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.     

Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography the Silent Diabetes Study

Aims/hypothesis

The primary aim of this study was to compare the results of HbA_1c measurements with those of an OGTT for early diagnosis of ??silent diabetes?? in patients with coronary artery disease (CAD) undergoing angiography without prediagnosed diabetes. A secondary aim was to investigate the correlation between the extent of CAD and the glycaemic status of the patient.

Methods

Data from 1,015 patients admitted for acute (n?=?149) or elective (n?=?866) coronary angiography were analysed. Patients with known diabetes were excluded from the study. Using the OGTT results, patients were classified as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. According to the results of the HbA_1c measurements, patients were classified into three groups: normal (HbA_1c <5.7% [<39?mmol/mol]), borderline (HbA_1c 5.7?C6.4% [39?C47?mmol/mol]) and diabetes (HbA_1c ??6.5% [??48?mmol/mol]).

Results

Based on the OGTT, 513 patients (51%) were classified with NGT, 10 (1%) with IFG, 349 (34%) with IGT and 149 (14%) were diagnosed with diabetes. According to HbA_1c measurements, 588 patients (58%) were classified as normal, 385 (38%) as borderline and 42 (4%) were diagnosed with diabetes. The proportion of patients with IGT and diabetes increased with the extent of CAD (IGT ???=?0.14, p?p?=?0.01). No differences in HbA_1c were seen among the groups with different extents of CAD (p?=?0.652).

Conclusions/interpretation

An OGTT should be performed routinely for diagnosis of diabetes in patients with CAD undergoing coronary angiography, since HbA_1c measurement alone appears to miss a substantial proportion of patients with silent diabetes. A limitation of the study is that the OGTT was not performed before the angiography.     

Defining the relationship between average glucose and HbA1c in patients with type 2 diabetes and chronic kidney disease

Aims

To examine the relationship between average glucose (AG) and HbA_1c in patients with and without chronic kidney disease (CKD) and type 2 diabetes.

Materials and methods

43 patients with diabetes and CKD (stages 3–5) with stable glycaemic control, and glucose-lowering and erythropoiesis stimulating agent (ESA) doses, were prospectively studied for 3 months and compared to 104 age-matched controls with diabetes, without CKD from the ADAG study. Over 3 months, AG was calculated from 7 to 8 point self-monitored blood glucose measurements (SMBG) and from continuous glucose monitoring (CGMS), and mean HbA_1c was calculated from 4 measurements. AG and HbA_1c relationships were determined using multivariable linear regression analyses.

Results

The CKD and non-CKD groups were well matched for age and gender. Mean AG tended to be higher (p = 0.08) but HbA_1c levels were similar (p = 0.68) in the CKD compared with non-CKD groups. A linear relationship between AG and HbA_1c was observed irrespective of the presence and stage of CKD. The relationship was weaker in patients with stage 4–5 CKD (non-CKD R² = 0.75, stage 3 CKD R² = 0.79 and stage 4–5 CKD R² = 0.34, all p < 0.01). The inclusion of ESA use in the model rendered the effect of CKD stage insignificant (R² = 0.67, p < 0.01).

Conclusions

In patients with type 2 diabetes and CKD there is a linear relationship between HbA_1c and AG that is attenuated by ESA use, suggesting that ESA results in a systematic underestimation of AG derived from HbA_1c.     

Hemoglobin A1c predicts heart failure hospitalization independent of baseline cardiac function or B-type natriuretic peptide level

Aims

Diabetes is a major risk factor for heart failure (HF). We examined whether baseline HbA_1c level predicts HF incidence independent of other HF risk factors, including baseline cardiac structural and functional abnormalities.

Methods

In patients with type 2 diabetes, multivariable Cox regression models were constructed to examine the independent association between baseline HbA_1c and future HF hospitalization.

Results

In 608 subjects (mean age, 66.5 years; men, 68%; mean HbA_1c, 9.1% (76 mmol/mol)), 92 were hospitalized for HF during a median follow-up of 6 years. For a 1% (11 mmol/mol) increase in baseline HbA_1c, the hazard ratio for HF was 1.23 (95% confidence interval, 1.1–1.7, p < 0.001) with adjustment for age, sex, body mass index, blood pressure and plasma B-type natriuretic peptide (BNP) level. The effect of HbA_1c on HF was independent of baseline left ventricular (LV) ejection fraction, the ratio of peak early to late diastolic filling velocity, and prevalent/incident coronary heart disease (CHD), and was more evident in patients with enlarged LV, decreased systolic function, prevalent CHD, or prevalent HF.

Conclusion

In patients with type 2 diabetes, HbA_1c significantly predicts future HF hospitalization independent of baseline BNP level or echocardiographic parameters.     

The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers

Aims/hypothesis

The increased all-cause mortality in patients with chronic diabetic foot ulcers cannot fully be explained by traditional cardiovascular risk factors. The significance of heart-rate-corrected QT (QTc) prolongation, a finding often seen in these patients, is unknown. Recently, the importance of metabolic control and hypoglycaemia has been discussed. The aim of this study was to evaluate the impact of different HbA_1c levels and QTc prolongation on all-cause mortality in the high-risk population of patients with type 2 diabetes mellitus and foot ulcers.

Methods

All patients with type 2 diabetes, younger than 80 years, visiting our diabetes foot unit, with a foot ulcer duration >4 weeks, were screened for participation. Patients on dialysis were excluded. Patients were grouped according to HbA_1c level and QTc time ≤ or >?440 ms.

Results

Patients (n?=?214, median age 69.1 years) were grouped according to HbA_1c level (HbA_1c?<?7.5% [<58 mmol/mol] n?=?81, 7.5–8.9% [58–74 mmol/mol] n?=?70, >8.9% [>74 mmol/mol] n?=?63). Baseline characteristics, including use of potential hypoglycaemic drugs, were similar between groups. During the 8 years of follow-up 151 patients died (70.6%) and HbA_1c?<?7.5% (<58 mmol/mol) was strongly associated with increased mortality. The highest mortality was seen in patients with a combination of HbA_1c?<?7.5% (<58 mmol/mol) and QTc prolongation, with an 8 year mortality of 92.1% as compared with 48.8% in those with HbA_1c?<?7.5% (<58 mmol/mol) but without QTc prolongation.

Conclusion/interpretations

HbA_1c?<?7.5% (<58 mmol/mol) in a high-risk population of patients with type 2 diabetes and foot ulcers is associated with a significantly higher mortality, particularly in patients with QTc prolongation.     

Undiagnosed coronary artery disease in long-term type 1 diabetes. The Dialong study

Aims

We studied the total prevalence of obstructive coronary artery disease (CAD), undiagnosed CAD and absent CAD in persons with ≥45-year duration of type 1 diabetes (T1D) versus controls, and associations with mean HbA_1c, LDL-cholesterol and blood pressure over 2–3 decades.

Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes

Aims/hypothesis

The aim of this study was to compare glycaemic control and maternal–fetal outcomes in women with type 1 diabetes managed on insulin pumps compared with multiple daily injections of insulin (MDI).

Methods

In a retrospective study, glycaemic control and outcomes of 387 consecutive pregnancies in women with type 1 diabetes who attended specialised clinics at three centres 2006–2010 were assessed.

Results

Women using insulin pumps (129/387) were older and had a longer duration of diabetes, more retinopathy, smoked less in pregnancy, and had more preconception care (p?<?0.01 for each). Among 113 pregnancies >20 weeks’ gestation in women on insulin pumps and 218 in women on MDI, there was a significant difference in HbA_1c in the first trimester (mean HbA_1c 6.90?±?0.71% (52?±?7.8 mmol/mol) vs 7.60?±?1.38% (60?±?15.1 mmol/mol), p?<?0.001), which persisted until the third trimester (mean HbA_1c 6.49?±?0.52% (47?±?5.7 mmol/mol) vs 6.81?±?0.85% (51?±?9.3 mmol/mol), p?=?0.002). Rates of diabetic ketoacidosis were similar in women on insulin pumps vs MDI (1.8% vs 3.0%, p?=?0.72). Despite lower HbA_1c, women on insulin pumps did not have an increased incidence of severe hypoglycaemia (8.0% vs 7.6%, p?=?0.90) or more weight gain (16.3?±?8.7 vs 15.2?±?6.2 kg, p?=?0.18). More large-for-gestational-age infants in the pump group (55.0% vs 39.2%, p?=?0.007) may have resulted from confounding by parity.

Conclusions/interpretation

In this large multicentre study, women using insulin pumps in pregnancy had lower HbA_1c without increased risk of severe hypoglycaemia or diabetic ketoacidosis but no improvement in other pregnancy outcomes. This information can help inform care providers and patients about the glycaemic effectiveness and safety of insulin pumps in pregnancy.     

Contrasting the clinical care and outcomes of 2,622 children with type 1 diabetes less than 6 years of age in the United States T1D Exchange and German/Austrian DPV registries

Aims/hypothesis

The study aimed to compare participant characteristics, treatment modalities and clinical outcomes in registry participants less than 6 years old.

Methods

Participant characteristics, treatment modalities and clinical outcomes (HbA_1c, severe hypoglycaemia [SH] and diabetic ketoacidosis [DKA]) as well as frequencies of attaining HbA_1c goals in line with the International Society for Pediatric and Adolescent Diabetes (<7.5% [<58 mmol/mol]) and ADA (<8.5% [<69 mmol/mol]) were compared.

Results

Insulin pump use was more frequent (74% vs 50%, p?<?0.001) and HbA_1c levels lower in the Prospective Diabetes Follow-up Registry (DPV) than in the T1D Exchange (T1DX) (mean 7.4% vs 8.2%, p?<?0.001). A lower HbA_1c level was seen in the DPV compared with the T1DX for both pump users (p?<?0.001) and injection users (p?<?0.001). More children from DPV were meeting the recommended HbA_1c goals, compared with children from T1DX (HbA_1c <7.5%: 56% vs 22%, p?<?0.001; HbA_1c <8.5%: 90% vs 66%, p?<?0.001). The adjusted odds of having an HbA_1c level <7.5% or <8.5% were 4.2 (p?<?0.001) and 3.6 (p?<?0.001) higher for the DPV than the T1DX, respectively. The frequency of SH did not differ between registries or by HbA_1c, whereas the frequency of DKA was higher for the T1DX and greater in those with higher HbA_1c levels.

Conclusions/interpretation

DPV data indicate that an HbA_1c of <7.5% can frequently be achieved in children with type 1 diabetes who are under 6 years old. An improved metabolic control of type 1 diabetes in young patients appears to decrease the risk of DKA without increasing SH. The greater frequency of suboptimal control in young patients in the T1DX compared with the DPV is not fully explained by a less frequent use of insulin pumps and may relate to the higher HbA_1c targets that are recommended for this age group in the USA.     

Adding glimepiride to insulin + metformin in type 2 diabetes of more than 10 years’ duration—A randomised,double-blind,placebo-controlled,cross-over study

Aims

To investigate the effect on glycaemic control of adding glimepiride to on-going treatment with metformin and insulin in patients with known diabetes more than 10 years.

Methods

Glimepiride 4 mg or placebo was added in randomised order for three months with a washout period of 6 weeks. All insulin regimens were allowed. Insulin doses were reduced if considered necessary. Continuous glucose monitoring was performed at the end of each period.

Results

Forty-three patients, median age 66 years (46–74), diabetes duration 16 (10–30), BMI 30 kg/m² (25–37) and mean HbA_1c 7.1% NGSP, (64 mmol/mol IFCC) were randomised. With placebo there was no change in HbA_1c while a decrease of 0.6%, (7 mmol/mol IFCC) (P < 0.001), was observed with glimepiride even though insulin doses had to be reduced in 23 patients (median change 29%, range 2–100%). Minor hypoglycaemia was reported but no severe hypoglycaemic event was observed. The ratio between C-peptide/glucose increased significantly (P < 0.001) with glimepiride, both fasting and postprandially and, in a stepwise multiple regression analysis of possible predictive factors for response, a more pronounced decrease in HbA_1c was associated with the magnitude of the increment in C-peptide/glucose. Older age was associated with a smaller response. Twenty-nine patients (67%) were defined as responders if this was defined as an HbA_1c decrease ≥0.5% (5 mmol/mol IFCC) or an insulin dose reduction ≥20%.

Conclusions

Even after long duration of diabetes, addition of glimepiride to insulin and metformin can be effective in lowering HbA_1c and/or reducing the need for exogenous insulin.     

Fasting plasma glucose and HbA1c in cardiovascular risk prediction: a sex-specific comparison in individuals without diabetes mellitus

Aims/hypothesis

This study aimed to assess the cardiovascular risk of individuals with fasting plasma glucose (FPG)- and/or HbA_1c-defined prediabetes (5.6–6.9 mmol/l and 39–47 mmol/mol [5.7–6.4%], respectively) or manifest diabetes mellitus and to evaluate whether FPG or HbA_1c can improve risk prediction beyond that estimated by the Systematic Coronary Risk Evaluation (SCORE) chart in individuals without diabetes mellitus.

Methods

Cox regression was employed to estimate HRs for primary incident cardiovascular events (CVEs) in a cohort of 8,365 individuals aged 50–74 years. Furthermore, HbA_1c and FPG were added individually to the variables of the SCORE and measures of model discrimination and reclassification were assessed.

Results

During 8 years of follow-up, 702 individuals had a primary CVE. After adjusting for conventional cardiovascular risk factors, HRs were attenuated close to one for the prediabetes groups (especially for women), whereas a 1.7- and a 1.9-fold increased risk persisted for men and women with diabetes, respectively. Extension of the SCORE variables by either FPG or HbA_1c did not improve its predictive abilities in individuals without diabetes. There was a non-significant net reclassification improvement for men when HbA_1c was added (2.2%, p?=?0.16).

Conclusions/interpretation

The increased cardiovascular risk of individuals with FPG- or HbA_1c-defined prediabetes can mainly be explained by other cardiovascular risk factors. Adding FPG or HbA_1c did not significantly improve CVE risk prediction by the SCORE variables in individuals without diabetes mellitus.     

Hemoglobin A(1c) proportion, mortality rate, and risk factors for death in diabetic patients with severe hypoglycemia: a multicenter retrospective survey over ten years

Objective

To investigate the HbA_1c proportion and mortality rate across diabetic patients with severe hypoglycemia and the risk factors for death.

Methods

All the diabetic patients with severe hypoglycemia were divided into HbA_1c < 6.5% group and HbA_1c ≥ 6.5% group. The proportion of HbA_1c, mortality rate and the risk factors for death were analyzed. Common causes for severe hypoglycemia were also analyzed.

Results

The percentages of HbA_1c in the HbA_1c < 6.5% and HbA_1c ≥ 6.5% groups were 51.2% and 48.8%, respectively. The mortality rates were not significantly different between the 2 groups (5.3% vs. 5.1%, χ² = 0.01, p = 0.17). Binary logistic regression analysis revealed that in both groups, creatinine, aspartate aminotransferase, and uric acid levels were the risk factors for death. In the HbA_1c < 6.5% and HbA_1c ≥ 6.5% groups, 65.0% and 64.2% showed common causes of severe hypoglycemia, respectively.

Conclusions

With respect to severe hypoglycemia, equal attention should be paid to patients with an HbA_1c level of ≥6.5% and those with an HbA_1c level of <6.5%. The mortality rate is approximately 5% in severe hypoglycemia no matter how the HbA_1c level is. Creatinine, aspartate aminotransferase, and uric acid are the main risk factors in both groups. Two-thirds of severe hypoglycemia cases could be prevented.     

Diabetic ketoacidosis at the onset of type 1 diabetes is associated with future HbA1c levels

Aims/hypothesis

We investigated the long-term impact of diabetic ketoacidosis (DKA) at onset on metabolic regulation and residual beta cell function in a Danish population with type 1 diabetes.

Methods

The study is based on data from DanDiabKids, a Danish national diabetes register for children. The register provides clinical and biochemical data on patients with type 1 diabetes diagnosed in 1996–2009 and then followed-up until 1 January 2012. Repeated-measurement models were used as statistical methods.

Results

The study population comprised 2,964 children <18 years. The prevalence of DKA at diagnosis was 17.9%. Of the total subjects, 8.3% had mild, 7.9% had moderate and 1.7% had severe DKA. DKA (moderate and severe) was associated with increased HbA_1c (%) levels (0.24; 95% CI 0.11, 0.36; p?=?0.0003) and increased insulin dose-adjusted HbA_1c (IDAA_1c, 0.51; 95% CI 0.31, 0.70; p?<?0.0001) during follow-up, after adjustment for covariates. Children without a family history of diabetes were more likely to present with DKA (19.2% vs 8.8%, p?<?0.0001); however, these children had a lower HbA_1c (%) level over time (?0.35; 95% CI ?0.46, ?0.24; p?<?0.0001). Continuous subcutaneous insulin infusion (CSII) was associated with a long-term reduction in HbA_1c, changing the effect of DKA, after adjustment for covariates (p?<?0.0001).

Conclusions/interpretation

DKA at diagnosis was associated with poor long-term metabolic regulation and residual beta cell function as assessed by HbA_1c and IDAA_1c, respectively; however, CSII treatment was associated with improvement in glycaemic regulation and residual beta cell function, changing the effect of DKA at onset in our population.     

Carbamylation is a competitor of glycation for protein modification in vivo

Aim

Chronic kidney disease (CKD) and diabetes mellitus are two diseases that accelerate protein molecular ageing through carbamylation and glycation reactions, characterized by the binding of urea-derived isocyanic acid and of sugars on proteins, respectively. These two reactions target the same protein amino groups and, thus, compete with each other. Such competition may arise especially in diabetic patients with nephropathy. This study aimed to evaluate their potential competitive effects in vitro and under conditions reproducing CKD and/or diabetes in vivo.

HbA1c variability is associated with an increased risk of retinopathy requiring laser treatment in type 1 diabetes

Aims/hypothesis

This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA_1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment.

Methods

The effect of HbA_1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n?=?1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n?=?1,346). The ratio of intrapersonal SD and mean of serially measured HbA_1c was considered an estimate of HbA_1c variability.

Results

A subcohort of 1,459 patients did not have laser treatment prior to the first FinnDiane visit and 174 of these patients were treated during a mean follow-up period of 5.2?±?2.2 years. The 5 year cumulative incidence of laser treatment was 19% (95% CI 15, 24) in the highest quartile of HbA_1c variability and 10% (95% CI 7, 12) in the lowest quartile (p?<?0.001, Gray’s test) with a corresponding HR of 1.6 (95% CI 1.1, 2.5; p?=?0.02) adjusted for renal status, diabetes duration, mean HbA_1c, blood pressure, sex and number of HbA_1c measurements. In a subcohort of 1,346 patients, 434 patients had proliferative diabetic retinopathy (PDR). Patients in the highest quartile of HbA_1c variability had an increased risk of PDR compared with the lowest quartile (HR 1.7 [95% CI 1.3, 2.2]; p?<?0.001]).

Conclusions/interpretation

HbA_1c variability was associated with an increased cumulative incidence and risk of retinopathy requiring laser treatment in type 1 diabetes.     

Residual dysglycemia when at target HbA1c of 7% (53 mmol/mol) in persons with type 2 diabetes

Aims

To understand the composition of the residual dysglycemia when HbA_1c is between 6.5% (48 mmol/mol) and 7% (53 mmol/mol), representing the definition of diabetes and the recommended treatment goal, respectively.

Methods

One hundred persons with type 2 diabetes and a HbA_1c < 7% (53 mmol/mol), treated with diet alone and/or oral hypoglycemic agents underwent continuous glucose monitoring (CGM) and were further divided into two subgroups 1 (n = 50) and 2 (n = 50) according to whether the HbA_1c was <6.5% (48 mmol/mol) or 6.5–6.9% (48–52 mmol/mol), respectively. A similar analysis was performed in those on diet alone: subgroups A (n = 34, HbA_1c < 6.5%, 48 mmol/mol) and B (n = 10, HbA_1c 6.5–6.9%, 48–52 mmol/mol). The residual dysglycemia determined from the CGM was assessed using glucose exposures defined as areas under curves (AUCs) and mean glucose values.

Results

Averaged 2-h postprandial glucose value (averaged PPG, mmol/L, mean ± SD) and postprandial glucose exposure (AUCpp, mean ± SD, mmol·L⁻¹·h) were significantly higher in subgroup 2 (mean HbA_1c = 6.7%, 50 mmol/mol) than in subgroup 1 (mean HbA_1c = 6.0%, 42 mmol/mol): averaged PPG = 8.1 ± 1.3 versus 7.3 ± 1.3 mmol/L (p < 0.002); AUCpp = 23.5 ± 8.6 versus 16.2 ± 8.6 (p < 0.0001). The percentages of persons with averaged PPG ≥ 7.8 mmol/L were 52% and 24% (p < 0.01) in subgroups 2 and 1, respectively. Similar results were observed in those (subgroups A and B) who were on diet alone.

Conclusions

The residual dysglycemia in type 2 diabetes with HbA_1c between 6.5 and 6.9% (48–52 mmol/mol) inclusive is mainly due to remnant abnormal postprandial glucose excursions. Consequently, HbA_1c < 6.5% (48 mmol/mol) is an achievable goal with therapeutic measures aimed at reducing postmeal glucose when the HbA_1c is at 7% (53 mmol/mol).     

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.     

Relation between HbA1c and incident cardiovascular disease over a period of 6 years in the Hong Kong population

Aim

The current trend on diabetes management advocates replacing the paradigm from a uniform to an individualized patient-centered haemoglobin A_1c (HbA_1c) target, but there is no consensus on the optimal HbA_1c level. The study aimed at examining the association between HbA_1c and the risk of cardiovascular diseases (CVD) for diabetic patients with different characteristics, in order to identify patient-centered treatment targets.

Effect of Continuous Positive Airway Pressure on Hemoglobin A1c in Patients with Obstructive Sleep Apnea: A Systematic Review and Meta-analysis

Background

There is little conclusive data regarding the effect of continuous positive airway pressure (CPAP) on glycated hemoglobin (HbA_1c). An earlier meta-analysis included two randomized controlled trials (RCTs) and found no significant effect of CPAP on HbA_1c. The meta-analysis presented here was conducted to include all relevant observational studies and RCTs on the effect of CPAP on HbA_1c.

Methods

We searched the PubMed database for all studies published prior to March 2012 for trials of the effect of CPAP on HbA_1c. Data from observational studies and RCTs that met the inclusion criteria were extracted for pre- and post-treatment HbA_1c.

Results

A total of nine studies that included 151 subjects met the inclusion criteria. The duration of the studies ranged from 41?days to 6?months. The mean net change in the HbA_1c was ?0.06?% [95?% CI: ?0.24, 0.12] (p?=?0.5). Five of the nine studies, with a total of 112 subjects, comprised patients with diabetes mellitus (DM) type 2. The mean net change in HbA_1c for the subjects with DM type 2 was 0.08?% [95?% CI: ?0.26, 0.42] (p?=?0.65). The mean net change in HbA_1c for subjects with DM type 2 in studies that were at least 3?months in duration was 0.16?% [95?% CI: ?0.26, 0.58] (p?=?0.45).

Conclusions

This meta-analysis found that CPAP does not reduce HbA_1c levels when used in the short term.     

A UK nationwide prospective study of treatment change in MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after discontinuing insulin and metformin

Aims/hypothesis

Treatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA_1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years.

Methods

This was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate.

Results

A total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA_1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years’ follow-up without treatment, p?=?0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA_1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA_1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m²) at the time of genetic diagnosis, compared with individuals (n?=?23/36) with an HbA_1c >58 mmol/mol (>7.5%) (or <58 mmol/mol [<7.5%] on additional treatment) at the 2 year follow-up. Overall, 64% (7/11) individuals with a diabetes duration of ≤11 years and an HbA_1c of ≤69 mmol/mol (≤8.5%) at time of the genetic test achieved good glycaemic control (HbA_1c ≤58 mmol/mol [≤7.5%]) with diet or sulfonylurea alone at 2 years, compared with no participants with a diabetes duration of >11 years and an HbA_1c of >69 mmol/mol (>8.5%) at the time of genetic diagnosis.

Conclusions/interpretation

In participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA_1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA_1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA_1c.

     

Saxagliptin improves glycemic control by modulating postprandial glucagon and C-peptide levels in Chinese patients with type 2 diabetes

Aims

Saxagliptin reduced glycated hemoglobin (HbA_1c), fasting plasma glucose (FPG), and postprandial glucose (PPG) in Asian patients with type 2 diabetes mellitus (T2DM). To understand the physiology of this effect, indices of α- and β-cell function were measured in a subpopulation of Chinese patients following a noodle mixed-meal tolerance test.

Methods

Data from Chinese patients were pooled from two phase 3, 24-week studies of saxagliptin 5 mg/d as monotherapy in drug-naive patients and as add-on to metformin in patients inadequately controlled with metformin alone. The end points for β- and α-cell function were change from baseline in C-peptide, insulin, and glucagon areas under the curve from 0 to 180 min (AUC_0–180), insulinogenic index, and insulin sensitivity from Matsuda index after a mixed meal. Also glycemic variables, HbA_1c, FPG, and PPG (AUC_0–180), and homeostasis model assessment (HOMA) 2β were measured.

Results

At 24 weeks, greater improvements in adjusted mean change from baseline HbA_1c (difference vs placebo [95% CI], −0.33% [−0.50%, −0.17%], [−4 (−5.5, −1.9) mmol/mol], P < 0.0001), FPG (−0.41 [−0.78, −0.03] mmol/L, P = 0.03), PPG AUC_0–180 (−168 [−245, −91.8] mmol min/L, P < 0.0001), C-peptide AUC_0–180 (19.7 [5.2, 34.2] nmol min/L, P = 0.008), insulinogenic index (0.06% [0.02%, 0.09%], P = 0.002), and greater suppression of glucagon secretion (glucagon AUC_0–180, −322 [−493.6, −150.7] pmol min/L, P = 0.0003) were observed with saxagliptin versus placebo.

Conclusion

In Chinese patients with T2DM, saxagliptin as monotherapy or as add-on to metformin improved glycemic control by modulating α- and β-cell function.