Higher HbA Research Articles

Screening for depression and diabetes‐related distress in a diabetes outpatient clinic

To investigate: (1) the willingness of patients with diabetes to participate in a screening programme; (2) the extent to which patients with diabetes who screen positive endorse need for psychosocial care; (3) the rate of referral to psychosocial care during screening vs. usual care. Four hundred and ninety-nine patients with diabetes were invited to complete the Center for Epidemiologic Studies Depression and the Problem Areas in Diabetes questionnaires. Patients screening positive on either instrument were invited for an interview. One year after screening was withdrawn, rates of referral to psychosocial care were assessed from physician reports of patient referrals. In total, 349/499 (70%) patients with diabetes completed the questionnaire. Patients who did not take up the screening were younger, smoked more often and had higher HbA(1c) values. 'No-shows' for clinical appointments accounted for 74% of non-participation. Of the 104 (30% of 349) patients screening positive, 45 accepted an invitation for an interview. Finally, 36/104 (35%) would like a referral for psychological care. Seven per cent of patients were referred to psychological care during screening compared with 1% when screening was withdrawn. Results raise questions as to whether screening is the most efficient way to identify patients with psychological problems. Many patients did not take up the screening, especially those with low adherence to diabetes care in general. Furthermore, few patients screening positive wanted to be referred. Screening should be evaluated in the context of consideration of alternative ways to identify at-risk patients, including providing resources to deal with patients with already known adjustment and adherence problems.

Adaptive changes of human islets to an obesogenic environment in the mouse

Aims/hypothesisIn this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment.MethodsNon-diabetic Rag2 –/– mice (n = 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbAlc or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation.ResultsTransplanted mice on an HFD gained significantly more weight (p < 0.001) and had higher fasting glycaemia (2–12 weeks; p = 0.0002) and consistently higher fasting human C-peptide levels (2–12 weeks; p = 0.04) compared with those on the control diet. Histology demonstrated doubling of human islet graft volume at 12 weeks in animals on the HFD and increased beta cell volume (p < 0.001), but no change in alpha cell volume. Human islet function (hyperbolic product HOMA2%BS) at 12 weeks was four times lower in HFD animals (p < 0.001 vs controls) because of insufficient beta cell adaptation to decreased (70%) sensitivity (HOMA%S). Human islets obtained from donors with metabolic dysfunction failed to adapt to the HFD.Conclusions/interpretationThis longitudinal study provides direct evidence that human islets adapt both endocrine and beta cell mass, function and gene expression to obesity in vivo. The present model will facilitate the identification of mechanisms by which human islets adapt to obesity in vivo and the cell type(s) responsible, and factors predisposing human beta cells to decompensation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2775-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The atherogenic dyslipidemia ratio [log(TG)/HDL-C] is associated with residual vascular risk, beta-cell function loss and microangiopathy in type 2 diabetes females

BackgroundAtherogenic dyslipidemia (AD), defined as low HDL-C plus elevated triglycerides (TG), comorbid to T2DM, increases cardiometabolic risk for CAD even when LDL-C is at target. In T2DM males, AD was shown to correlate with β-cell function loss, yet it is not established whether this applies across gender.AimTo establish the prevalence and severity of AD in T2DM females, and to determine how it relates to cardiometabolic phenotype, glucose homeostasis, micro- and macrovascular complications, and 10-year absolute CV risk (UKPDS Risk Engine).Methods340 T2DM females were ranked according to quintiles (Q) of the continuous variable log(TG)/HDL-C, with AD prevalence defined as HDL-C <50 mg.dL-1 plus TG ≥150 mg.dL-1, and β-cell function assessed with HOMA.ResultsAD prevalence was 35%; mean HDL-C and TG were 52 (15) and 160 (105) mg.dL-1. AD was significantly related to central fat, metabolic syndrome, sedentarity and skeletal sarcopenia, as well as to hsCRP, fibrinogen, uric acid, cystatin-C, Big ET-1, and 10-year UKPDS CV risk. AD correlated stepwise with lower β-cell function and hyperbolic product, and with accelerated loss of residual insulin secretion, higher HbA1c and prevalent microangiopathy.Conclusionslog(TG)/HDL-C is a simple means to grade AD and residual macrovascular risk in T2DM females. This ratio associates with major non-LDL cardiometabolic variables and ranks predicted CAD risk. In addition, log(TG)/HDL-C identifies worsening glucose homeostasis, poorer glycemic control, and prevalent microangiopathy.

High normal HbA1c levels were associated with impaired insulin secretion without escalating insulin resistance in Japanese individuals: the Toranomon Hospital Health Management Center Study 8 (TOPICS 8)

We aimed to characterize the association of insulin resistance, impaired insulin secretion and β-cell dysfunction in relation to HbA(1c) levels in a non-diabetic range in Japanese individuals without clinically diagnosed diabetes. This cross-sectional study included 1444 individuals without a history of outpatient treatment of diabetes or use of insulin or oral hypoglycaemic agents. The homeostasis model assessment of insulin resistance and beta-cell function, insulinogenic index, Matsuda index and disposition index were calculated using data from 75-g oral glucose tolerance tests and compared across quintile (Q) categories of HbA(1c) levels. Fasting plasma glucose and 30-min and 60-min plasma glucose (PG) levels were significantly higher when HbA(1c) exceeded 36 mmol/mol (5.4%). A HbA(1c) concentration of 36-37 mmol/mol (5.4-5.5%) (Q3) was significantly associated with a 15% lower homeostasis model assessment of β-cell function value and 31% lower insulinogenic index value compared with HbA(1c) ≤ 32 mmol/mol (≤ 5.1%) (Q1) (P <0.01). Further, a HbA(1c) concentration of 38-40 mmol/mol (5.6-5.8%) (Q4) was associated with 17% (P <0.01) and 24% (P <0.05) reductions in those indexes, respectively. However, the homeostasis model assessment of insulin resistance was not significantly elevated and the Matsuda index was not significantly lower unless HbA(1c) exceeded 41 mmol/mol (5.9%). Individuals with HbA(1c) ≥ 41 mmol/mol (≥ 5.9%) (Q5) had a 69% lower disposition index than those with a HbA(1c) concentration of ≤ 32 mmol/mol (≤ 5.1%) (Q1). Elevated HbA(1c) levels ≥ 41 mmol/mol (≥ 5.9%) were associated with substantial reductions in insulin secretion, insulin sensitivity and β-cell dysfunction in Japanese individuals not treated for diabetes. High normal HbA(1c) levels of 36-40 mmol/mol (5.4-5.8%) were also associated with impaired insulin secretion without marked insulin resistance in Japanese individuals.

Type 1 diabetes in pre‐school children – long‐term metabolic control, associated autoimmunity and complications

To identify clinical characteristics and co-morbidity rates of children diagnosed with Type 1 diabetes mellitus at younger than 6 years of age. Data were obtained from a retrospective chart review of 103 patients diagnosed with Type 1 diabetes at younger than 6 years (study group) and 220 patients at older than 6 years (comparison group). Measures of glycaemic control and occurrence of co-morbidities (coeliac disease, autoimmune thyroid disease, hypertension, nephropathy and retinopathy) were compared. The mean follow-up period was more than 8 years. For the study group, mean HbA(1c) levels ranged from 64 mmol/mol to 66 mmol/mol (8.0-8.2%) until age 10 years, and then rose to 73 mmol/mol (8.8%). The HbA(1c) levels were higher in the study than in the comparison group for comparable ages (P = 0.003). After adjustment for duration of diabetes this difference was not significant. The overall rate of severe hypoglycaemic events was greater in the study group than in the comparison group (P = 0.03). Kaplan-Meier diagnosis rates of celiac disease, 10 years after Type 1 diabetes diagnosis, were 14.4% and 4.2% in the study and comparison groups, respectively (P log-rank = 0.03). There were no differences in rates of autoimmune thyroid disease, hypertension, nephropathy or retinopathy. Children diagnosed with Type 1 diabetes before the age of 6 years were in greater risk of developing celiac disease, compared with children diagnosed after the age of 6 years. For children diagnosed with Type 1 diabetes aged under 6 years, good metabolic control was achievable until age 10 years, after which it deteriorated. Higher HbA(1c) levels observed in children diagnosed before the age of 6 years were associated with longer duration of disease.

Care delivery and outcomes among Belgian children and adolescents with type 1 diabetes

We aimed to investigate care processes and outcomes among children and adolescents with type 1 diabetes treated in hospital-based multidisciplinary paediatric diabetes centres. Our retrospective cross-sectional study among 12 Belgian centres included data from 974 patients with type 1 diabetes, aged 0-18 years. Questionnaires were used to collect data on demographic and clinical characteristics, as well as process of care completion and outcomes of care in 2008. Most patients lived with both biological or adoption parents (77 %) and had at least one parent of Belgian origin (78 %). Nearly all patients (≥95 %) underwent determination of HbA(1c) and BMI. Screening for retinopathy (55 %) and microalbuminuria (73 %) was less frequent, but rates increased with age and diabetes duration. Median HbA(1c) was 61 mmol/mol (7.7 %) [interquartile range 54-68 mmol/mol (7.1-8.4 %)] and increased with age and insulin dose. HbA(1c) was higher among patients on insulin pump therapy. Median HbA(1c) significantly differed between centres [from 56 mmol/mol (7.3 %) to 66 mmol/mol (8.2 %)]. Incidence of severe hypoglycaemia was 30 per 100 patient-years. Admissions for ketoacidosis had a rate of 3.2 per 100 patient-years. Patients not living with both biological or adoption parents had higher HbA(1c) and more admissions for ketoacidosis. Parents' country of origin was not associated with processes and outcomes of care. Outcomes of care ranked well compared to other European countries, while complication screening rates were intermediate. The observed centre variation in HbA(1c) remained unexplained. Outcomes were associated with family structure, highlighting the continuing need for strategies to cope with this emerging challenge.

Health‐related quality of life and glycaemic control in patients with Type 2 diabetes mellitus in Singapore

To investigate the health-related quality of life of patients with diabetes mellitus in Singapore and its associations with diabetes-related characteristics and glycaemic control. An interviewer-administered, cross-sectional survey was conducted in a sample of 301 adult diabetes patients under primary care. The survey questionnaire included both a generic health-related quality of life measure, the Euroqol 5-D and a diabetes-specific instrument, the Audit of Diabetes-dependent Quality of Life. Patients' most recent HbA(1c) values were extracted from their medical records. After excluding patients who lacked the 90-day HbA(1c) test result, the final number of responses analysed was 282. Pain/discomfort was the most common complaint among the five Euroqol 5-D domains (by 28.0% of the respondents). Lack of freedom to eat was the Audit of Diabetes-dependent Quality of Life domain with the greatest negative average weighted impact (= -3.8, on a scale of -9 to 3). A significant association was observed between Audit of Diabetes-dependent Quality of Life average weighted impact and both duration of diabetes and use of insulin. A negative correlation was found between health-related quality of life and HbA(1c) values in both health-related quality of life measures (both r=-0.2, P=0.001). Patients with diabetes in primary-care settings frequently reported problems with pain/discomfort and restrictions in diet. Poorer health-related quality of life was found to be associated with higher HbA(1c) values. The chronicity of diabetes and insulin therapy may have a negative impact on patients' diabetes-related health-related quality of life. This study indicates the importance of achieving better disease management to improve the health-related quality of life of patients with diabetes.

Physician Reasons for Nonpharmacologic Treatment of Hyperglycemia in Older Patients Newly Diagnosed with Type 2 Diabetes Mellitus

IntroductionTo identify reasons why primary care physicians (PCPs) do not treat older patients newly diagnosed with type 2 diabetes mellitus (T2DM) with antihyperglycemic agents following diagnosis.MethodsUS PCPs were surveyed via the internet regarding their reasons for not treating patients aged >65 years diagnosed with T2DM and had not yet initiated antihyperglycemic therapy for ≥6 months after diagnosis. PCPs were requested to provide relevant clinical information for untreated older patients and select applicable reasons for not initiating treatment from a list of 35 possibilities, grouped into five categories.ResultsA total of 508 PCPs completed the online survey and provided complete clinical data for 770 patients. The reasons provided by the first-ranked physician for not initiating antihyperglycemic therapy were related to diet and exercise (57.5%); mild hyperglycemia (23.8%); patient’s concerns (13.4%); concerns about antihyperglycemic agents (3.0%); and comorbidities and polypharmacy (2.3%). The “diet and exercise” category was the most common first-ranked non-treatment reason, regardless of recent hemoglobin A1c (HbA1c) stratum. Reasons within the “patient’s concerns,” “concerns related to antihyperglycemic agents,” and “comorbidities and polypharmacy” categories tended to be selected more often as first-ranked reasons by physicians for patients with higher HbA1c values. Of the 158 patients whose physicians planned to initiate antihyperglycemic therapy within the next month, 54.4% already had a most recent HbA1c value above their physician-stated threshold for treatment initiation.ConclusionIn the PCPs studied, there was a tendency to select appropriate reasons for non-treatment with antihyperglycemic agents given their patients’ glycemic status. However, there was inertia related to the initiation of pharmacological therapy in some older patients with newly diagnosed T2DM. Important factors included physicians’ perceptions of “mild” hyperglycemia and the HbA1c threshold for using antihyperglycemic agents.

HbA1c Measured in Stored Erythrocytes Is Positively Linearly Associated with Mortality in Individuals with Diabetes Mellitus

IntroductionObservational studies have shown that glycated haemoglobin (HbA1c) is related to mortality, but the shape of the association is less clear. Furthermore, disease duration and medication may modify this association. This observational study explored the association between HbA1c measured in stored erythrocytes and mortality. Secondly, it was assessed whether disease duration and medication use influenced the estimates or were independently associated with mortality.MethodsWithin the European Prospective Investigation into Cancer and Nutrition a cohort was analysed of 4,345 individuals with a confirmed diagnosis of diabetes at enrolment. HbA1c was measured in blood samples stored up to 19 years. Multivariable Cox proportional hazard regression models for all-cause mortality investigated HbA1c in quartiles as well as per 1% increment, diabetes medication in seven categories of insulin and oral hypoglycaemic agents, and disease duration in quartiles.ResultsAfter a median follow-up of 9.3 years, 460 participants died. Higher HbA1c was associated with higher mortality: Hazard Ratio for 1%-increase was 1.11 (95% CI 1.06, 1.17). This association was linear (P-nonlinearity =0.15) and persistent across categories of medication use, disease duration, and co-morbidities. Compared with metformin, other medication types were not associated with mortality. Longer disease duration was associated with mortality, but not after adjustment for HbA1c and medication.ConclusionThis prospective study showed that persons with lower HbA1c had better survival than those with higher HbA1c. The association was linear and independent of disease duration, type of medication use, and presence of co-morbidities. Any improvement of HbA1c appears to be associated with reduced mortality risk.

Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies

Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm2) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case–control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA1C were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM.

Relation Between Hemoglobin A1c and Outcomes in Heart Failure Patients With and Without Diabetes Mellitus

In patients with diabetes mellitus (DM) in the general population, elevated glycosylated hemoglobin (HbA(1c)) increases the risk for developing heart failure (HF). However, in patients with established HF, the association of HbA(1c) level with outcomes is not well established. The aim of this study was to investigate the relation between HbA(1c) and outcomes in patients with HF with and without DM. A total of 845 patients with advanced HF followed at the Ahmanson-UCLA Cardiomyopathy Center were studied, stratified by the presence (n = 358) or absence (n = 487) of DM and by DM-specific HbA(1c) quartiles (patients with DM: Q1 ≤6.4%, Q2 6.5% to 7.2%, Q3 7.3% to 8.5%, and Q4 ≥8.6%; patients without DM: Q1 ≤5.6%, Q2 5.7% to 6.0%, Q3 6.1% to 6.5%, and Q4 ≥6.6%). The primary outcomes analyzed were death and death or urgent heart transplantation. In the cohort with DM, 2-year event-free survival was 61% and 65% in Q3 and Q4 compared to 48% and 42% in Q1 and Q2 (p = 0.005). In the cohort without DM, there was no difference in outcomes by HbA(1c) quartile. Risk-adjusted analysis in the diabetic cohort showed significantly increased hazard ratios for death or urgent heart transplantation in Q1 and Q2 compared to Q4. For every unit HbA(1c) increase, there was a 15% decreased hazard ratio of death or urgent heart transplantation and all-cause mortality (p = 0.006 and p = 0.036, respectively). In the cohort without DM, multivariate models revealed similar hazard ratios among HbA(1c) quartiles. In conclusion, in this cohort of patients with advanced HF, higher HbA(1c) levels were associated with improved outcomes in patients with DM. This relation was not observed in patients without DM. Further investigations into mechanisms underlying the relation between HbA(1c), DM, and survival in advanced HF are warranted.

Update on Insulin Therapy for Type 2 Diabetes

Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion at diagnosis and by progressive β-cell dysfunction over time. Insulin therapy is thus frequently required during the course of the disease to maintain glycemic control and prevent diabetes complications. Insulin should be initiated when alternative antihyperglycemic agents have failed or when symptomatic or marked hyperglycemia is present. Recent studies demonstrate that the addition of basal, prandial, basal/bolus, or premixed insulins to existing antihyperglycemic regimens effectively lowers glycosylated hemoglobin (HbA1c). The long-acting insulin analogs cause less nocturnal hypoglycemia than bedtime NPH, with comparable HbA1c reductions. Insulin detemir confers a weight advantage over glargine or NPH. Rapid-acting insulin analogs control postprandial hyperglycemia more effectively than regular insulin and modestly lower HbA1c. For selected patients with severe insulin resistance, U-500 is a less expensive and potentially more effective alternative to U-100 insulin. Adverse effects of insulin, including weight gain and hypoglycemia, can be minimized by initial use of basal insulins in combination with metformin, incretin mimetics, or dipeptidyl-peptidase-IV inhibitors. Although in vitro studies suggest that hyperinsulinemia may promote tumorigenesis, no currently available insulin has been shown to increase cancer rates. Targeting near-normal glucose levels in insulin-treated patients should be reserved for those of younger age with a longer life expectancy, a shorter duration of diabetes, and little or no end-organ complications. A higher HbA1c target of 7–8% is more appropriate for patients less likely to benefit from intensive control and in those at high risk for severe hypoglycemia.

Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes

Incretin-based glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitor therapies provide glycaemic control with reduced risks associated with weight gain or hypoglycaemia. Incretin therapies are compared with their mechanisms of action, effects on haemoglobin A(1C) (HbA(1C)), fasting plasma glucose (FPG), post-prandial glucose (PPG), body weight, β-cell function, cardiovascular biomarkers and in their safety profiles to aid clinicians in the selection of individualized pharmacotherapy for patients with type 2 diabetes. Relevant articles for a systematic review were identified through PubMed. Randomized, head-to-head comparison studies among incretin therapies were identified and included in the review. Additionally, randomized, controlled monotherapy and combination therapy studies examining glycaemic and extraglycaemic effects of individual incretin therapies from 2007 to 2011 were reviewed. Glucagon-like peptide-1 receptor agonists are generally preferred over DPP-4 inhibitors because of their greater effectiveness in reducing HbA(1C) , FPG and PPG excursions, and greater weight loss potentiation. As a monotherapy option, longer-acting GLP-1 RAs, including liraglutide and exenatide once-weekly, may be preferred at higher HbA(1C) because of their more pronounced effects on FPG. At lower/near normal HbA(1C) , a short-acting GLP-1 RA, such as exenatide twice-daily, may be a better choice as its effects are more pronounced with PPG. Ideal patients or patient situations for DPP-4 inhibitors include patients who need minimal reduction in HbA(1C,) elderly patients, patients who are unwilling or unable to take an injectable agent, when GLP-1 RAs are contraindicated or when the patient will not benefit from weight loss. Treatment benefits common to all incretin-based therapies include minimal hypoglycaemia risk, potential preservation of β-cell function and effective targeting of multiple organs underlying type 2 diabetes and of comorbidities commonly associated with type 2 diabetes, such as obesity and hypertension. Key differences in mechanisms of action and in glycaemic and extra-glycaemic treatment outcomes exist among incretin therapies, both within the GLP-1 RA class, and between GLP-1 RAs and DPP-4 inhibitors. Clinical judgment acknowledging important differences among incretin therapies and treatment-related patient characteristics will aid in the selection of the appropriate incretin agent for individualized pharmacotherapy.

Re‐examining a measure of diabetes‐related burden in parents of young people with Type 1 diabetes: the Problem Areas in Diabetes Survey – Parent Revised version (PAID‐PR)

In a pediatric patients, the burden of diabetes lies within the family. In the current era of intensive insulin therapy, perceived parental burden may affect the family's efforts at effective diabetes management. The aims of this study were to re-examine and revise a measure of perceived parental burden associated with caring for a child with diabetes in the current era. A geographically diverse population of young people (N = 376) with Type 1 diabetes and their parents included participants in the Juvenile Diabetes Research Foundation continuous glucose monitoring study and patients from the Joslin Diabetes Center. Participants provided data on demographics, diabetes management, diabetes-specific family conflict, and quality of life at baseline and after 6 months of follow-up. Young people were 12.9 ± 2.7 years old with diabetes duration of 6.3 ± 3.5 years. Mean HbA(1C) was 8.0 ± 1.2%(64 mmol/mol), 58% received insulin pump therapy, and young people monitored blood glucose 5.2 ± 2.3 times/day. Factor analysis yielded two factors, 'Immediate Burden' and 'Theoretical Burden'. The Problem Areas in Diabetes Survey - Parent Revised version (PAID-PR) demonstrated excellent internal consistency (Cronbach's α = 0.87; factor 1 α = 0.78; factor 2 α = 0.83). Greater parental burden was associated with more frequent blood glucose monitoring, higher HbA(1C) levels, greater diabetes-specific family conflict, and lower quality of life. Test-retest analysis was acceptable (r = 0.62). The PAID-PR demonstrated excellent internal consistency, good test-retest reliability, and associations with diabetes-specific family conflict and quality of life. This brief measure may have both clinical and research utility in the management of young people with Type 1 diabetes.

Obesity-Independent Inverse Association between Regular Alcohol Consumption and Hemoglobin A1C

Objective: The aim of this study was to determine whether obesity influences relationships between habitual alcohol drinking and hemoglobin A_1C (HbA_1C) level. Methods: Japanese men (35–70 years old, n = 24858) were divided into non-, light (<22 g ethanol/day), moderate (≧22 and <44 g ethanol/day), and heavy (≧44 g ethanol/day) drinkers. Relationships of alcohol with HbA_1C were investigated in overall subjects and subjects of quartile groups for degree of obesity. Results: HbA_1C tended to be higher as quartiles of BMI and waist-to-height ratio increased. HbA_1C was significantly lower in light, moderate and heavy drinkers than in nondrinkers. These associations in overall subjects were also found in all of the quartiles of BMI and waist-to-height ratio, except for light drinkers in the 3rd and 4th quartiles of BMI and the 4th quartile of waist-to-height ratio. Odds ratios versus nondrinkers for high HbA_1C were significantly lower than a reference level of 1.0 in all drinker groups, and these associations were not altered after adjustment for age, history of smoking, and BMI or waist-to-height ratio. Conclusion: The results suggest that alcohol consumption is associated with lower HbA_1C level independent of degree of obesity.

Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds

There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA(1c) and the risks of vascular complications and death in such patients. Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA(1c) measurements during follow-up and prior to the first event. Adjusted risks for each HbA(1c) decile were estimated using Cox models. Possible differences in the association between HbA(1c) and risks at different levels of HbA(1c) were explored using linear spline models. There was a non-linear relationship between mean HbA(1c) during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA(1c) studied (5.5-10.5%), there was evidence of 'thresholds', such that below HbA(1c) levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA(1c) level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p < 0.0001). In patients with type 2 diabetes, HbA(1c) levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.

Association Between Glycemic Control and Adverse Outcomes in People With Diabetes Mellitus and Chronic Kidney Disease

Better glycemic control as reflected by lower hemoglobin A(1c) (HbA(1c)) level may prevent or slow progression of nephropathy in people with diabetes mellitus (DM). Whether a lower HbA(1c) level improves outcomes in people with DM and chronic kidney disease (CKD) is unknown. From all people with serum creatinine measured as part of routine care in a single Canadian province from 2005 through 2006, we identified those with CKD based on laboratory data (estimated glomerular filtration rate [eGFR], <60.0 mL/min/1.73 m(2)]) and DM using a validated algorithm applied to hospitalization and claims data. Patients were classified based on their first HbA(1c) measurement; Cox regression models were used to assess independent associations between HbA(1c) level and 5 study outcomes (death, progression of kidney disease based on a doubling of serum creatinine level, or new end-stage renal disease [ESRD], cardiovascular events, all-cause hospitalization). We identified 23,296 people with DM and an eGFR lower than 60.0 mL/min/1.73 m(2). The median HbA(1c) level was 6.9% (range, 2.8%-20.0%), and 11% had an HbA(1c) value higher than 9%. Over the median follow-up period of 46 months, 3665 people died, and 401 developed ESRD. Regardless of baseline eGFR, a higher HbA(1c) level was strongly and independently associated with excess risk of all 5 outcomes studied (P < .001 for all comparisons). However, the association with mortality was U-shaped, with increases in the risk of mortality apparent at HbA(1c) levels lower than 6.5% and higher than 8.0%. The increased risk of ESRD associated with a higher HbA(1c) level was attenuated at a lower baseline eGFR (P value for interaction, <.001). Specifically, among those with an eGFR of 30.0 to 59.9 mL/min/1.73 m(2), the risk of ESRD was increased by 22% and 152% in patients with HbA(1c) levels of 7% to 9% and higher than 9%, respectively, compared with patients with an HbA(1c) level lower than 7% (P < .001), whereas corresponding increases were 3% and 13%, respectively, in those with an eGFR of 15.0 to 29.9 mL/min/1.73 m(2). A hemoglobin A(1c) level higher than 9% is common in people with non-hemodialysis-dependent CKD and is associated with markedly worse clinical outcomes; lower levels of HbA(1c) (<6.5%) also seemed to be associated with excess mortality. The excess risk of kidney failure associated with a higher HbA(1c) level was most pronounced among people with better kidney function. These findings suggest that appropriate and timely control of HbA(1c) level in people with DM and CKD may be more important than previously realized, but suggest also that intensive glycemic control (HbA(1c) level <6.5%) may be associated with increased mortality.

Incidence and progression of diabetic retinopathy in Japanese adults with type 2 diabetes: 8 year follow-up study of the Japan Diabetes Complications Study (JDCS)

The aim of this study was to determine the incidence and progression rates of diabetic retinopathy and their associations in Japanese individuals with type 2 diabetes. This is a part of the Japan Diabetic Complications Study (JDCS), a multi-centred randomised trial of type 2 diabetes patients aged 40-70 years with an 8 year follow-up. There were 1,221 patients without diabetic retinopathy at baseline; incidence of diabetic retinopathy was defined as the development of any diabetic retinopathy. There were 410 patients with mild non-proliferative diabetic retinopathy at baseline; progression of diabetic retinopathy was defined as the development of severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy. We used multivariate proportional Cox hazard models, and generalised additive models were also applied to identify potential threshold effect. The incidence and progression rate of diabetic retinopathy was 38.3/1,000 person-years and 21.1/1,000 person-years, respectively. Higher HbA(1c) (adjusted HR [aHR] per 1% [10.9 mmol/mol] 1.36 [95% CI 1.28-1.45]), longer duration of diabetes (aHR per 5 year period 1.26 [95% CI 1.17-1.35]), higher systolic blood pressure (aHR per +10 mmHg 1.01 [95% CI 1.00-1.02]) and higher body mass index (aHR per 1 kg/m(2) 1.05 [95% CI 1.00-1.09]) were associated with incident diabetic retinopathy. The association between HbA(1c) and incident diabetic retinopathy was linear; the association with duration of diabetes increased rapidly between 5 and 10 years. Higher HbA(1c) was also associated with progression of diabetic retinopathy (aHR per 1% [10.9 mmol/mol] 1.66 [95% CI 1.41-1.96]). Observed incidence and progression rates of diabetic retinopathy seemed lower than that in western populations. HbA(1c) was the only factor associated with both incidence and progression of diabetic retinopathy. The strength of the association between duration of diabetes and incidence of diabetic retinopathy increased rapidly during a period of 5 to 10 years duration of diabetes. C000000222 ( www.umin.ac.jp ) This study is supported by the Ministry of Health, Labour and Welfare, Japan.

Frequent Hypoglycemia Among Elderly Patients With Poor Glycemic Control

Episodes of hypoglycemia are particularly dangerous in the older population. To reduce the risk of hypoglycemia, relaxation of the standard hemoglobin A(1c) (HbA(1c)) goals has been proposed for frail elderly patients. However, the risk of hypoglycemia in this population with higher HbA(1c) levels is unknown. Patients 69 years or older with HbA(1C) values of 8% or greater were evaluated with blinded continuous glucose monitoring for 3 days. Forty adults (mean [SD] age, 75 [5] years; HbA(1C) value, 9.3% [1.3%]; diabetes duration, 22 [14] years; 28 patients [70%] with type 2 diabetes mellitus; and 37 [93%] using insulin) were evaluated. Twenty-six patients (65%) experienced 1 or more episodes of hypoglycemia (glucose level <70 mg/dL). Among these, 12 (46%) experienced a glucose level below 50 mg/dL and 19 (73%), a level below 60 mg/dL. The average number of episodes was 4; average duration, 46 minutes. Eighteen patients (69%) had at least 1 nocturnal episode (10 pm to 6 am). Of the total of 102 hypoglycemic episodes, 95 (93%) were unrecognized by finger-stick glucose measurements performed 4 times a day or by symptoms. Hypoglycemic episodes are common in older adults with poor glycemic control. Raising HbA(1C) goals may not be adequate to prevent hypoglycemia in this population.

Characterizing sudden death and dead‐in‐bed syndrome in Type 1 diabetes: analysis from two childhood‐onset Type 1 diabetes registries

Type 1 diabetes mellitus increases the risk for sudden unexplained death, generating concern that diabetes processes and/or treatments underlie these deaths. Young (< 50 years) and otherwise healthy patients who are found dead in bed have been classified as experiencing 'dead-in-bed' syndrome. We thus identified all unwitnessed deaths in two related registries (the Children's Hospital of Pittsburgh and Allegheny County) yielding 1319 persons with childhood-onset (age < 18 years) Type 1 diabetes diagnosed between 1965 and 1979. Cause of death was determined by a Mortality Classification Committee (MCC) of at least two physician epidemiologists, based on the death certificate and additional records surrounding the death. Of the 329 participants who had died, the Mortality Classification Committee has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were sudden unexplained deaths (13 male) and seven met dead-in-bed criteria. The Mortality Classification Committee adjudicated cause of death in the seven dead-in-bed persons as: diabetic coma (n =4), unknown (n=2) and cardiomyopathy (n=1, found on autopsy). The three dead-in-bed individuals who participated in a clinical study had higher HbA(1c) , lower BMI and higher daily insulin dose compared with both those dying from other causes and those surviving. Sudden unexplained death in Type 1 diabetes seems to be increased 10-fold and associated with male sex, while dead-in-bed individuals have a high HbA(1c) and insulin dose and low BMI. Although sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to sudden unexplained death and dead-in-bed death.