Ethnic Differences in Glycemic Markers in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies have reported hemoglobin A_1c (HbA_1c) differences across ethnic groups that could limit its use in clinical practice. The authors of the A1C-Derived Average Glucose study have advocated to report HbA_1c in estimated average glucose (AG) equivalents. The aim of this study was to assess the relationships between HbA_1c and the mean of three 7-point self-monitored blood glucose (BG) profiles, and to assess whether estimated AG is an accurate measure of glycemia in different ethnic groups.

RESEARCH DESIGN AND METHODS

We evaluated 1,879 participants with type 2 diabetes in the DURABLE trial who were 30 to 80 years of age, from 11 countries, and, according to self-reported ethnic origin, were Caucasian, of African descent (black), Asian, or Hispanic. We performed logistic regression of the relationship between the mean self-monitored BG and HbA_1c, and estimated AG, according to ethnic background.

RESULTS

Baseline mean (SD) HbA_1c was 9.0% (1.3) (75 [SD, 14] mmol/mol), and mean self-monitored BG was 12.1 mmol/L (3.1) (217 [SD, 55] mg/dL). In the clinically relevant HbA_1c range of 7.0–9.0% (53–75 mmol/mol), non-Caucasian ethnic groups had 0.2–0.5% (2–6 mmol/mol) higher HbA_1c compared with Caucasians for a given BG level. At the mean self-monitored BG levels ≤11.6 mmol/L, estimated AG overestimated the actual average BG; at levels >11.6 mmol/L, estimated AG underestimated the actual BG levels.

CONCLUSIONS

For a given degree of glycemia, HbA_1c levels vary among different ethnic groups. Ethnicity needs to be taken into account when using HbA_1c to assess glycemic control or to set glycemic targets. Estimated AG is not a reliable marker for mean glycemia and therefore is of limited clinical value.The results of hemoglobin A_1c (HbA_1c) measurements are used to evaluate quality of glycemic control in individuals with diabetes mellitus (1). However, several studies have reported that HbA_1c levels may be significantly higher in non-Caucasian patients with diabetes for a given blood glucose (BG) range (2–4). It has become clear that HbA_1c levels not only depend on the long-term BG concentration (5–7) but also may be influenced by genetic factors (8–10) as well as environmental factors such as smoking and obesity (11).The authors of the A1C-Derived Average Glucose study proposed to translate HbA_1c into estimated average glucose (AG) equivalents for monitoring glycemic control (12). They asserted that this could facilitate the patient’s comprehension of the value of a given HbA_1c measurement and could be used instead of HbA_1c. However, the potential racial and ethnic differences in hemoglobin glycation (3) and the impact of hemoglobin variants and erythrocyte survival on the HbA_1c assay (13) suggest that estimated AG may be a biased estimate of mean self-monitored BG (SMBG), depending on the specific ethnic group.The aims of the current study were to analyze in the participants of the DURABLE trial the relationships between HbA_1c and mean SMBG across different ethnic groups with type 2 diabetes and to compare HbA_1c-derived estimated AG with mean SMBG to determine whether estimated AG is an accurate measure of glycemia.     

Hemoglobin A1c as a predictor of incident diabetes

OBJECTIVE

Several studies have suggested that HbA_1c levels may predict incident diabetes. With new recommendations for use of HbA_1c in diagnosing diabetes, many patients with HbA_1c results below the diagnostic threshold will be identified. Clinicians will need to categorize risk for a subsequent diabetic diagnosis in such patients. The objective of this study was to determine the ability of HbA_1c to predict the incidence of a diabetic diagnosis.

RESEARCH DESIGN AND METHODS

We performed a historical cohort study using electronic medical record data from two Department of Veterans Affairs Medical Centers. Patients (n = 12,589) were identified with a baseline HbA_1c <6.5% between January 2000 and December 2001 and without a diagnosis of diabetes. Patients (12,375) had at least one subsequent follow-up visit. These patients were tracked for 8 years for a subsequent diagnosis of diabetes.

RESULTS

During an average follow-up of 4.4 years, 3,329 (26.9%) developed diabetes. HbA_1c ≥5.0% carried a significant risk for developing diabetes during follow-up. When compared with the reference group (HbA_1c <4.5%), HbA_1c increments of 0.5% between 5.0 and 6.4% had adjusted odds ratios of 1.70 (5.0–5.4%), 4.87 (5.5–5.9%), and 16.06 (6.0–6.4%) (P < 0.0001). Estimates of hazard ratios similarly showed significant increases for HbA_1c ≥5.0%. A risk model for incident diabetes within 5 years was developed and validated using HbA_1c, age, BMI, and systolic blood pressure.

CONCLUSIONS

The incidence of diabetes progressively and significantly increased among patients with an HbA_1c ≥5.0%, with substantially expanded risk for those with HbA_1c 6.0–6.4%.HbA_1c is a well-established test to track long-term glucose control and the risk for developing microvascular complications in patients with diabetes (1). However, until recently, HbA_1c was not an accepted test for diagnosing diabetes because of concerns about both lower specificity and sensitivity compared with fasting plasma glucose (2). A number of threshold values that relate HbA_1c to a diabetic diagnosis have been proposed in the past (3–7), but none were broadly adopted. A recent report by an International Expert Committee (8) proposed that HbA_1c ≥6.5% on two repeated tests may be used to diagnose diabetes. These recommendations were subsequently accepted by the American Diabetes Association (9). Implementation of the recommendations will increase the number and frequency of HbA_1c tests obtained in patients at risk for diabetes. Indeed, the Expert Committee raised concerns about how to identify and manage higher risk individuals, as there is yet no accepted HbA_1c threshold value for initiating preventive strategies.Evidence suggests that clinicians have been using HbA_1c in the evaluation of patients without known diabetes in the absence of clearly accepted threshold values for establishing a diagnosis. As an example, in the Veterans Health Administration (VHA) in fiscal years 2006 and 2007 there were >500,000 patients without a prior diagnosis of diabetes who had HbA_1c tests—representing 37 and 39% of all patients having an HbA_1c test performed in those years (P.R.C., unpublished observations).To better understand the relationship between HbA_1c levels and the subsequent risk of diagnosed diabetes, we identified a cohort of patients without diabetes in whom an HbA_1c was obtained and tracked these individuals for up to 8 years for evidence of a diabetic diagnosis. We hypothesized that a baseline HbA_1c level has predictive information for the future development of diabetes and can be used to risk stratify patients. Our data confirm the continuum of risk associated with increasing levels of HbA_1c and also identify a HbA_1c threshold value, below which the risk is nominal.     

Incidence of Type 2 Diabetes Using Proposed HbA1c Diagnostic Criteria in the European Prospective Investigation of Cancer�CNorfolk Cohort: Implications for preventive strategies

OBJECTIVE

To evaluate the incidence and relative risk of type 2 diabetes defined by the newly proposed HbA_1c diagnostic criteria in groups categorized by different baseline HbA_1c levels.

RESEARCH DESIGN AND METHODS

Using data from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with repeat HbA_1c measurements, we estimated the prevalence of known and previously undiagnosed diabetes at baseline (baseline HbA_1c ≥6.5%) and the incidence of diabetes over 3 years. We also examined the incidence and corresponding odds ratios (ORs) by different levels of baseline HbA_1c. Incident diabetes was defined clinically (self-report at follow-up, prescribed diabetes medication, or inclusion on a diabetes register) or biochemically (HbA_1c ≥6.5% at the second health assessment), or both.

RESULTS

The overall prevalence of diabetes was 4.7%; 41% of prevalent cases were previously undiagnosed. Among 5,735 participants without diabetes at baseline (identified clinically or using HbA_1c criteria, or both), 72 developed diabetes over 3 years (1.3% [95% CI 1.0–1.5]), of which 49% were identified using the HbA_1c criteria. In 6% of the total population, the baseline HbA_1c was 6.0–6.4%; 36% of incident cases arose in this group. The incidence of diabetes in this group was 15 times higher than in those with a baseline HbA_1c of <5.0% (OR 15.5 [95% CI 7.2–33.3]).

CONCLUSIONS

The cumulative incidence of diabetes defined using a newly proposed HbA_1c threshold in this middle-aged British cohort was 1.3% over 3 years. Targeting interventions to individuals with an HbA_1c of 6.0–6.4% might represent a feasible preventive strategy, although complementary population-based preventive strategies are also needed to reduce the growing burden of diabetes.Type 2 diabetes is a major public health concern worldwide. An estimated 439 million people will have the disease by 2030 (1). It is possible to halve the incidence of type 2 diabetes among individuals at high risk through lifestyle and pharmacologic interventions (2–4). However, it is unlikely that population screening for impaired glucose tolerance using an oral glucose tolerance test (OGTT) is a feasible method of identifying those at high risk in clinical practice (5) because it is time- and resource-consuming and has poor reproducibility (6). If a measure of blood glucose were to be used to define the risk of developing diabetes, then it would seem logical to use the same test for diagnosis and informing treatment decisions (7).Glycated hemoglobin (HbA_1c) is a reliable measure of long-term glycemic exposure (8) that correlates well with the risk of microvascular and macrovascular complications of diabetes (9,10). It does not necessitate fasting or timed blood samples. Previous concerns regarding the standardization of assays have largely been resolved (11). Consequently, the American Diabetes Association (ADA) recently recommended that HbA_1c be included as a diagnostic test for diabetes, with a diagnostic threshold of ≥6.5% (12).To better estimate the burden of the disease and potential benefits of preventive interventions, it is necessary to have accurate data on incidence. Reported estimates of incidence in adult populations have varied considerably, from 2 to 25 per 1,000 person-years (13–16). However, many of the studies were restricted to high-risk populations (13) and defined diabetes using a clinical rather than a biochemical diagnosis (14). Fewer studies have investigated the incidence of diabetes based on longitudinal repeat blood glucose measurements in population-based samples (15,16), and none have examined diabetes incidence using repeated measures of HbA_1c.In this study we estimated the prevalence and incidence of diabetes defined using the newly proposed HbA_1c cutoff of 6.5% in a population-based British cohort. To inform the choice of appropriate HbA_1c thresholds to identify individuals at high risk to whom preventive interventions might be offered, we used data on longitudinal repeat HbA_1c values at baseline and after 3 years of follow-up to examine the incidence and relative risk of clinically diagnosed diabetes and diabetes defined using HbA_1c diagnostic criteria in groups defined by different baseline HbA_1c values.     

HbA1c and the Risks for All-Cause and Cardiovascular Mortality in the General Japanese Population: NIPPON DATA90

OBJECTIVE

Associations between HbA_1c and cardiovascular diseases (CVD) have been reported mainly in Western countries. It is not clear whether HbA_1c measurements are useful for assessing CVD mortality risk in East Asian populations.

RESEARCH DESIGN AND METHODS

The risk for cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. A total of 7,120 participants (2,962 men and 4,158 women; mean age 52.3 years) free of previous CVD were followed for 15 years. Adjusted hazard ratios (HRs) and 95% CIs among categories of HbA_1c (<5.0%, 5.0–5.4%, 5.5–5.9%, 6.0–6.4%, and ≥6.5%) for participants without treatment for diabetes and HRs for participants with diabetes were calculated using a Cox proportional hazards model.

RESULTS

During the study, there were 1,104 deaths, including 304 from CVD, 61 from coronary heart disease, and 127 from stroke (78 from cerebral infarction, 25 from cerebral hemorrhage, and 24 from unclassified stroke). Relations to HbA_1c with all-cause mortality and CVD death were graded and continuous, and multivariate-adjusted HRs for CVD death in participants with HbA_1c 6.0–6.4% and ≥6.5% were 2.18 (95% CI 1.22–3.87) and 2.75 (1.43–5.28), respectively, compared with participants with HbA_1c <5.0%. Similar associations were observed between HbA_1c and death from coronary heart disease and death from cerebral infarction.

CONCLUSIONS

High HbA_1c levels were associated with increased risk for all-cause mortality and death from CVD, coronary heart disease, and cerebral infarction in general East Asian populations, as in Western populations.Since the association between HbA_1c and microangiopathy was established in patients with diabetes, HbA_1c has been used for not only the determination of glucose control among patients with diabetes but also the diagnosis of diabetes (1). Measurement of HbA_1c is also recommended for cardiovascular risk assessment in asymptomatic adults without a diagnosis of diabetes (2) because the association between HbA_1c and the risk for cardiovascular disease (CVD) in general populations has been reported, mainly from Western countries (3–10).There have been only a few studies regarding the associations between HbA_1c and CVD in Asian populations (11–13). Furthermore, these studies were from Japan, and HbA_1c measurements were expressed mainly using Japan Diabetes Society (JDS) values rather than National Glycohemoglobin Standardization Program (NGSP) values; thus, we cannot compare these results with those from Western countries. Recently, the JDS provided an equation for the conversion from HbA_1c (JDS) to HbA_1c (NGSP) units (14), which allows a comparison of the results from Japanese studies and previous studies from Western countries.CVD in East Asian people is characterized by a higher rate of stroke and lower rate of coronary heart disease compared with CVD in Western populations (15). In one previous study evaluating the association between HbA_1c and incidence of stroke in Japan, ischemic stroke, but not hemorrhagic stroke, was associated with HbA_1c in Asian populations (12). Other studies from Japan (11,13) showed a significant association between HbA_1c and CVD; however, the number of participants and CVD events were too small to calculate the risk by subtype of CVD, such as coronary heart disease, stroke, cerebral infarction, and cerebral hemorrhage.The current study was performed to examine the association between HbA_1c using NGSP values and the risks for death from all causes and from CVD (coronary heart disease, cerebral infarction, and cerebral hemorrhage) in a 15-year cohort study of representative Japanese men and women randomly selected from the overall Japanese population.     

Hemoglobin A1c and mean glucose in patients with type 1 diabetes: analysis of data from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial

OBJECTIVE

To determine the relationship between mean sensor glucose concentrations and hemoglobin A_1c (HbA_1c) values measured in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications laboratory at the University of Minnesota in a cohort of subjects with type 1 diabetes from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial.

RESEARCH DESIGN AND METHODS

Near-continuous glucose sensor data (≥4 days/week) were collected for 3 months before a central laboratory–measured HbA_1c was performed for 252 subjects aged 8–74 years, the majority of whom had stable HbA_1c values (77% within ±0.4% of the patient mean).

RESULTS

The slope (95% CI) for mean sensor glucose concentration (area under the curve) versus a centrally measured HbA_1c was 24.4 mg/dL (22.0–26.7) for each 1% change in HbA_1c, with an intercept of −16.2 mg/dL (−32.9 to 0.6). Although the slope did not vary with age or sex, there was substantial individual variability, with mean sensor glucose concentrations ranging from 128 to 187 mg/dL for an HbA_1c of 6.9–7.1%. The root mean square of the errors between the actual mean sensor glucose concentration versus the value calculated using the regression equation was 14.3 mg/dL, whereas the median absolute difference was 10.1 mg/dL.

CONCLUSIONS

There is substantial individual variability between the measured versus calculated mean glucose concentrations. Consequently, estimated average glucose concentrations calculated from measured HbA_1c values should be used with caution.Hemoglobin A_1c (HbA_1c) is a time-honored gold standard measure of overall diabetes control, and HbA_1c values serve as the targets for diabetes management (1). The chemistry of glycation predicts a straightforward relationship between mean glucose concentrations and HbA_1c values over the average lifespan of a patient’s red cells (2). Because the Diabetes Control and Complications Trial (DCCT) (3) demonstrated that improved glycemic control, measured as HbA_1c, decreased the risk of long-term diabetic complications, most HbA_1c measurements have been standardized to the DCCT values via the National Glycohemoglobin Standardization Program. Current HbA_1c assays can be fast, precise, and accurate (4).Determining the true relationship between mean glucose concentrations and HbA_1c values has been hampered by limitations in accessing mean glucose concentrations in groups of patients over a period of ≥3 months. Discrete glucose measurements obtained infrequently over the day often fail to capture the true magnitude of glycemic excursions commonly found in patients with type 1 diabetes (5) and underestimate the extent and frequency of nocturnal hypoglycemia (6).In contrast, the recently completed Juvenile Diabetes Research Foundation (JDRF)-sponsored continuous glucose monitoring (CGM) trial provided data to closely examine the relationship between mean glucose concentrations, measured in a near-continuous fashion for 3 months, and the subsequent HbA_1c values measured centrally in the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) laboratory in patients with type 1 diabetes.     

Skin intrinsic fluorescence is associated with hemoglobin A(1c )and hemoglobin glycation index but not mean blood glucose in children with type 1 diabetes

OBJECTIVE

To evaluate the relationship between skin advanced glycation end products (sAGEs) with mean blood glucose (MBG), hemoglobin A_1c (HbA_1c), and MBG-independent, between-patient differences in HbA_1c among children with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Children aged 5 to 20 years with type 1 diabetes of at least 1 year duration participated. At a clinic visit, sAGE was estimated noninvasively by measurement of skin intrinsic fluorescence (SIF). SIF data were adjusted to correct for variation in skin pigmentation. MBG-independent, between-patient differences in HbA_1c were examined by statistically controlling HbA_1c for MBG or alternatively by use of a hemoglobin glycation index (HGI). Results were similar whether HbA_1c, MBG, and HGI were analyzed as single values from the time of the SIF examination visit or as the mean values from all available visits of the patient.

RESULTS

HbA_1c was correlated with MBG (r = 0.5; P < 0.001; n = 110). HbA_1c and HGI, but not MBG, were statistically associated with SIF after adjustment for age, duration of diabetes, race, sex, and BMI z-score. SIF increased with age and duration of diabetes and was higher in girls than boys.

CONCLUSIONS

sAGE levels estimated by SIF increase with age, duration of diabetes, and female sex. sAGE is correlated with MBG-independent biological variation in HbA_1c, but not with MBG itself. These results suggest that factors besides MBG that influence HbA_1c levels also contribute to accumulation of sAGE.Chronically elevated blood glucose levels are associated with the development of serious microvascular complications in patients with type 1 diabetes (1). One mechanism for development of complications is through enhanced nonenzymatic glycation of important proteins facilitated by hyperglycemia (2,3). As conventionally understood, the formation of glycated proteins is dependent on glucose concentration. For example, over short periods of time glucose can reversibly attach to hemoglobin and other proteins to form a Schiff base. With more time, the Schiff base can chemically rearrange in a nearly irreversible process to form an Amadori product, glycated hemoglobin (HbA_1c) (4). Clinically, HbA_1c is highly correlated with mean blood glucose (MBG) levels from the preceding weeks and months (5), and both have been shown to be predictors for the development and progression of microvascular diabetes complications (1,6).Other proteins besides hemoglobin are also susceptible to nonenzymatic glycation. Structural proteins have a longer life span than the 120 days typical of hemoglobin. Over weeks to months, the glycated moieties of long-lived proteins can form covalent complexes known as advanced glycation end products (AGEs). Formation of AGEs in tissues causes alteration in the normal structure and function of the involved proteins, which can elicit pathological changes (2,3). Tissue burden of AGEs has been assessed by direct chemical measurement of these substances from biopsy samples. The Epidemiology of Diabetes Interventions and Complications (EDIC) study found that AGE levels from biopsied skin were predictive for the progression of microvascular complications in patients with type 1 diabetes (7,8). Furthermore, these investigators found that HbA_1c levels were correlated with skin AGE burden (8). Thus concentrations of an early-stage, shorter-lived glycation product, HbA_1c, are associated with the amount of AGEs accumulated in tissue over time. Thus both HbA_1c and AGEs appear to be predictors for development and progression of microvascular diabetes complications (8).The high correlation between HbA_1c and MBG has led to the more easily measurable HbA_1c becoming a widely used method to estimate glycemic control and guide therapy in patients with diabetes. In addition to MBG, HbA_1c levels have been shown to be influenced by MBG-independent factors, which are manifested by consistent between-individual differences in HbA_1c level regardless of the preceding background MBG (9,10). Previously, we developed a hemoglobin glycation index (HGI) to quantify such between-patient differences from readily available clinical data (9–11). We found that MBG-independent between-patient HbA_1c differences are predictive for development of diabetes complications (10). As HbA_1c and MBG are highly correlated, we hypothesized that tissue AGEs would be associated with both MBG from patient self-monitored capillary blood samples as well as corresponding HbA_1c levels. Furthermore, we hypothesized that MBG-independent differences in HbA_1c would also be associated with tissue accumulation of AGEs.Recently, methods have been developed to noninvasively estimate skin AGEs in vivo by measurement of skin intrinsic fluorescence (SIF) (12–15). SIF is highly correlated with AGEs assayed directly from skin biopsy (15). The technology can rapidly and noninvasively estimate skin AGEs from large numbers of individuals and thus is particularly suitable for use in children. We used the SIF technology to test our hypotheses in a well-characterized group of children with type 1 diabetes.     

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.     

Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes

OBJECTIVE

To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A_1c (HbA_1c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients.

RESULTS

The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA_1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference −0.27%; 95% CI −0.47 to −0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009).

CONCLUSIONS

Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA_1c in children and adults with type 1 diabetes.The benefits of intensive treatment of type 1 diabetes, established almost 20 years ago (1), are difficult to achieve, despite the increased use of insulin analogs and insulin pumps, with only a minority of patients maintaining their glycated hemoglobin A_1c (HbA_1c) within the target range (2). Intensive insulin treatment and lower HbA_1c increase exposure to hypoglycemia (3,4). The risk of hypoglycemia is even higher in children and adolescents (5,6) and increases with the duration of diabetes (7). Frequent hypoglycemia is associated with hypoglycemia unawareness (8,9), which may in turn lead to reduced adherence to therapeutic decisions (10). Finally, hypoglycemia may be associated with permanent damage to the central nervous system (11) and may permanently influence cognitive functions in children (12) but not in adults (13).Recently, devices for real-time continuous glucose monitoring have been introduced to aid self-management of glycemic control and have been shown to improve HbA_1c levels in people with type 1 diabetes (14–17). In clinical practice recommendations, it has also been suggested that continuous glucose monitoring is especially useful in patients with hypoglycemia unawareness and/or frequent episodes of hypoglycemia (18). However, the hypoglycemia preventive effect of continuous glucose monitoring has not been established. Therefore, we designed a randomized, controlled, multicenter clinical trial to evaluate the effect of continuous glucose monitoring on hypoglycemia in children and adults with type 1 diabetes.     

Real-Time Continuous Glucose Monitoring Among Participants in the T1D Exchange Clinic Registry

OBJECTIVE

To assess the frequency of continuous glucose monitoring (CGM) device use, factors associated with its use, and the relationship of CGM with diabetes outcomes (HbA_1c, severe hypoglycemia [SH], and diabetic ketoacidosis [DKA]).

RESEARCH DESIGN AND METHODS

Survey questions related to CGM device use 1 year after enrollment in the T1D Exchange clinic registry were completed by 17,317 participants. Participants were defined as CGM users if they indicated using real-time CGM during the prior 30 days.

RESULTS

Nine percent of participants used CGM (6% of children <13 years old, 4% of adolescents 13 to <18 years, 6% of young adults 18 to <26 years, and 21% of adults ≥26 years). CGM use was more likely with higher education, higher household income, private health insurance, longer duration of diabetes, and use of insulin pump (P < 0.01 all factors). CGM use was associated with lower HbA_1c in children (8.3% vs. 8.6%, P < 0.001) and adults (7.7% vs. 7.9%, P < 0.001). In adults, more frequent use of CGM (≥6 days/week) was associated with lower mean HbA_1c. Only 27% of users downloaded data from their device at least once per month, and ≤15% of users reported downloading their device at least weekly. Among participants who used CGM at baseline, 41% had discontinued within 1 year.

CONCLUSIONS

CGM use is uncommon but associated with lower HbA_1c in some age-groups, especially when used more frequently. Factors associated with discontinuation and infrequent use of retrospective analysis of CGM data should be considered in developing next-generation devices and education on CGM use.Real-time continuous glucose monitoring (CGM) has the potential to aid patients and providers in both the daily management of blood glucose levels and retrospective review of glucose patterns. Multicenter randomized controlled trials and meta-analyses have shown that CGM is associated with improved glycemic control, achievement or maintenance of target glycated hemoglobin (HbA_1c) levels, and reduction of severe hypoglycemia (SH) events in adults (1–7). For children in the JDRF-sponsored multicenter trial, which randomized patients to CGM or self-monitoring of blood glucose (SMBG), there was a larger percentage of subjects 8–14 years old using CGM who achieved at least a 10% decrease in HbA_1c and a target HbA_1c <7%, compared with children using SMBG (6). Some studies have shown that near-daily (as opposed to occasional) use of CGM is associated with better glycemic control, as measured by HbA_1c (5,8), leading to a practice guideline recommending CGM for adults who are able to use it at least 6 days a week (9). In clinical trials of CGM versus SMBG use in children, those who used near-daily CGM had a greater reduction in HbA_1c (−0.3 to −0.8%) and a greater percentage of blood glucose values in target range compared with those who used it less frequently (10–12). Other studies in children have reported reduced time spent in hypoglycemia with near-daily use (reviewed in 11), but such frequent use is more difficult to achieve in pediatric patients. In addition, subjects and their caregivers who participated in randomized CGM trials have reported high satisfaction and no negative impact on quality of life with CGM (12,13). Although these potential benefits of CGM are known, the actual rates of CGM device use and clinical outcomes of use in real-world clinical settings have not been well studied and few large studies have investigated the specific factors that influence CGM use outside of controlled trials.The T1D Exchange Clinic Network (14) registry database provides the opportunity to understand the characteristics of CGM device use in a large clinic-based population. In this study, we report the frequency of CGM device use and the demographic and clinical factors associated with its use in this clinic-based cohort. We also investigated the relationship of CGM with diabetes outcomes including HbA_1c, SH events, and diabetic ketoacidosis (DKA). Finally, data were obtained regarding the attributes of CGM that participants identified as the most useful and most challenging, as well as why CGM is tried but discontinued. Understanding the factors that influence use of CGM in this registry can help optimize the use of this technology in clinical diabetes care.     

Does Glucose Variability Influence the Relationship Between Mean Plasma Glucose and HbA1c Levels in Type 1 and Type 2 Diabetic Patients?

OBJECTIVE

The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between HbA_1c and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the association of several glucose variability indices and the MPG-HbA_1c relationship.

RESEARCH DESIGN AND METHODS

Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self-monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-HbA_1c relationship.

RESULTS

GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-HbA_1c relationship in type 1 diabetic patients so that high GV led to a higher HbA_1c level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the HbA_1c level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency.

CONCLUSIONS

In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with HbA_1c. This effect is more pronounced at higher HbA_1c levels. However, the impact of GV on the HbA_1c level in type 1 diabetes is modest, particularly when HbA_1c is close to the treatment target of 7%.Since the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) (1,2) established the relationship between HbA_1c and the development of long-term diabetes complications, HbA_1c has become the key monitoring tool in diabetes management.During the lifetime of the erythrocyte, hemoglobin (Hb) is gradually glycated. The proportion of the glycated sites, HbA_1c, within the erythrocyte increases throughout its life span and reflect the exposure to mean blood glucose (MBG) levels during the preceding 2–3 months (3). This nonenzymatic posttranslational modification is relatively slow. In vivo and in vitro studies have shown that HbA_1c levels are directly proportional to the time-averaged concentration of glucose during the erythrocyte’s life span (3–6). Given the kinetics of glycation, brief periods of hyperglycemia should not have a major impact on HbA_1c levels (7–9).However, increased glycated protein levels are documented in some nondiabetic pathological states. So, hyperglycemia is not the complete answer to the etiology of increased early glycated products in nondiabetic conditions. A common denominator is oxidative stress. It has been hypothesized that oxidative stress either via increasing reactive oxygen species or by depleting the antioxidants may modulate the genesis of early glycated proteins in vivo (10,11). Hyperglycemia stimulates oxidative stress (12) and glucose variability; in particular, postprandial glucose excursions have been regarded as potentially deleterious as a result of, among other factors, their association with the increase of oxidative stress (13). Therefore, glucose variability (GV) could influence the glycation of HbA_1c.Previous studies have examined whether the relationship between mean plasma glucose (MPG) levels and HbA_1c is influenced by glucose variability and found no or minimal influence (10,14,15). However, these studies used limited self-monitoring of blood glucose (SMBG) data to assess mean glucose levels and variability in relatively small numbers of measurements. These methods could underestimate glycemic excursions. Continuous glucose monitoring (CGM) provides a more complete view of glycemic excursions, including the duration and frequency of the excursions, and allows calculation of features of GV. Our aim was to examine the influence of GV on the MPG-HbA_1c relationship in the A1C-Derived Average Glucose (ADAG) study.     

No Ethnic Differences in the Association of Glycated Hemoglobin With Retinopathy: The National Health and Nutrition Examination Survey 2005–2008

OBJECTIVE

Current recommendations for the use of hemoglobin A_1c (HbA_1c) in diabetes screening and diagnosis aim to identify those at greatest risk for diabetic microvascular complications. However, there is current controversy regarding the clinical implications of ethnic differences in HbA_1c values. The objective of this study was to determine whether the association between HbA_1c and retinopathy differs by ethnic group in a representative sample of U.S. adults.

RESEARCH DESIGN AND METHODS

The study was a cross-sectional analysis of 2,945 non-Hispanic white, 1,046 non-Hispanic black, and 1,231 Hispanic American participants aged ≥40 years from the 2005–2008 National Health and Nutrition Examination Survey.

RESULTS

Among nondiabetic adults, the mean HbA_1c was 5.5% in non-Hispanic whites, 5.7% in non-Hispanic blacks, and 5.6% in Hispanic Americans. Among those with diagnosed diabetes, mean HbA_1c was 6.9% in non-Hispanic whites, 7.5% in non-Hispanic Blacks, and 7.7% in Hispanic Americans. Overall, non-Hispanic blacks had the highest prevalence of retinopathy. In multivariable logistic models, HbA_1c clinical categories were strongly associated with prevalent retinopathy. However, the magnitude of the association did not differ by ethnic group (all P values for interaction ≥ 0.7). Similar results were observed with HbA_1c modeled continuously (per one percentage point) and stratified by diabetes status (all P for interactions > 0.3).

CONCLUSIONS

We observed no ethnic differences in the association of HbA_1c with retinopathy. These data do not support ethnic-specific cut points for HbA_1c for diagnosis or screening of diabetes mellitus.Hemoglobin A_1c (HbA_1c) was recently recommended for use in the diagnosis of diabetes (1,2). Recommended clinical categories for diabetes diagnosis using HbA_1c largely are based on the established association of HbA_1c with prevalent retinopathy (3–6) and evidence from clinical trials demonstrating that lowering HbA_1c can reduce microvascular complications (7). Nonetheless, recent studies document persistent ethnic differences in HbA_1c values (8–12), raising concerns that the performance of HbA_1c may differ in certain subpopulations and that new recommendations for the use of HbA_1c for diagnosis might be problematic in individuals of non-European ancestry (13–19). Data about the association of HbA_1c with clinical outcomes in different ethnic groups are critical to inform this debate.The objective of this study was to characterize the ethnic-specific associations between HbA_1c and retinopathy in the U.S. population aged 40 years and older using data from the 2005–2008 National Health and Nutrition Examination Survey (NHANES) and to formally test for effect modification by ethnicity.     

Longitudinal trajectories of HbA1c and fasting plasma glucose levels during the development of type 2 diabetes: the Toranomon Hospital Health Management Center Study 7 (TOPICS 7)

OBJECTIVE

To describe the trajectory of HbA_1c and glucose concentrations before the diagnosis of diabetes.

RESEARCH DESIGN AND METHODS

The study comprised 1,722 nondiabetic Japanese individuals aged 26–80 years. Fasting plasma glucose (FPG) and HbA_1c were measured annually for a mean of 9.5 (SD 1.8) years.

RESULTS

Diabetes occurred in 193 individuals (FPG ≥7.0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA_1c ≥6.5%). Mean HbA_1c values were >5.6% each year before diagnosis in diabetes cases. Mean HbA_1c (5.69% [95% CI 5.50–5.88]) was higher in the 21 individuals who developed diabetes 10 years after the baseline examination than in nondiabetic individuals after 10 years (5.27% [5.25–5.28]). From 3 years to 1 year prediagnosis, HbA_1c increased 0.09% (SE 0.01)/year, reaching 5.90% (5.84–5.96) 1 year prediagnosis. In the entire group, marked increases in HbA_1c of 0.3% (SE 0.05%)/year and FPG of 0.63 (0.07) mmol/L/year predicted diabetes.

CONCLUSIONS

HbA_1c trajectory increased sharply after gradual long-term increases in diabetic individuals.Trajectories of plasma glucose concentrations, insulin resistance, and insulin secretion to reflect the pathogenesis of type 2 diabetes were studied (1–8). Although HbA_1c is used to diagnose diabetes or indicate a prediabetic state in some countries (9), the long-term trajectory of HbA_1c before diabetes is little known. We retrospectively examined 10-year longitudinal data on apparently healthy Japanese individuals to investigate prediabetic changes in HbA_1c and compare such changes with those of fasting plasma glucose (FPG).     

Glycemic Control and Blood Glucose Monitoring Over Time in a Sample of Young Australians With Type 1 Diabetes: The role of personality

OBJECTIVE

To determine whether personality traits (conscientiousness, agreeableness, emotional regulation, extraversion, and openness to experience) are associated with glycemic control and blood glucose monitoring behavior, and change or stability of these outcomes over time, in young people with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A 3-year longitudinal study was conducted using data from 142 individuals with type 1 diabetes, 8–19 years of age. Personality was assessed at baseline using the Five-Factor Personality Inventory for Children. Data relating to glycemic control (HbA_1c) and frequency of blood glucose monitoring (based on meter memory) were collected annually. Relationships between personality traits and HbA_1c and monitoring frequency were examined using regression models and mixed-design ANOVA.

RESULTS

Three of the Five-Factor domains were independently associated with glycemic control. Individuals high in conscientiousness and agreeableness had a lower and more stable HbA_1c across the 3-year study period. In contrast, the HbA_1c of individuals scoring low on these traits was either consistently worse or deteriorated over time. Low or high emotional regulation scores were also associated with worse glycemic control. By the third year, these domains, together with initial HbA_1c, accounted for 39% of HbA_1c variance. Conscientiousness was the only personality factor associated with blood glucose monitoring behavior.

CONCLUSIONS

Results of this study underline the importance of personality in contributing to diabetes outcomes. Attention to a young person’s personality, and appropriate tailoring of diabetes management to ensure an individualized approach, may help to optimize diabetes outcomes.In Australia, and many other countries, a large proportion of young people with diabetes are not reaching glycemic targets (1–6). This is likely to have life-long consequences. Indeed, those subjects who were randomized to the conventional treatment arm of the Diabetes Control and Complications Trial (7) and who had an average HbA_1c of 9.1% during the course of the study continued to develop significantly more micro- and macrovascular complications compared with the intensive group when followed up in the Epidemiology of Diabetes Interventions and Complications study. This occurred despite the rapid convergence of mean HbA_1c between the groups at the end of the active study phase (8).While there are many factors that contribute to suboptimal control, there is mounting evidence that an individual’s personality may play an important role. Several studies in the late 1980s showed that personality traits could account for substantial variability in glycemic control in school-aged children (9,10). However, there has been increasing complexity in treatment regimens since that time. For example, current treatment now involves multiple daily injections or insulin pump therapy. Today, therefore, young people and their families are required to make more complex medical decisions on a daily basis.The role of personality in these new treatment contexts is not well-understood. Personality can be understood in terms of the Five-Factor model. The Five-Factor model states that there are five broad, independent, and stable dimensions that make up an individual’s personality (11). These factors are termed conscientiousness, agreeableness, emotional regulation, extraversion, and openness to experience. Conscientiousness refers to an individual’s tendency to be reliable, perseverant, and self-disciplined. Agreeableness refers to one’s tendency to be empathetic, considerate, friendly, and helpful. Emotional regulation refers to a person’s capability to regulate their emotional responses to their environment and others. Extraversion refers to an individual’s tendency to be gregarious, assertive, and seek out social situations. Openness refers to one’s tendency to be imaginative, sensitive, and have intellectual curiosity.Recent work by Vollrath et al. (12) suggests that personality, as measured using the Five-Factor model, influences glycemic control in the first 2 years following diagnosis of type 1 diabetes. In particular, higher levels of conscientiousness and agreeableness appear to have a positive influence on management of blood glucose values, while moderate levels of emotional regulation also appear to be protective (12). Further studies are needed to confirm these relationships between personality and glycemic control and to determine whether this is ameliorated by duration of diabetes. Studies are also needed to examine the role of personality in terms of self-care behavior.Accordingly, this study was designed to answer two research questions. 1) Are Five-Factor model personality traits associated with a young person’s glycemic control, as measured by HbA_1c, and their frequency of self-monitoring of blood glucose (SMBG)? 2) Are these traits associated with change or stability in HbA_1c and SMBG over time?     

Elevated HbA1c and Fasting Plasma Glucose in Predicting Diabetes Incidence Among Older Adults: Are two better than one?

OBJECTIVE

To determine which measures—impaired fasting glucose (IFG), elevated HbA_1c, or both—best predict incident diabetes in older adults.

RESEARCH DESIGN AND METHODS

From the Health, Aging, and Body Composition study, we selected individuals without diabetes, and we defined IFG (100–125 mg/dL) and elevated HbA_1c (5.7–6.4%) per American Diabetes Association guidelines. Incident diabetes was based on self-report, use of antihyperglycemic medicines, or HbA_1c ≥6.5% during 7 years of follow-up. Logistic regression analyses were adjusted for age, sex, race, site, BMI, smoking, blood pressure, and physical activity. Discrimination and calibration were assessed for models with IFG and with both IFG and elevated HbA_1c.

RESULTS

Among 1,690 adults (mean age 76.5, 46% men, 32% black), 183 (10.8%) developed diabetes over 7 years. Adjusted odds ratios of diabetes were 6.2 (95% CI 4.4–8.8) in those with IFG (versus those with fasting plasma glucose [FPG] <100 mg/dL) and 11.3 (7.8–16.4) in those with elevated HbA_1c (versus those with HbA_1c <5.7%). When FPG and HbA_1c were considered together, odds ratios were 3.5 (1.9–6.3) in those with IFG only, 8.0 (4.8–13.2) in those with elevated HbA_1c only, and 26.2 (16.3–42.1) in those with both IFG and elevated HbA_1c (versus those with normal FPG and HbA_1c). Addition of elevated HbA_1c to the model with IFG resulted in improved discrimination and calibration.

CONCLUSIONS

Older adults with both IFG and elevated HbA_1c have a substantially increased odds of developing diabetes over 7 years. Combined screening with FPG and HbA_1c may identify older adults at very high risk for diabetes.Impaired fasting glucose (IFG) (100–125 mg/dL) has been traditionally used for identifying persons at high risk for the subsequent development of diabetes in the U.S. Recent guidelines have additionally endorsed the use of HbA_1c 5.7–6.4% to identify those at risk (1). However, multiple studies, including one conducted among older persons (2), suggest that HbA_1c may identify different individuals at risk for diabetes than traditional glucose measures (3–6). Although several recent investigations confirm that HbA_1c is strongly predictive of future diabetes in predominantly middle-aged populations (7–10), less is known about how well HbA_1c identifies older persons at risk for diabetes.Despite the high prevalence of type 2 diabetes in the elderly (10.9 million Americans in 2010) and the high incidence (390,000 new cases in 2010) of late-onset type 2 diabetes (>65 years) (11,12), there are few specific studies on prediction of diabetes in this group. One such study, based on an earlier Health, Aging, and Body Composition (Health ABC) analysis, developed a prediction rule for diabetes development, which included several factors: advanced age, female sex, elevated fasting plasma glucose (FPG), and triglyceride levels (13). However, HbA_1c was not examined as a potential predictor. In the Cardiovascular Health Study of men and women ≥65 years of age, BMI, waist-to-hip ratio, and weight gain were associated with a higher risk of diabetes, but the impact of glycemic measures on diabetes was not specifically examined (14). An Italian study of older adults (age 65–84 years) found that the combination of abnormal FPG (defined using World Health Organization [WHO] criteria: 110 to <126 mg/dL), increased waist circumference, and HbA_1c ≥7.0% increased the probability of incident diabetes roughly 14-fold (15). However, neither a direct comparison of current prediabetes categories (based upon FPG and HbA_1c) for prediction of diabetes nor an analysis of the utility of combined testing has previously been conducted in this population.We therefore evaluated the odds for diabetes based upon baseline IFG and elevated HbA_1c among the participants of the longitudinal Health ABC study. We directly compared FPG- and HbA_1c-based criteria for predicting the eventual development of diabetes, and we evaluated the utility of combined testing for identifying older persons who develop diabetes. Since HbA_1c values are consistently higher in blacks compared with whites (3,16), we additionally explored race differences in diabetes prediction.     

Efficacy of Metabolic and Psychological Screening for Mood Disorders Among Children With Type 1 Diabetes

OBJECTIVE

To compare the diagnostic accuracy and time expenditure of screening models based on glycated hemoglobin (HbA_1c) level and psychometric measures for mood disorder (MD) among children with type 1 diabetes.

RESEARCH DESIGN AND METHODS

With semistructured clinical interviews (Schedule for Affective Disorders and Schizophrenia for Children–Present and Lifetime version, 120 min/patient) as a reference for diagnosing MD, including major depressive disorder (MDD), we tested 163 subjects, aged 8 to 18 years, with type 1 diabetes. We evaluated four screening approaches: 1) Children’s Depression Inventory (CDI) at 30 min/patient, 2) HbA_1c level, 3) HbA_1c level plus CDI, and 4) HbA_1c level plus Children''s Depression Rating Scale (CDRS) at 40 min/patient. These tests were conducted with all participants, and the total time expenditure for all four approaches was calculated as the total time needed to implement successfully the screening for MD or MDD in the center.

RESULTS

HbA_1c performed on par with individual psychometric tests in diagnosing MD or MDD. The HbA_1c plus CDRS model was the best screening procedure for both MD and MDD, with diagnostic thresholds for HbA_1c established at 8.7% and 9.0%, respectively. Cutoff points for CDRS assessed after filtering by HbA_1c were 26 (MD) and 30 (MDD) points. Center-wide application of this procedure would result in an 83% reduction of the examination time necessary for the psychiatrist for MD screening and a 91% reduction for MDD screening, as compared with standard screening with CDI.

CONCLUSIONS

Use of HbA_1c level followed by CDRS is a time-efficient procedure to screen for MD in children with type 1 diabetes.Diabetes is a risk factor for comorbid psychiatric disorders among children. During a 10-year observation period, nearly half of prospectively evaluated children with type 1 diabetes met diagnostic criteria for psychiatric comorbidity, with major depressive disorder (MDD) showing the highest prevalence (27%) (1). Psychiatric comorbidity leads to nonadherence, lower quality of life, poor metabolic control, and resultant diabetes complications (2–5). Mood disorders (MDs) are of particular importance because of the increased intensity of depressive symptoms. Their presence, as confirmed by a dedicated screening tool, was associated with a 2.5-fold increased risk of hospitalization for diabetic ketoacidosis in youth with type 1 diabetes (6). Identification of patients with MDs should therefore be considered an important aspect of pediatric diabetes care. American Diabetes Association guidelines for children and adolescents with type 1 diabetes include routine screening for psychiatric disorders among youth who do not have achievement of treatment goals or who experience recurrent diabetic ketoacidosis. Routine annual screening for depression should be performed for all patients >10 years old (7). The diabetic care team, which typically evaluates a patient several times per year and has access to medical records and family information, is well-positioned to observe symptoms of psychiatric disorders (8); however, recognition of depressive symptoms requires skill, careful attention, and sufficient time for individualized assessment.Whereas the U.S. Preventive Services Task Force recommends that primary care clinicians screen adolescents (9), the International Society for Pediatric and Adolescent Diabetes states that this screening should be performed by mental health professionals (10). The screening itself may be time-consuming and costly and it may require the assistance of dedicated, specialized personnel. We hypothesized that routine measurements of glycated hemoglobin (HbA_1c) levels could be used as first-line screening for MDs in children with diabetes. Such a combined psychological and metabolic screening procedure could capitalize on the uniqueness of pediatric diabetic care and reduce the projected time expenditure by implementing psychometric tools on a center-wide scale. The study was an attempt to estimate the efficiency and required time expenditure of initial screening composed of a combination of psychometric tools and HbA_1c and to establish the most effective model which could be feasibly introduced to routine pediatric diabetologic practice.     

Self-Monitoring of Blood Glucose in Noninsulin-Using Type 2 Diabetic Patients: It is time to face the evidence

Given the importance of glycemic control in the development of diabetes complications, the plethora of tools now available to monitor the day-to-day trends in glycemia is remarkable. In this regard, self-monitoring of blood glucose (SMBG) has been considered a key component of patient management. Arguably, there remains almost universal agreement that SMBG should be available to all diabetic patients regardless of current treatment strategy. However, recently there have been reports that have challenged the current paradigm that all patients should use SMBG and concluded that SMBG for type 2 diabetic patients not on insulin may not be beneficial on glycemic control and must be weighed against the expense and inconvenience. In this two-part point-counterpoint narrative, Malanda et al. and Polonsky and Fisher take opposing views on the utility of SMBG to be valuable for individuals with type 2 diabetes not using insulin. In the narrative below, Malanda et al. suggest that the evidence for potentially beneficial SMBG-induced effects on glycemic control, hypoglycemic periods, and potential harms in type 2 diabetic patients who are not treated with insulin does not justify the use of SMBG. Moreover, the use of SMBG is associated with huge costs, which should be better redirected to effective strategies to improve health for this category of patients.—William T. Cefalu, md Editor in Chief, Diabetes CareSelf-monitoring of blood glucose (SMBG) is considered a key component of the treatment regimen in patients with type 2 diabetes using insulin (1). There is almost universal agreement that SMBG should be available to all diabetic patients. Even for patients not using insulin, the use of SMBG is widely taken up in clinical practice guidelines (2) and is accepted as a part of their diabetes management.SMBG is used as an early warning to detect or confirm hypoglycemia and to improve patients’ recognition of severe hyperglycemia. Given that real-time data on blood glucose levels reflects the influence of physical activity and diet, SMBG has the potential to help patients better understand the impact of lifestyle on glycemic control (1). Furthermore, information derived from consecutive series’ of SMBG measurements could be of use for a treating physician to modify the glucose-lowering treatment. Despite these potential benefits, there is a limited evidence base for an effect of SMBG on hemoglobin A_1c (HbA_1c) in type 1 (3) and type 2 diabetic patients using insulin (4). We have summarized and labeled the available evidence of an effect of SMBG on HbA_1c and hypoglycemia in patients using insulin (type 1 and type 2 diabetes) and patients not using insulin (type 2 diabetes) using a grading system modeled after existing methods (Open in a separate window     

Hemoglobin A1c as a screen for previously undiagnosed prediabetes and diabetes in an acute-care setting

OBJECTIVE

Hemoglobin A_1c (HbA_1c) is recommended for identifying diabetes and prediabetes. Because HbA_1c does not fluctuate with recent eating or acute illness, it can be measured in a variety of clinical settings. Although outpatient studies identified HbA_1c-screening cutoff values for diabetes and prediabetes, HbA_1c-screening thresholds have not been determined for acute-care settings. Using follow-up fasting blood glucose (FBG) and the 2-h oral glucose tolerance test (OGTT) as the criterion gold standard, we determined optimal HbA_1c-screening cutoffs for undiagnosed dysglycemia in the emergency department setting.

RESEARCH DESIGN AND METHODS

This was a prospective observational study of adults aged ≥18 years with no known history of hyperglycemia presenting to an emergency department with acute illness. Outpatient FBS and 2-h OGTT were performed after recovery from the acute illness, resulting in diagnostic categorizations of prediabetes, diabetes, and dysglycemia (prediabetes or diabetes). Optimal cutoffs were determined and performance data identified for cut points.

RESULTS

A total of 618 patients were included, with a mean age of 49.7 (±14.9) years and mean HbA_1c of 5.68% (±0.86). On the basis of an OGTT, the prevalence of previously undiagnosed prediabetes and diabetes was 31.9 and 10.5%, respectively. The optimal HbA_1c-screening cutoff for prediabetes was 5.7% (area under the curve [AUC] = 0.659, sensitivity = 55%, and specificity = 71%), for dysglycemia 5.8% (AUC = 0.717, sensitivity = 57%, and specificity = 79%), and for diabetes 6.0% (AUC = 0.868, sensitivity = 77%, and specificity = 87%).

CONCLUSIONS

We identified HbA_1c cut points to screen for prediabetes and diabetes in an emergency department adult population. The values coincide with published outpatient study findings and suggest that an emergency department visit provides an opportunity for HbA_1c-based dysglycemia screening.There are 26.8 million people with diabetes in the U.S., and by the year 2030, it is estimated to increase to 36 million people (1). Current estimates are that 27% of individuals with diabetes remain undiagnosed, and by the time of diagnosis, there often are microvascular and macrovascular abnormalities found (2–4). Early recognition is important because lifestyle modifications and medications can reduce the incidence of diabetes in people at high risk (5), and the treatment of diabetes can prevent or delay microvascular end-organ complications.The use of hemoglobin A_1c (HbA_1c) to diagnose prediabetes and diabetes recently was recommended by the American Diabetes Association (ADA) (6). HbA_1c testing has an advantage over glucose-based testing because it does not require fasting, and the test can be performed at any time. Guidelines recommend an HbA_1c ≥6.5% to diagnose diabetes and HbA_1c between 5.7 and 6.4% for identifying prediabetes. These cutoff values for HbA_1c are derived in part from outpatient studies and are based on populations of those not acutely ill at the time of testing (7–9).Less attention has been given to screening and diagnosing diabetes and prediabetes in acute-care settings such as the emergency department, where blood is routinely drawn to manage acute illness and clinicians are available to interpret the results. The HbA_1c test can be quickly performed in many different clinical settings, including the hospital. However, it is not known whether HbA_1c thresholds differ between the higher-risk acute-care and the general outpatient populations. The purpose of this study was to determine optimal HbA_1c-screening cutoff points for undiagnosed dysglycemia in the emergency department setting using follow-up fasting blood glucose (FBS) and 2-h oral glucose tolerance tests (OGTTs) as the criterion gold standard.     

Diagnostic testing for diabetes using HbA(1c) in the Abu Dhabi population: Weqaya: the Abu Dhabi cardiovascular screening program

OBJECTIVE

The validity of HbA_1c as a population diagnostic tool was tested against oral glucose tolerance testing in Abu Dhabi nationals.

RESEARCH DESIGN AND METHODS

The screening tool of HbA_1c and random glucose was validated against the “gold standard” oral glucose tolerance test according to World Health Organization criteria.

RESULTS

The HbA_1c threshold of 6.4% provided the optimum balance between sensitivity (72.0%) and specificity (84.3%) with positive and negative predictive values of 47.9 and 93.7% and area under the receiver operating characteristics curve of 0.78. This threshold compares with a threshold of 6.5% recommended by the International Scientific Committee and American Diabetes Association and of 6.3% in a recent study in China.

CONCLUSIONS

This study successfully validates the feasibility and threshold of HbA_1c for diagnosis of diabetes at the population level in a Middle-Eastern population. This result is a major step in the fight to tackle the increasing burden of diabetes in the United Arab Emirates.The United Arab Emirates (UAE) has been reported as having the second highest world prevalence of diabetes by the World Health Organization (2005) (1) and the International Diabetes Federation (2). The Weqaya program screened >92% of the UAE national population for cardiovascular disease risk factors including diabetes (3). The International Expert Committee on Diabetes (4) and the American Diabetes Association (5) recommended that an HbA_1c threshold of 6.5% should be diagnostic of diabetes. This article seeks to determine the utility of HbA_1c as a population-level diagnostic tool.     

Clinical and Economic Benefits Associated With the Achievement of Both HbA1c and LDL Cholesterol Goals in Veterans With Type 2 Diabetes

OBJECTIVE

This study compared the clinical and economic benefits associated with dual-goal achievement, glycated hemoglobin (HbA_1c) <7% (53 mmol/mol) and LDL cholesterol (LDL-C) <100 mg/dL, with achievement of only the LDL-C goal or only the HbA_1c goal in veterans with type 2 diabetes mellitus (T2DM).

RESEARCH DESIGN AND METHODS

This retrospective cohort analysis evaluated electronic medical records (Veterans Integrated Service Network 16) in adult T2DM patients with two or more measurements of LDL-C and HbA_1c between 1 January 2004 and 30 June 2010 (N = 75,646). Cox proportional hazards models were used to compare microvascular and cardiovascular outcomes by goal achievement status; generalized linear regression models were used to assess diabetes-related resource utilization (hospitalization days and number of outpatient visits) and medical service costs.

RESULTS

Relative to achievement of only the LDL-C goal, dual-goal achievement was associated with lower risk of microvascular complications (adjusted hazard ratio [aHR] 0.79), acute coronary syndrome (0.88), percutaneous coronary intervention (0.78), and coronary artery bypass graft (CABG) (0.74); it was also associated with fewer hospitalization days (adjusted incidence rate ratio [aIRR] 0.93) and outpatient visits (0.88), as well as lower diabetes-related annual medical costs (−$130.89). Compared with achievement of only the HbA_1c goal, dual-goal achievement was associated with lower risk of the composite cardiovascular-related end point (aHR 0.87) and CABG (aHR 0.62), as well as fewer outpatient visits (aIRR 0.98).

CONCLUSIONS

Achieving both HbA_1c and LDL-C goals in diabetes care is associated with additional clinical and economic benefits, as compared with the achievement of either goal alone.The American Diabetes Association recommends that patients with type 2 diabetes mellitus (T2DM) maintain levels of glycated hemoglobin (HbA_1c) <7% (53 mmol/mol) and LDL cholesterol (LDL-C) <100 mg/dL (1). The level of HbA_1c, an indicator of average glycemia over several months, is a strong predictor of diabetes-related complications (1). Intensive treatments aimed at decreasing HbA_1c levels have been associated with a reduced risk of microvascular complications (e.g., nephropathy and retinopathy) in patients with T2DM (1–4). The beneficial effects of decreasing HbA_1c levels on the rate of cardiovascular events is less evident, with recent data showing that cardiovascular benefits of tight glycemic control are predominantly observed in patients who are newly diagnosed with diabetes and have minimal comorbidities (5). Conversely, treatments aimed at lowering LDL-C levels in patients with diabetes, especially in individuals with a high baseline cardiovascular risk, have been associated with significantly lower rates of cardiovascular events, including death (6–10). In addition, studies suggest that in diabetes, a condition estimated to incur direct annual costs (2007) of $116 billion in the U.S. (11), treatments aimed at glycemic (12–15) and LDL-C control (16–18) are generally considered cost-effective.Cardiovascular disease is the most frequent underlying cause of death in diabetic patients (19). Although the cardiovascular benefits of LDL-C control in patients with diabetes have been well established (1), the benefits of achieving the HbA_1c goal in addition to achieving the LDL-C goal are not clear. In diabetes, multifactorial interventions (i.e., targeting several risk factors simultaneously, including HbA_1c, LDL-C, blood pressure, and lifestyle) have been associated with significant reductions in microvascular and cardiovascular morbidity and mortality when compared with conventional treatments in several studies, including the Steno-2 Study (20,21), and appear to be cost-effective (22,23). However, existing research has not assessed the additional benefits associated with appropriate control of both HbA_1c and LDL-C levels versus the control of only one.Since the cardiovascular benefits associated with HbA_1c goal achievement in addition to LDL-C goal achievement are not clear, the primary objective of our study was to assess the clinical and economic benefits associated with the achievement of both HbA_1c and LDL-C goals compared with achievement of only the LDL-C goal. Additional objectives included comparisons of clinical and economic outcomes in dual-goal achievers versus HbA_1c-only achievers, dual-goal achievers versus no-goal achievers, and each group of single-goal achievers versus no-goal achievers.