The combination of fasting plasma glucose and glycosylated hemoglobin predicts type 2 diabetes in Japanese workers

OBJECTIVES: We examined the usefulness of the combined use of fasting plasma glucose (FPG) and hemoglobin Alc (HbA1c) levels to predict the progression of diabetes in a Japanese population. METHODS: A retrospective cohort study was conducted from 1995 to 2002 among 449 non-diabetic Japanese workers, ages 23-65, in whom baseline FPG levels and HbA1c were measured. Subjects were classified into six groups according to their baseline FPG level: low normal fasting glucose (NFG) (<5.55 mmol/l); high NFG (5.55-6.09 mmol/l); or impaired fasting glucose (IFG) (6.10-6.99 mmol/l), in combination with baseline HbA1c level: low HbA1c (<5.8%) and high HbA1c (> or =5.8%). The cumulative incidence of diabetes in 2002, as defined by the 1997 American Diabetes Association (ADA) diagnostic criteria, was compared between groups. RESULTS: The overall cumulative incidence of diabetes was 3.8% (17/449). The cumulative incidence of diabetes was 0.6% (2/339) in those with low NFG/normal HbA1c; 0% (0/24) with low NFG/high HbA1c; 6.4% (3/47) with high NFG/normal HbA1c; 23.1% (3/13) with high NFG/high HbA1c; 17.6% (3/17) with IFG/normal HbA1c; and 66.7% (9/17) with IFG/high HbA1c. The odds ratios for diabetes, adjusted for age, sex, body mass index (BMI) and family history of diabetes, were 5.3 (95% CI, 3.0-9.3) and 3.0 (1.7-5.3), per 0.56 mmol/l increase in FPG and 0.5% increase in HbA1c, respectively. CONCLUSIONS: The combined use of FPG and HbA1c levels predicts the progression to diabetes in individuals with no apparent risk. In particular, the combination is recommended for individuals with a FPG > or =5.55 mmol/l.     

Validation of an algorithm combining haemoglobin A1c and fasting plasma glucose for diagnosis of diabetes mellitus in UK and Australian populations

Aim To determine whether glycated haemoglobin (HbA_1c) can be used in combination with fasting plasma glucose (FPG) for the diagnosis of diabetes in patients with impaired fasting glucose (IFG) and in a broader spectrum of patients. Methods An algorithm was derived from oral glucose tolerance test (OGTT) capillary samples in 500 consecutive UK patients with IFG by World Health Organization criteria. It was validated in a further 500 UK patients and, with venous specimens, in 1175 unselected Australian patients. Results The derivation cohort was aged 61 years (50–69 years) (median IQ range) with 52% male and 12% South Asian. Diabetes Control and Complications Trial‐aligned HbA_1c was 6.2% (5.8–6.6%) (reference interval < 6.0%) and FPG 6.7 mmol/l (6.3–7.2 mmol/l). FPG was in the diabetes range in 36% of patients, with an OGTT identifying a further 12% with diabetes. The derived algorithm, (HbA_1c ≥ 6.0% with FPG < 7.0 mmol/l) identified those patients requiring an OGTT to diagnose diabetes. When applied to the UK validation cohort, sensitivity was 97% and specificity 100%. The algorithm was equally effective in the unselected group, aged 59 years (49–68 years) and 54% male, with sensitivity 93% and specificity 100%. HbA_1c was 6.0% (5.6–6.6%) and FPG 6.0 mmol/l (5.3–6.8 mmol/l), with 26% having IFG. Use of the algorithm would reduce the number of OGTTs performed in the UK validation cohort by 33% and by 66% in the Australian patients studied. Conclusions Use of this algorithm would simplify procedures for diagnosis of diabetes and could also be used for monitoring pre‐diabetes. Validation is now required in other populations and patient groups.     

The relative merits of haemoglobin A1c and fasting plasma glucose as first-line diagnostic tests for diabetes mellitus in non-pregnant subjects

HbA_1c was measured by high-performance ion-exchange chromatography in 401 non-pregnant patients undergoing oral glucose tolerance tests (OGTT). All those with HbA_1c>6.2 % (reference range 3.8–5.5 %) had diabetic OGTT (sensitivity 41 %, specificity 100 %). Although a fasting plasma glucose (FPG) cut-off ≥7.0 mmol l⁻¹, as recommended by the American Diabetes Association (ADA), had greater sensitivity (78 %), false positives (12 %) limited its usefulness, so more diagnostic confidence could be placed in a positive HbA_1c. In agreement with the ADA, we found FPG gave only slightly lower diabetes prevalence than the OGTT, but this masked a significant number of individual discrepancies (false positives and negatives) cancelling out each other. The new ADA category of impaired fasting glucose did not correlate well with impaired glucose tolerance. HbA_1c is insufficiently sensitive as a direct substitute for the OGTT. A third of subjects diabetic on OGTT had normal HbA_1c values, so it cannot exclude diabetes as currently defined, but HbA_1c screening could make sufficient positive diagnoses to reduce our non-pregnant OGTTs by one-fifth. If a ‘risk threshold’ for diabetic complications could be applied to HbA_1c, it could replace the OGTT as a more pragmatic diagnostic/prognostic test. © 1998 John Wiley & Sons, Ltd.     

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.     

Non-diabetic hyperglycaemia correlates with angiographic coronary artery disease prevalence and severity

AimThe role of glycaemia as a coronary artery disease (CAD) risk factor is controversial, and the optimal glucose level is still a matter of debate. For this reason, we assessed the prevalence and severity of angiographic CAD across hyperglycaemia categories and in relation to haemoglobin A_1c (HbA_1c) levels.MethodsWe studied 273 consecutive patients without prior revascularization undergoing coronary angiography for suspected ischaemic pain. CAD severity was assessed using three angiographic scores: the Gensini's score; extent score; and arbitrary index. Patients were grouped, according to 2003 American Diabetes Association criteria, into those with normal fasting glucose (NFG), impaired fasting glucose (IFG) and diabetes mellitus (DM).ResultsCAD prevalence was 2.5-fold higher in both the IFG and DM groups compared with the NFG group. Deterioration of glycaemic profile was a multivariate predictor of angiographic CAD severity (extent score: P = 0.027; arbitrary index: P = 0.007). HbA_1c levels were significantly higher among CAD patients (P = 0.016) and in those with two or more diseased vessels (P = 0.023) compared with the non-CAD group. HbA_1c levels remained predictive of CAD prevalence even after adjusting for conventional risk factors, including DM (adjusted OR: 1.853; 95% CI: 1.269–2.704).ConclusionNon-diabetic hyperglycaemia, assessed either categorically by fasting glucose categories or continuously by HbA_1c levels, correlates with the poorest angiographic outcomes.     

Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATETM study

Aims: To compare efficacy and safety of two fasting plasma glucose (FPG) titration targets [4.4–6.1 mmol/l (80–110 mg/dl) and 3.9–5.0 mmol/l (70–90 mg/dl)] using a patient‐directed, treat‐to‐target algorithm for once‐daily basal insulin in insulin‐naïve subjects with type 2 diabetes suboptimally treated with oral antidiabetes drugs (OADs). Methods: In this 20‐week, randomized, controlled, open‐label, multicentre, treat‐to‐target study, 244 insulin‐naïve subjects with type 2 diabetes, HbA_1c≥7.0 and ≤9.0% on OAD treatment, were randomized (1 : 1) to one of two treatment arms using 3.9–5.0 or 4.4–6.1 mmol/l FPG as titration targets. Once‐daily insulin detemir doses were adjusted using algorithm‐guided patient‐directed titration to achieve target FPG values. Results: Overall, the combined treatment groups achieved a mean HbA_1c level of 6.9% at the end of the study. Substantial reductions in HbA_1c were seen in both treatment groups, with the majority of subjects in both titration groups at the end of the study achieving the American Diabetes Association (ADA)‐recommended HbA_1c level of <7%. In the 3.9–5.0 mmol/l FPG target treatment group, HbA_1c values decreased from a baseline mean of 8.0% to 6.8% at 20 weeks. In the 4.4–6.1 mmol/l FPG target group, HbA_1c values decreased from 7.9% at baseline to 7.0% at 20 weeks (Intention to treat ‐ last observation carried forward data set). These decreases were significantly different between the two treatment groups (Least squares mean difference = ?0.271, 95% CI ?0.441 to ?0.101, p = 0.0019), favouring the FPG target of 3.9–5.0 mmol/l vs. the 4.4–6.1 mmol/l target. At the end of the study period, 64.3% of subjects in the 3.9–5.0 mmol/l treatment group achieved HbA_1c levels <7% compared with 54.5% of subjects in the 4.4–6.1 mmol/l group (95% CI 1.03–3.37, odds ratio 1.86, p = 0.04). Insulin detemir dosing patterns were similar between treatment groups, with the 3.9–5.0 mmol/l group using slightly greater doses throughout the study period (0.57 U/kg vs. 0.51 U/kg at the end of the study). Overall rates of hypoglycaemia episodes were low and were comparable between treatment groups (7.73 and 5.27 events/subject/year for the 3.9–5.0 and 4.4–6.1 mmol/l groups, respectively). A single event of major hypoglycaemia was reported in the 3.9–5.0 mmol/l group. Mean weight changes from baseline to the end of the study were small and did not differ significantly between treatment groups. Conclusions: The 3.9–5.0 mmol/l FPG target showed superior efficacy compared with the 4.4–6.1 mmol/l target, although both FPG titration targets resulted in substantial reductions of HbA_1c in patients with type 2 diabetes using a patient‐directed insulin titration algorithm. A majority of subjects in both titration groups achieved the ADA‐recommended guideline of <7% HbA_1c at the end of the study with low rates of hypoglycaemia. These data indicate that lowering the fasting glucose target using a self‐directed titration algorithm with once‐daily detemir is safe and increases the likelihood of achieving the target level of HbA_1c. Indeed, using this approach, a majority of patients can achieve an HbA_1c of <7%.     

Comparison of fasting plasma glucose and haemoglobin A1c point-of-care tests in screening for diabetes and abnormal glucose regulation in a rural low income setting

Aims

Glycated haemoglobin (HbA_1C) has been suggested to replace glucose tests in identifying diabetes and pre-diabetes. We assessed agreement between fasting plasma glucose (FPG) and HbA_1C rapid tests in classifying abnormal glucose regulation (AGR), and their utility for preventive screening in rural Africa.

Methods

A population-based survey of 795 people aged 35–60 years was conducted in a mainly rural district in Uganda. FPG was measured using On-Call^® Plus glucometers, and classified using World Health Organization (WHO) and American Diabetes Association (ADA) criteria. HbA_1C was measured using A1cNow^® kits and classified using ADA criteria. Body mass index and blood pressure were measured. Percentage agreement between the two tests was computed.

Results

Using HbA_1C, 11.3% of participants had diabetes compared with 4.8% for FPG. Prevalence of HbA_1C-defined pre-diabetes (26.4%) was 1.2 times and 2.5 times higher than FPG-defined pre-diabetes using ADA (21.8%) and WHO (10.1%) criteria, respectively. With FPG as the reference, agreement between FPG and HbA_1C in classifying diabetes status was moderate (Kappa = 22.9; Area Under the Curve (AUC) = 75%), while that for AGR was low (Kappa = 11.0; AUC = 59%). However, agreement was high (over 90%) among negative tests and among participants with risk factors for type 2 diabetes (obesity, overweight or hypertension). HbA_1C had more procedural challenges than FPG.

Conclusions

Although low in the general sample, agreement between HbA_1C and FPG is excellent among persons who test negative with either test. A single test can therefore identify the majority at lower risk for type 2 diabetes. Nurses if trained can conduct these tests.     

Impact of lowering the criterion for impaired fasting glucose on identification of individuals with insulin resistance. The GISIR database

OBJECTIVE: We assessed the accuracy of the American Diabetes Association (ADA)2003 definition of impaired fasting glucose (IFG) in identifying subjects with low insulin sensitivity, and determined cardiovascular risk factors in ADA2003 IFG subjects. RESEARCH DESIGN AND METHODS: This study included 930 non-diabetic Italian Caucasians from the GISIR database in which subjects underwent a hyperinsulinaemic-euglycaemic clamp performed with a standard technique. Low insulin sensitivity was defined as being in the lower quartile of glucose metabolized during the last hour of the clamp (M). Subjects were stratified in the following groups: normal fasting glucose (NFG) (<100 mg/dL), IFG100 (100-109 mg/dL), ADA1997 IFG110 (110-125 mg/dL), and ADA2003 IFG (100-125 mg/dL). RESULTS: The sensitivity of identifying subjects with low insulin sensitivity increased adopting the ADA2003 criterion. After Bonferroni correction for multiple comparisons, both IFG100 and ADA1997 IFG110 showed significantly higher body mass index (BMI), waist, systolic blood pressure (SBP) and diastolic blood pressure (DBP), triglyceride, fasting plasma insulin (FPI) and fasting plasma glucose (FPG), and lower insulin sensitivity as compared with NFG. As compared with IFG100, ADA1997 IFG110 showed significantly higher BMI, waist, SBP, FPI, FPG, and lower insulin sensitivity. ADA2003 IFG group showed significantly higher BMI, waist, SBP and DBP, triglyceride, cholesterol, FPI, and FPG, but lower HDL levels and insulin sensitivity compared with NFG subjects. CONCLUSIONS: Although neither the ADA2003 nor the ADA1997 definition of IFG appears to be particularly efficacious for the identification of subjects' low insulin sensitivity, lowering the criterion to the ADA2003 glucose threshold increased the sensitivity without affecting the specificity. ADA2003 IFG showed a worse cardiovascular risk profile compared with NFG.     

Progression rates from HbA1c 6.0–6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis

Aims/hypothesis

Precise estimates of progression rates from ‘prediabetes’ to type 2 diabetes are needed to optimise prevention strategies for high-risk individuals. There is acceptance of prediabetes defined by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), but there is some controversy surrounding HbA_1c-defined prediabetes ranges, with some favouring 6.0–6.4% (42–46 mmol/mol). Comparing progression rates between groups might aid this issue, thus we aimed to accurately estimate progression rates to diabetes from different prediabetes categories.

Methods

Meta-analysis of prospective observational studies in which participants had prediabetes at baseline (ADA-defined IFG [5.6–6.9 mmol/l], WHO-defined IFG [6.1–6.9 mmol/l], IGT (7.8–11.0 mmol/l) or raised HbA_1c [6.0–6.4%/42–46 mmol/mol]) and were followed up for incident diabetes. Incidence rates were combined using Bayesian random effects models.

Results

Overall, 70 studies met the inclusion criteria. In the six studies that used raised HbA_1c, the pooled incidence rate (95% credible interval) of diabetes was 35.6 (15.1, 83.0) per 1,000 person-years. This rate was most similar to that for ADA-defined IFG (11 studies; 35.5 [26.6, 48.0]) and was non-significantly lower than WHO-defined IFG (34 studies; 47.4 [37.4, 59.8]), IGT (46 studies, 45.5 [37.8, 54.5]) and IFG plus IGT (15 studies, 70.4 [53.8, 89.7]). Similar results were seen when the data were analysed by the criteria used to diagnose diabetes.

Conclusions/interpretation

This study provides evidence that progression rates differ by prediabetes definition, which has implications for the planning and implementation of diabetes prevention programmes. HbA_1c 6.0–6.4% might identify people at a lower diabetes risk than other prediabetes definitions, but further research is needed.     

Comparison of Hemoglobin A1c and Fasting Glucose Criteria to Diagnose Diabetes Among People With Metabolic Syndrome and Fasting Glucose Above 100 mg/dL (5.5 mmol/L)

J Clin Hypertens(Greenwich). 2010;12:543–548. © 2010 Wiley Periodicals, Inc. The aim of this study was to compare hemoglobin A_1c (HbA_1c) and fasting glucose for the diagnosis of diabetes among people with metabolic syndrome and fasting glucose >100 mg/dL (5.5 mmol/L). Consecutive individuals (N=142) with metabolic syndrome and fasting glucose >100 mg/dL (5.5 mmol/L) but without a self-reported history of diabetes who visited the outpatient lipid and obesity clinic of the University Hospital of Ioannina, Greece from January through September 2009 were included. HbA_1c≥6.5% and fasting glucose ≥126 mg/dL (7 mmol/L) were used separately to define diabetes. Overall, 29.5% of patients had both HbA_1c≥6.5% and fasting glucose ≥126 mg/dL (7 mmol/L), 25.3% had HbA_1c≥6.5% but fasting glucose <126 mg/dL (7 mmol/L), and 9.1% had HbA_1c <6.5% but fasting glucose ≥126 mg/dL (7 mmol/L). A greater proportion of patients reached a diagnosis of diabetes based on the HbA_1c criterion (n=78, 54.9%) compared with the fasting glucose criterion (n=55, 38.7%, P=.000). A large proportion of patients (44.8%) with impaired fasting glucose (fasting glucose 100–125 mg/dL; 5.6–6.9 mmol/L) would be classified as diabetics using the HbA_1c criterion. Implication of the HbA_1c criterion may increase the rate of diabetes diagnosis among people with metabolic syndrome and fasting glucose >100 mg/dL (5.5 mmol/L).     

Size and shape of the associations of glucose,HbA<Subscript>1c</Subscript>, insulin and HOMA-IR with incident type 2 diabetes: the Hoorn Study

Aims/hypothesis

Glycaemic markers and fasting insulin are frequently measured outcomes of intervention studies. To extrapolate accurately the impact of interventions on the risk of diabetes incidence, we investigated the size and shape of the associations of fasting plasma glucose (FPG), 2 h post-load glucose (2hPG), HbA_1c, fasting insulin and HOMA-IR with incident type 2 diabetes mellitus.

Methods

The study population included 1349 participants aged 50–75 years without diabetes at baseline (1989) from a population-based cohort in Hoorn, the Netherlands. Incident type 2 diabetes was defined by the WHO 2011 criteria or known diabetes at follow-up. Logistic regression models were used to determine the associations of the glycaemic markers, fasting insulin and HOMA-IR with incident type 2 diabetes. Restricted cubic spline logistic regressions were conducted to investigate the shape of the associations.

Results

After a mean follow-up duration of 6.4 (SD 0.5) years, 152 participants developed diabetes (11.3%); the majority were screen detected by high FPG. In multivariate adjusted models, ORs (95% CI) for incident type 2 diabetes for the highest quintile in comparison with the lowest quintile were 9.0 (4.4, 18.5) for FPG, 6.1 (2.9, 12.7) for 2hPG, 3.8 (2.0, 7.2) for HbA_1c, 1.9 (0.9, 3.6) for fasting insulin and 2.8 (1.4, 5.6) for HOMA-IR. The associations of FPG and HbA_1c with incident diabetes were non-linear, rising more steeply at higher values.

Conclusions/interpretation

FPG was most strongly associated with incident diabetes, followed by 2hPG, HbA_1c, HOMA-IR and fasting insulin. The strong association with FPG is probably because FPG is the most frequent marker for diabetes diagnosis. Non-linearity of associations between glycaemic markers and incident type 2 diabetes should be taken into account when estimating future risk of type 2 diabetes based on glycaemic markers.

     

Effect of HbA1c combined FPG on screening diabetes in health check-up

ObjectiveTo appraise the effectiveness of HbA_1c and fasting plasma glucose (FPG) on screening diabetes in health check-up.MethodsA total of 1 337 individuals (male 850, female 487), aged 27 to 91 years with HbA_1c test were included. Participates with HbA_1c ?6.0% or FPG?6.1 mmol/L underwent oral glucose tolerance test (OGTT). Diabetes mellitus was diagnosed according to the criteria of WHO in 1999, FPG?7.0 mmol/L and/or OGTT 2 h-postload plasm glucose (2 h-PG)?11.1 mmol/L. The sensitivity and specificity of HbA_1c thresholds and FPG or combination test on screening of diabetes were analyzed.ResultsA total of 842 subjects had HbA_1c <6.0%, in which 32 had isolated FPG?6.1 mmol/L, of 495 had HbA_1c?6.0%. Subjects with HbA_1c?6.0% had significant increased disorder indexes than those with HbA_1c<6.0%. 527 subjects who had HbA_1c?6.0% or FPG?6.1 mmol/L underwent OGTT. A total of 234 subjects were newly diagnosed diabetes, including 123 (123/234, 52.56%) with FPG?7.0 mmol/L, and 111 subjects (111/234, 47.43%) with isolated 2 h-PG?11.1 mmol/L. Among 234 new diabetes, 91.88% (215 subjects) had HbA_1c?6.3%, and 77.40% (181 subjects) had HbA_1c?6.5%. HbA_1c?6.3% combined FPG ?7.0 mmol/L increased the positive rate of newly diagnosed diabetes from 91.88% to 96.58%.ConclusionsHbA_1c is a practical and convenient tool for screening undiagnosed diabetes in routine health check-up of a large population. Combined use of HbA_1c?6.3% and/or FPG?7.0 mmol/L is efficient for early detection of diabetes.     

The general use of glycated haemoglobin for the diagnosis of diabetes and other categories of glucose intolerance: still a long way to go

Glycated haemoglobin (HbA_1c) is considered the ‘gold standard’ for monitoring metabolic control in diabetes. An International Expert Committee recently recommended HbA_1c as a better method than measurement of glucose to use in the diagnosis of diabetes, based on its strong association with microvascular complications, a lower day-to-day variability and ease of use, not necessarily in the fasting state. These recommendations have been embraced by the American Diabetes Association (ADA), which stated in its Standards of Medical Care in Diabetes 2010 that “A_1c, fasting plasma glucose or the 2 h 75 g oral glucose tolerance test (OGTT) are appropriate for testing diabetes and assessing the risk of future diabetes,” and that “a confirmed A_1c ≥ 6.5% is diagnostic for diabetes.” Measuring HbA_1c has several advantages over glucose measurements, but its exclusive use should only be considered if the test is conducted under standardised conditions and its limitations are taken into due account. The impact of its use on the epidemiology of diabetes and other categories of glucose intolerance, as seen from recent reports, is also discussed.     

Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study

Aims/hypothesis  Hyperglycaemia is a risk factor for cardiovascular disease (CVD) and all-cause mortality in individuals without diabetes. We investigated: (1) whether the risk of all-cause and CVD mortality extended continuously throughout the range of fasting plasma glucose (FPG), 2 h plasma glucose (2hPG) and HbA_1c values; and (2) the ability of these measures to improve risk prediction for mortality. Methods  Data on 10,026 people aged ≥25 years without diagnosed diabetes were obtained from the population-based Australian Diabetes, Obesity and Lifestyle study. Between 1999 and 2000, FPG, 2hPG and HbA_1c were assessed and all-cause (332 deaths) and CVD (88 deaths) mortality were obtained after 7 years. Results  Both 2hPG and HbA_1c exhibited linear relationships with all-cause and CVD mortality, whereas FPG showed J-shaped relationships. The adjusted HR (95% CI) for all-cause mortality per SD increase was 1.2 (1.1–1.3) for 2hPG and 1.1 (1.0–1.2) for HbA_1c. The HR for FPG <5.1 mmol/l (per SD decrease) was 2.0 (1.3–3.0); for FPG ≥5.1 mmol/l (per SD increase) the HR was 1.1 (1.0–1.2). Corresponding HRs for CVD mortality were 1.2 (1.0–1.4), 1.2 (1.0–1.3), 4.0 (2.1–7.6) and 1.3 (1.1–1.4). The discriminative ability of each measure was similar; no measure substantially improved individual risk identification over traditional risk factors. Conclusions/interpretation  In individuals without diagnosed diabetes, 2hPG and FPG, but not HbA_1c were significant predictors of all-cause mortality, whereas all measures were significant predictors of CVD mortality. However, these glucose measures did not substantially improve individual risk identification.     

Development of a new scoring system for predicting the 5?year incidence of type 2 diabetes in Japan: the Toranomon Hospital Health Management Center Study 6 (TOPICS 6)

Aims/hypothesis

The aims of this study were to assess the clinical significance of introducing HbA_1c into a risk score for diabetes and to develop a scoring system to predict the 5?year incidence of diabetes in Japanese individuals.

Methods

The study included 7,654 non-diabetic individuals aged 40–75?years. Incident diabetes was defined as fasting plasma glucose (FPG) ≥7.0?mmol/l, HbA_1c ≥6.5% (48?mmol/mol) or self-reported clinician-diagnosed diabetes. We constructed a risk score using non-laboratory assessments (NLA) and evaluated improvements in risk prediction by adding elevated FPG, elevated HbA_1c or both to NLA.

Results

The discriminative ability of the NLA score (age, sex, family history of diabetes, current smoking and BMI) was 0.708. The difference in discrimination between the NLA + FPG and NLA + HbA_1c scores was non-significant (0.836 vs 0.837; p?=?0.898). A risk score including family history of diabetes, smoking, obesity and both FPG and HbA_1c had the highest discrimination (0.887, 95% CI 0.871, 0.903). At an optimal cut-off point, sensitivity and specificity were high at 83.7% and 79.0%, respectively. After initial screening using NLA scores, subsequent information on either FPG or HbA_1c resulted in a net reclassification improvement of 42.7% or 52.3%, respectively (p?<?0.0001). When both were available, net reclassification improvement and integrated discrimination improvement were further improved at 56.7% (95% CI 47.3%, 66.1%) and 10.9% (9.7%, 12.1%), respectively.

Conclusions/interpretation

Information on HbA_1c or FPG levels after initial screening by NLA can precisely refine diabetes risk reclassification.     

Predicting steady‐state HbA1c responses to sitagliptin in patients with type 2 diabetes mellitus*

Aims: To develop predictive formulas using short‐term changes in glycaemic parameters [haemoglobin A_1c (HbA_1c) and fasting plasma glucose (FPG)] with sitagliptin, a highly selective dipeptidyl peptidase‐4 inhibitor, to assess longer term steady‐state changes in HbA_1c. Methods: Results from two, 12‐week, double‐blind studies of sitagliptin in Japanese patients with type 2 diabetes mellitus receiving once‐daily sitagliptin 100 mg were used to construct linear models to develop predictive formulas based on study 1 (S1) and to validate them using study 2 (S2). HbA_1c and FPG were the primary and the key secondary end‐point for both studies and were both used to develop predictive formulas. Results: The predictive formulas using HbA_1c ± FPG results (slope of change) from week 0 to week 4 in S1 showed high correlations between fitted and observed week 12 HbA_1c: for HbA_1c alone R² = 0.76, for HbA_1c + FPG R² = 0.89. When using the sitagliptin 100 mg group of S2 data set to assess the validity of the predictive formulas, high correlations for HbA_1c alone (R² = 0.76) and for HbA_1c + FPG (R² = 0.77) were also observed. Data using a lower dose (25 mg once daily) of sitagliptin also demonstrated similar results. Conclusions: The early responses (over 4 weeks) in HbA_1c and FPG with sitagliptin can be used to accurately predict later responses (at week 12) in HbA_1c in Japanese patients with type 2 diabetes mellitus. Additional studies applying this approach to other agents with diverse mechanisms are important.     

Comparison of nateglinide and gliclazide in combination with metformin,for treatment of patients with Type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone

Aims To compare the effects of nateglinide plus metformin with gliclazide plus metformin on glycaemic control in patients with Type 2 diabetes. Methods Double‐blind, double‐dummy, parallel group, randomized, multicentre study over 24 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to additionally receive nateglinide (n = 133) or gliclazide (n = 129). Changes from baseline in HbA_1c, fasting plasma glucose (FPG) and mealtime glucose and insulin excursions were examined. Results HbA_1c was significantly (P < 0.001) decreased from baseline in both treatment groups (mean changes: nateglinide ?0.41%, gliclazide ?0.57%), but with no significant difference between treatments. Proportions of patients achieving a reduction of HbA_1c ≥ 0.5% or an end point HbA_1c < 7% were also similar (nateglinide 58.1%, gliclazide 60.2%). Changes from baseline in FPG were similarly significant in both treatment groups (nateglinide ?0.63, gliclazide ?0.82 mmol/l). Reduction from baseline in maximum postprandial glucose excursion were significant in the nateglinide group only (nateglinide ?0.71, gliclazide ?0.10 mmol/l; P = 0.037 for difference). Postprandial insulin levels were significantly higher with nateglinide compared with gliclazide. The overall rate of hypoglycaemia events was similar in the nateglinide group compared with the gliclazide group. Conclusions No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA_1c. However, the nateglinide combination demonstrated better postprandial glucose control.     

Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial

Aims/hypothesis

As glycaemia and the incidence of microvascular diabetes complications follow a log-linear relationship, it becomes increasingly difficult to demonstrate a microvascular benefit of glucose-lowering when the HbA_1c level is close to normal.

Methods

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomised 12,537 people with diabetes, impaired glucose tolerance or impaired fasting glucose to receive standard glycaemic care or standard care with the addition of basal insulin glargine (A21Gly,B31Arg,B32Arg human insulin), targeting a fasting plasma glucose level ≤5.3 mmol/l. Microvascular outcomes during a median follow-up of 6.2 years were examined in participants whose baseline HbA_1c was above or below the median of 6.4% (46.4 mmol/mol).

Results

Allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA_1c level was ≥6.4% (46.4 mmol/mol; HR 0.90 [95% CI 0.81, 0.99]) but not in participants with a lower baseline HbA_1c (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). In people whose baseline HbA_1c level was ≥6.4% (46.4 mmol/mol), the median post-randomisation change in HbA_1c was ?0.65% (interquartile range ?0.16, ?0.91%) after allocation to insulin glargine and ?0.33% (?0.83, 0.13%) after allocation to standard care (median HbA_1c difference 0.33%; p?<?0.0001). A smaller median difference of 0.22% was noted in people whose baseline HbA_1c was <6.4% (p?<?0.0001).

Conclusions/interpretation

In patients with dysglycaemia, intervention targeting normal fasting glucose levels reduced HbA_1c and attenuated the risk of microvascular outcomes in participants with a baseline HbA_1c level ≥6.4% (46.4 mmol/mol). A neutral effect was seen in those with a lower baseline HbA_1c level.

Trial registration:

ClinicalTrials.gov NCT00069784     

Risks of Diabetic Nephropathy with Variation in Hemoglobin A1c and Fasting Plasma Glucose

Background

This study examined whether annual variation in glycosylated hemoglobin A_1c (HbA_1c) and fasting plasma glucose (FPG), as represented by the coefficient of variation (CV), can predict diabetic nephropathy independently of mean FPG, mean HbA_1c, and other risk factors in patients with type 2 diabetes.

Methods

A computerized database of patients with type 2 diabetes aged ≥30 years and free of diabetic nephropathy (n = 3220) who were enrolled in the Diabetes Care Management Program of China Medical University Hospital before 2007 was used in a time-dependent Cox proportional hazards regression model.

Results

The incidence rates of diabetic nephropathy were 16.11, 22.95, and 28.86 per 1000 person-years in the first, second, and third tertiles of baseline HbA_1c-CV, respectively; the corresponding incidence rates for FPG-CV were 9.46, 21.23, and 37.51 per 1000 person-years, respectively. After multivariate adjustment, the corresponding hazard ratios for the second and third tertiles versus the first tertile of annual HbA_1c-CV were 1.18 (95% confidence interval [CI], 0.88-1.58) and 1.58 (95% CI, 1.19-2.11), respectively, and 1.55 (95% CI, 0.99-2.41) and 4.75 (95% CI, 3.22-7.01) for FPG-CV, respectively. The risks of diabetic nephropathy for HbA_1c-CV and FPG-CV stratified according to age, gender, renal function, and hypertension status were provided.

Conclusions

Annual FPG and HbA_1c variations have a strong association with diabetic nephropathy in patients with type 2 diabetes. Whether intervention for reducing glucose variation should be administered needs to be examined in a future study.     

Hemoglobin A1c as a marker for identifying diabetes and cardiovascular risk factors: the China Health and Nutrition Survey 2009

Hemoglobin A_1c (HbA_1c) has been recommended as an optional method for diagnosing diabetes. The impact of HbA_1c on the diagnosis of diabetes has not been evaluated in China, a country with the greatest number of people with diabetes in the world. Hence, we aim to examine how well HbA_1c performs as compared with fasting plasma glucose (FPG) for diagnosing diabetes in Chinese population. We conducted a cross-sectional analysis of 7,641 Chinese men and women aged ≥18 years using data from the China Health and Nutrition Survey 2009 in which FPG and standardized HbA_1c were measured. HbA_1c was measured with high-performance liquid chromatography system. Diabetes is defined as having FPG ≥7 mmol/l or HbA_1c ≥6.5 %. Overall, 5.0 and 5.8 % had undiagnosed diabetes by FPG ≥7 mmol/l and HbA_1c ≥6.5 %, respectively. Overlap between HbA_1c- and FPG-based diagnosis of diabetes was limited (n = 214, 34.9 %). Similar trends were noted in both genders, all age groups, urban/rural settings, regions, body mass index (BMI) categories, waist circumference (WC) groups, and blood pressure status. Solely HbA_1c-defined individuals exhibited higher levels of BMI, WC, total cholesterol, and hypersensitive C-reactive protein and lower levels of homeostasis model assessment of insulin resistance. We note limited overlap between FPG- and HbA_1c-based diagnosis of diabetes. The limited overlap between FPG- and HbA_1c-based diagnosis of diabetes persisted in each evaluated subgroup. HbA_1c criterion for the diagnosis of diabetes identifies individuals with a worse cardiovascular risk profile compared with FPG.