, age, treatment group, strata, and duration of diabetes. RESULTS: Likelihood ratio and t tests on HGI rejected the assumption that HbA(1c) levels were determined by MBG alone. At 7 years' follow-up, patients in the high-HGI group (higher-than-predicted HbA(1c)) had three times greater risk of retinopathy (30 vs. 9%, P < 0.001) and six times greater risk of nephropathy (6 vs. 1%, P < 0.001) compared with the low-HGI group. CONCLUSIONS: Between-individual biological variation in HbA(1c), which is distinct from that attributable to MBG, was evident among type 1 diabetic patients in the DCCT and was a strong predictor of risk for diabetes complications. Identification of the processes responsible for biological variation in HbA(1c) could lead to novel therapies to augment treatments directed at lowering blood glucose levels and preventing diabetes complications.     

Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c)

OBJECTIVE: The exact contributions of postprandial and fasting glucose increments to overall hyperglycemia remain controversial. The discrepancies between the data published previously might be caused by the interference of several factors. To test the effect of overall glycemic control itself, we analyzed the diurnal glycemic profiles of type 2 diabetic patients investigated at different levels of HbA(1c). RESEARCH DESIGN AND METHODS: In 290 non-insulin- and non-acarbose-using patients with type 2 diabetes, plasma glucose (PG) concentrations were determined at fasting (8:00 A.M.) and during postprandial and postabsorptive periods (at 11:00 A.M., 2:00 P.M., and 5:00 P.M.). The areas under the curve above fasting PG concentrations (AUC(1)) and >6.1 mmol/l (AUC(2)) were calculated for further evaluation of the relative contributions of postprandial (AUC(1)/AUC(2), %) and fasting [(AUC(2) - AUC(1))/AUC(2), %] PG increments to the overall diurnal hyperglycemia. The data were compared over quintiles of HbA(1c). RESULTS: The relative contribution of postprandial glucose decreased progressively from the lowest (69.7%) to the highest quintile of HbA(1c) (30.5%, P < 0.001), whereas the relative contribution of fasting glucose increased gradually with increasing levels of HbA(1c): 30.3% in the lowest vs. 69.5% in the highest quintile (P < 0.001). CONCLUSIONS: The relative contribution of postprandial glucose excursions is predominant in fairly controlled patients, whereas the contribution of fasting hyperglycemia increases gradually with diabetes worsening. These results could therefore provide a unifying explanation for the discrepancies as observed in previous studies.     

Hemodynamic effects of acute hyperglycemia in type 2 diabetic patients

OBJECTIVE: The aim of the present study was to evaluate the hemodynamic effects of acute hyperglycemia in type 2 diabetic patients and to see whether these effects are related to changes in nitric oxide (NO) availability. RESEARCH DESIGN AND METHODS: Twenty newly diagnosed complication-free diet-treated type 2 diabetic patients participated in the study. All patients underwent 3 hyperglycemic glucose clamps in random order: 1) the control study was performed with plasma glucose clamped at 18 mmol/l for 2 h; 2) the octreotide study with plasma insulin blocked at basal levels during the clamp; and 3) the L-arginine study with L-arginine (1 g/min) infused during the last 30 min of the clamp. A group of 8 patients also underwent a glutathione infusion (600 mg as an intravenous bolus followed by 5 mg/min infusion) during the clamp. RESULTS: During hyperglycemia, there were significant increments of systolic (sBP) (from 115.5 +/- 9.1 to 120.3 +/- 8.2 mmHg, P < 0.01) and diastolic (dBP) (from 70.3 +/- 7.8 to 79.7 +/- 5.3 mmHg, P < 0.01) blood pressure, as well as heart rate (from 75.2 +/- 7.8 to 80.8 +/- 5.4 beats/min, P < 0.01) and plasma catecholamines (P < 0.05). Squatting ratios, a measure of the baroreflex activity, significantly deteriorated after hyperglycemia (P < 0.01). The infusion of octreotide, used to avoid the possible confounding influence of insulin, did not change the hemodynamic effects of hyperglycemia. Glutathione, a free radical scavenger, completely prevented the vascular effects of hyperglycemia. L-Arginine produced a fall in sBP and dBP to baseline values and normalized squatting ratios. CONCLUSIONS: Acute hyperglycemia in newly diagnosed type 2 diabetic patients causes significant hemodynamic changes that are independent of endogenous insulin and are prevented by glutatione and reversed by L-arginine, suggesting an interference with endogenous NO availability. These observations could help explain the adverse cardiovascular effects of hyperglycemic spikes.     

Reducing the probability of falsely elevated HbA1c results in diabetic patients by applying automated and educative HbA1c re-testing intervals

IntroductionToo frequent HbA1c measurements may lead to unnecessary treatment modifications of diabetic patients. The aim of this study was to estimate the percentage of falsely elevated HbA1c results in two hospitals, Landeskrankenhaus/Uniklinikum Salzburg (LKH) and Landesklinik St. Veit (STV), as well as to retrospectively investigate the effect of an automated and an educative 60-day re-testing interval (RTI).MethodsThe amount of estimated falsely elevated results (eFER), based on odds calculated using the baseline and the follow-up values and the time between these measurements, the number of HbA1c re-testings within 60 days as well as the overall number of ordered and performed HbA1c analyses were calculated. In LKH, an automated algorithm cancelling inappropriate HbA1c testing was applied, and in STV, educational actions were taken.ResultsBefore RTI-implementation, eFER were 0.9% and 2.1% and within-60-days-re-testing were 15.0% and 7.4% of cases in LKH and STV, respectively. After RTI-implementation, these numbers decreased to 0.2% (p < .001) and 1.8% (p = .869) and within-60-days-re-testing decreased to 1.1% (p < .001) and 3.6% (p = .003) in LKH and STV, respectively. Median monthly HbA1c measurements decreased by 15.8% (p < .001) and 21.1% (p = .002) in LKH and STV, respectively.ConclusionBoth the educational and the automated 60-day-RTI were proven to be efficient in reducing overall HbA1c measurements, re-testing within 60 days and eFER.     

Progression of retinopathy in insulin-treated type 2 diabetic patients

OBJECTIVE: To study the progression of retinopathy 3 years after initiation of insulin therapy. RESEARCH DESIGN AND METHODS: In a prospective, observational case-control study, 42 type 2 diabetic patients were examined at baseline and 1, 3, 6, 12, 24, and 36 months after change to insulin therapy. Retinopathy was graded based on fundus photographs using the Wisconsin scale; HbA(1c) and IGF-1 were measured. RESULTS: During the observation period of 3 years, 26 patients progressed in the retinopathy scale; 11 patients progressed at least three levels. After 3 years of insulin therapy, HbA(1c) and IGF-1 were significantly lower than at baseline. Progression of retinopathy greater than or equal to three levels was related to high IGF-1 levels. CONCLUSIONS: A relationship was found between high IGF-1 levels at 3 years and progression of retinopathy in type 2 diabetic patients.     

2型糖尿病患者糖化血红蛋白与脉搏波传导速度及内皮依赖性血管舒张功能的关系研究

目的 探讨2型糖尿病患者不同糖化血红蛋白(HbA1c)水平与踝臂动脉脉搏波传导速度(baPWV)及内皮依赖性血管舒张功能(FMD)的关系.方法 对338例2型糖尿病患者按HbA1c水平分为正常组(A组,HbA1c≤6.0％,74例),正常高值组(B组,6.0％＜HbA1c≤6.5％,102例)和升高组162例(C组,HbA1c ＞6.5％),测量BaPWV及FMD作为反映大动脉硬度及血管舒张功能的指标.结果 与A组比较,B、C组BaPWV明显增高[(1734±343)cm/s与(1537±313)cm/s;1853±364)cm/s与(1537±313)cm/s;P均＜0.001),与B组比较,C组BaPWV明显升高[(1853±364)cm/s与(1734±343)cm/s;P=0.006).与A组比较,B、C组FMD明显减低[(4.20±3.13)％与(5.29±3.92)％;(4.09±2.79)％与(5.29±3.92)％;P均＜0.01)].直线相关分析显示,BaPWV与HbA1c水平呈正相关(r=0.53,P＜0.01),与FMD水平呈负相关(r=-0.25,P＜0.01).Logistic回归分析显示,HbA1c(OR 32.19,95％ CI 11.26 ～53.12;P ＜0.001)与年龄(OR 14.21,95％ CI 11.43～17.00;P ＜0.001)、收缩压(OR7.36,95％CI 6.12 ～8.59;P ＜0.001)和胆固醇(OR 40.31,95％ CI 9.97～70.64;P=0.009)为影响BaPWV的独立危险因素.结论 2型糖尿病患者BaPWV与HbA1c水平密切相关,将HbA1c控制在理想水平是降低大动脉硬化的手段之一.     

More impact of microalbuminuria on retinopathy than moderately reduced GFR among type 2 diabetic patients

OBJECTIVE

The current study aimed to investigate whether microalbuminuria or moderately decreased glomerular filtration rate (GFR) is a better predictor for the development and progression of retinopathy in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

Type 2 diabetic patients without cardiovascular diseases, malignancy, pregnancy, and acute intercurrent illness were enrolled between 1 August 2001 and 31 December 2002. All participants provided their detailed medical history and underwent an eye fundus examination. They were followed up in outpatient clinics, and serum creatinine, urinary albumin-to-creatinine ratio (UACR), and retinal photographs were followed up annually until 31 December 2009. The primary outcomes were development and progression of diabetic retinopathy and nephropathy. The secondary outcomes were cardiovascular events and all-cause mortality.

RESULTS

Among 487 participants, 81 subjects had normoalbuminuria and moderate renal impairment (baseline eGFR 30–59.9 mL/min/1.73 m²), and 106 subjects had microalbuminuria and baseline eGFR ≥60 mL/min/1.73 m². Patients with microalbuminuria and eGFR ≥60 mL/min/1.73 m² had a significantly greater risk for development and progression of diabetic retinopathy (HR 3.34 [95% CI 1.04–10.70]) compared with those with moderate renal impairment and normoalbuminuria after multivariate adjustment. Risks for renal outcome, cardiovascular events, and all-cause mortality were not significantly different between the two groups.

CONCLUSIONS

Microalbuminuria has a greater impact on predicting the development and progression of diabetic retinopathy compared with moderate decline in GFR among type 2 diabetic patients.Diabetic retinopathy is a highly specific vascular complication and a sight-threatening problem related to diabetes. Diabetic retinopathy is characterized by gradually progressive alterations in the retinal microvasculature, leading to retinal nonperfusion, increased vascular permeability, and pathologically intraocular proliferation of retinal vessels. Both diabetic retinopathy and nephropathy are microvascular complications of diabetes. With the retina and glomerulus, diabetes-specific microvascular disease is characterized by similar pathophysiologic features. Chronic hyperglycemia is the central initiating factor for all types of diabetic microvascular disease. In exposure to high plasma glucose, hyperglycemic damage is limited to some cell types. Endothelial cells develop intracellular hyperglycemia, since they cannot downregulate glucose transport (1). The common pathologic trait of diabetic microvascular disease is progressive narrowing and eventual occlusion of vascular lumina, subsequently leading to inadequate perfusion of the affected tissues. In the retina, diabetes induces programmed cell death of Muller and ganglion cells (2) and pericytes and endothelial cells (3). In the glomerulus, urinary protein loss and renal function decline are associated with widespread capillary occlusion and podocyte loss.Elevated urinary albumin excretion has been found to increase the risk of proliferative diabetic retinopathy (PDR) and is associated with a higher prevalence of PDR (4–8). Diabetic retinopathy is present in virtually all type 1 diabetic patients with nephropathy, whereas only 50–60% of type 2 diabetic patients with nephropathy have retinopathy (5). Accordingly, nephropathy and retinopathy are not concurrent in type 2 diabetes. Although the prevalence and risk factors for diabetic retinopathy in type 2 diabetes have been extensively investigated (6–8), there are little data addressing the issue of whether microalbuminuria or moderate decline of estimated glomerular filtration rate (eGFR) (30–59.9 mL/min/1.73 m²) is a competing risk factor for the development and progression of diabetic retinopathy. Therefore, the current study strived to investigate whether microalbuminuria or moderately decreased eGFR is a better predictor for the retinal outcome in a type 2 diabetic cohort.