A1C Between 5.7 and 6.4% as a Marker for Identifying Pre-Diabetes, Insulin Sensitivity and Secretion, and Cardiovascular Risk Factors: The Insulin Resistance Atherosclerosis Study (IRAS)

OBJECTIVE

A1C is an optional method for diagnosing diabetes and also for detecting individuals at increased risk of the disease. However, how A1C compares with fasting (FPG) and 2-h plasma glucose for detecting at-risk individuals is not well known.

RESEARCH DESIGN AND METHODS

A 2-h glucose tolerance test, frequently sampled intravenous glucose tolerance test, and A1C were obtained at the follow-up examination in 855 participants in the Insulin Resistance Atherosclerosis Study (IRAS). For this report, 385 individuals were at increased risk of diabetes as defined by A1C between 5.7 and 6.4%, impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG).

RESULTS

IFG and IGT identified 69.1 and 59.5% of all individuals at increased risk of diabetes, respectively. A1C 5.7–6.4% detected 23.6% of all at-risk individuals, although more African Americans (31.4%) and Hispanics (35.2%) than non-Hispanic whites (9.9%). Relative to A1C, FPG was more strongly related to fasting insulin (r = 0.38 vs. 0.26; P < 0.01), acute insulin response (r = – 0.20 vs. – 0.09; P < 0.01), and waist circumference (r = 0.43 vs. 0.25; P < 0.001) by the Spearman correlation test. Similarly, 2-h plasma glucose was more strongly related to Si (r = – 0.40 vs. – 0.27; P < 0.01) and triglycerides (r = 0.30 vs. 0.08; P < 0.001).

CONCLUSIONS

A1C 5.7–6.4% is less sensitive for detecting at-risk individuals than IFG and IGT, particularly among non-Hispanic whites. Single determinations of FPG and 2-h plasma glucose seem to be more precise correlates of insulin resistance and secretion than A1C and, in general, better for other metabolic disorders.A1C has been proposed by the American Diabetes Association (ADA) as an optional assay for diagnosing diabetes and also for detecting individuals at increased risk of the disease (1). A1C has been shown to predict future onset of diabetes (2–4) and is better than fasting plasma glucose (FPG) for predicting microvascular complications (1). A1C may be superior to FPG in predicting mortality and cardiovascular risk in nondiabetic individuals (5) but inferior to 2-h glucose concentration (2-h plasma glucose) in most studies (6–8), albeit not all (9). The A1C assay has advantages over the measurement of plasma glucose including convenience (not requiring fasting samples) and superior technical attributes (1). Conversely, the number of individuals diagnosed with diabetes by the 6.5% A1C threshold is significantly smaller than the number of those diagnosed by the 2003 American Diabetes Association (ADA) criteria (10–13). A1C, FPG, and 2-h plasma glucose assess different aspects of glucose metabolism (1), but differences in the relation of these three glycemic measures to insulin resistance, insulin secretion, and other metabolic abnormalities have not been described.A1C between 5.7 and 6.4% (A1C 5.7–6.4%) is now considered a category of increased risk for diabetes in addition to impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (1). However, studies that compare A1C 5.7–6.4% with IFG and IGT are lacking. Therefore, our aim was twofold: 1) to analyze A1C, FPG, and 2-h plasma glucose for their ability to identify individuals at increased risk of diabetes; and 2) to examine the relation of these glycemic measures to other metabolic abnormalities, particularly measured insulin resistance and secretion in nondiabetic subjects.     

Minimal Contribution of Fasting Hyperglycemia to the Incidence of Type 2 Diabetes in Subjects With Normal 2-h Plasma Glucose

OBJECTIVE

To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration.

RESEARCH DESIGN AND METHODS

A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7–8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations.

RESULTS

In subjects with 2-h plasma glucose <140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a strong predictor of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes.

CONCLUSIONS

An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.Impaired fasting glucose (IFG) was introduced in 1997 by the American Diabetes Association (ADA) (1), and, analogous with impaired glucose tolerance (IGT), it was meant to represent an intermediate stage in the transition from normal glucose tolerance (NGT) to overt type 2 diabetes. Both IFG and IGT indicate an increased risk for future type 2 diabetes (2–4). Previously (5–7), we have shown that the 1-h plasma glucose concentration has better predictive power than either fasting plasma glucose (FPG) or 2-h plasma glucose, suggesting that the 1-h plasma glucose concentration may have greater utility in identifying subjects at increased risk for type 2 diabetes in routine clinical practice.Previous studies have reported that IFG and IGT represent separate clinical entities, which are characterized by distinct metabolic abnormalities (8–13). Subjects with IGT manifest insulin resistance in skeletal muscle (9–12) and impaired β-cell function (both early and late phases of insulin secretion) (10,14–16), whereas subjects with IFG are characterized by increased hepatic insulin resistance (9,16), impaired early insulin response (12), and decreased non–insulin-dependent glucose clearance (15). Because of the prominent role of progressive β-cell failure in the development of hyperglycemia (17), the impairment in β-cell function in subjects with IGT represents a major pathogenic factor for their increased risk for future type 2 diabetes. Although the increase in fasting plasma glucose is associated with a decrease in first-phase insulin secretion (11–13,18), subjects with IFG have robust second-phase insulin secretion, and, when related to their prevailing level of insulin resistance, they have second-phase insulin secretion comparable with that of subjects with NGT (12,13). Thus, impaired β-cell function cannot fully explain the increased incidence of type 2 diabetes associated with the increase in FPG concentration, e.g., in subjects with isolated IFG.Previously we have shown a strong correlation between insulin resistance in skeletal muscle and liver (16). Thus, a strong correlation between FPG and postload plasma glucose concentrations is anticipated. Therefore, we hypothesized that the increased type 2 diabetes risk associated with the increase in FPG, at least in part, is due to the increased postprandial plasma glucose concentration associated with the increase in FPG and is not due to the increase in FPG per se. The aim of this study was to test this hypothesis.     

Declining ��-Cell Function Relative to Insulin Sensitivity With Increasing Fasting Glucose Levels in the Nondiabetic Range in Children

OBJECTIVE

In adults, higher fasting plasma glucose (FPG) levels, even within the normoglycemic range, are associated with increased diabetes risk. This investigation tested the hypothesis that β-cell function relative to insulin sensitivity decreases with increasing FPG in youth.

RESEARCH DESIGN AND METHODS

A total of 223 youth with FPG <126 mg/dl underwent evaluation of first- and second-phase insulin secretion during a 2-h hyperglycemic (∼225 mg/dl) clamp, insulin sensitivity during a 3-h hyperinsulinemic-euglycemic clamp, body composition, and abdominal adiposity with dual-energy X-ray absorptiometry and computed tomographic scan. β-Cell function relative to insulin sensitivity was calculated as the product of first-phase insulin and insulin sensitivity, i.e., glucose disposition index (GDI). The subjects were divided into three FPG categories: ≤90, >90–<100, and ≥100–<126 mg/dl.

RESULTS

GDI decreased significantly across the three categories as FPG increased (1,086 ± 192 vs. 814 ± 67 and 454 ± 57 mg/kg/min, P = 0.002). This decline remained significant after adjustment for race, sex, BMI, and percent body fat or visceral fat. Within each FPG category, GDI declined with increasing BMI percentiles.

CONCLUSIONS

The impairment in β-cell function relative to insulin sensitivity is apparent even within the nondiabetic FPG range in children. At the current cutoff of 100 mg/dl for impaired fasting glucose (IFG), there is an ∼49% decline in the GDI independent of obesity and race. This observation may reflect a heightened risk of β-cell dysfunction and progression to diabetes in these children. Considering the near doubling of IFG prevalence among youth between National Health and Nutrition Examination Survey 1999–2000 and 2005–2006, our findings have important public health implications.Higher fasting plasma glucose (FPG) levels within the currently accepted normoglycemic range seem to have an impact on diabetes risk in adults (1–3). FPG levels >125 mg/dl indicate a provisional diagnosis of diabetes (4). FPG levels below this cutoff but above normal increase the risk of developing diabetes (5) and are associated with a higher cardiovascular disease risk (6,7). The American Diabetes Association classifies this intermediate state of FPG as impaired fasting glucose (IFG) (4) and initially defined it as fasting glucose of 110–125 mg/dl (8), which was lowered to 100 mg/dl in 2003 to better identify subjects at risk of diabetes development (9). Several studies in adults suggested that future diabetes risk increases continually with increasing FPG even below this lower cutoff for normoglycemia (1,2). In adults, fasting glucose levels of 90–94 mg/dl conferred a 49% greater risk of developing diabetes compared with levels <85 mg/dl (2). FPG levels in the top quintiles (95–99 mg/dl) of the normoglycemic range constituted an independent risk factor for type 2 diabetes among young men in the Israeli army after adjustment for several risk factors (1). In a Mauritius population-based study, parameters related to diabetes and cardiovascular disease such as higher BMI, cholesterol, triglycerides, and hypertension were positively correlated with higher FPG values in an approximately linear relationship (3). In addition, a meta-analysis of prospective studies showed a continuous relationship between baseline fasting glucose and subsequent cardiovascular risk (10). These observations raise a fundamental question: are insulin secretion and sensitivity impaired at higher levels of FPG but within the normal range? Few studies in adults have investigated this question, and results are conflicting (11–13). However, none of these studies used robust methodologies of assessing in vivo insulin secretion and sensitivity to derive a glucose disposition index (GDI), which is accepted to be the best indicator of β-cell dysfunction (14). Currently there are no published data assessing the relationship between high-normal fasting glucose levels and insulin sensitivity and secretion in children. The pre-diabetes cutoff levels for FPG in pediatrics are based on adult data and not on data generated in pediatric populations.In this study, we investigated the relationship between levels of fasting glucose and insulin secretion relative to insulin sensitivity, i.e., GDI, in children. Based on adult observations we hypothesized that β-cell function relative to insulin sensitivity decreases as FPG concentrations increase within the currently accepted nondiabetic range in children.     

Active Care Management Supported by Home Telemonitoring in Veterans With Type 2 Diabetes: The DiaTel randomized controlled trial

OBJECTIVE

We compared the short-term efficacy of home telemonitoring coupled with active medication management by a nurse practitioner with a monthly care coordination telephone call on glycemic control in veterans with type 2 diabetes and entry A1C ≥7.5%.

RESEARCH DESIGN AND METHODS

Veterans who received primary care at the VA Pittsburgh Healthcare System from June 2004 to December 2005, who were taking oral hypoglycemic agents and/or insulin for ≥1 year, and who had A1C ≥7.5% at enrollment were randomly assigned to either active care management with home telemonitoring (ACM+HT group, n = 73) or a monthly care coordination telephone call (CC group, n = 77). Both groups received monthly calls for diabetes education and self-management review. ACM+HT group participants transmitted blood glucose, blood pressure, and weight to a nurse practitioner using the Viterion 100 TeleHealth Monitor; the nurse practitioner adjusted medications for glucose, blood pressure, and lipid control based on established American Diabetes Association targets. Measures were obtained at baseline, 3-month, and 6-month visits.

RESULTS

Baseline characteristics were similar in both groups, with mean A1C of 9.4% (CC group) and 9.6% (ACM+HT group). Compared with the CC group, the ACM+HT group demonstrated significantly larger decreases in A1C at 3 months (1.7 vs. 0.7%) and 6 months (1.7 vs. 0.8%; P < 0.001 for each), with most improvement occurring by 3 months.

CONCLUSIONS

Compared with the CC group, the ACM+HT group demonstrated significantly greater reductions in A1C by 3 and 6 months. However, both interventions improved glycemic control in primary care patients with previously inadequate control.Within the Veterans Health Administration, ∼500,000 veterans receive care for diabetes annually; diabetes is a leading cause of morbidity and mortality and a major contributor to health care cost (1,2). Sampling data from 2009 indicate that ∼28% of veterans nationally have suboptimal glycemic control with A1C ≥8% (3). Increases in A1C levels above the normal range in patients with diabetes are associated with progressive increases in morbidity and mortality due to micro- and macrovascular disease (4). Intensive glycemic control can reduce microvascular complications in both type 1 and type 2 diabetes (5,6). However, recent studies have not demonstrated that intensive glycemic control for 3–6 years with achieved A1C targets from 6.4 to 6.9% reduces macrovascular complications in patients with long-standing type 2 diabetes (7–9). In contrast, intensive glycemic control initiated early in the course of either type 1 or type 2 diabetes appears to reduce the risk of subsequent macrovascular complications significantly even when glycemic control later deteriorates (10,11).Home-based telemedicine has been examined as a tool for management of chronic diseases (12), including diabetes (13–19). This approach can obviate geographic barriers; provide automated education, feedback, and data transmission; and facilitate provider-to-patient communication (12). However, outcomes with home telemonitoring in diabetes and other chronic diseases have been variable (12). Of several randomized controlled trials (RCTs) using home telemonitoring in diabetes care (13–19), only two have reported significant improvement in A1C (17,18). Neither of these trials included active medication management by a provider in response to real-time transmission of self-monitored blood glucose (SMBG) data or have specifically targeted patients not meeting glycemic control goals in response to pharmacological therapy under conditions of usual care.The present study compared the efficacy of home telemonitoring coupled with active medication management by a nurse practitioner (ACM+HT intervention) with a lower-intensity care coordination intervention (CC intervention) consisting of monthly telephone contact with a diabetes nurse educator. Our study specifically targeted veterans with A1C levels ≥8% after ≥1 year receiving pharmacological therapy under conditions of usual care.     

Dietary Patterns and Risk for Diabetes: The Multiethnic Cohort

OBJECTIVE

The high diabetes incidence among Japanese Americans and Native Hawaiians cannot be explained by BMI. Therefore, we examined the influence of three dietary patterns of “fat and meat,” “vegetables,” and “fruit and milk” on diabetes risk in the Hawaii component of the Multiethnic Cohort with 29,759 Caucasians, 35,244 Japanese Americans, and 10,509 Native Hawaiians.

RESEARCH DESIGN AND METHODS

Subjects aged 45–75 years completed a baseline food frequency questionnaire. After 14 years of follow-up, 8,587 subjects with incident diabetes were identified through self-reports or health plan linkages. Risk was assessed using Cox regression stratified by age and adjusted for ethnicity, BMI, physical activity, education, total energy, smoking, alcohol intake, marital status, and hypertension.

RESULTS

Fat and meat was significantly associated with diabetes risk in men (hazard ratio 1.40 [95% CI 1.23–1.60], P_trend < 0.0001) and women (1.22 [1.06–1.40], P_trend = 0.004) when extreme quintiles were compared. Except in Hawaiian women, the magnitude of the risk was similar across ethnic groups although not always significant. After stratification by BMI, fat and meat remained a predictor of disease primarily among overweight men and among overweight Japanese women. Vegetables lowered diabetes risk in men (0.86 [0.77–0.95], P_trend = 0.004) but not in women, whereas fruit and milk seemed to be more beneficial in women (0.85 [0.76–0.96], P_trend = 0.005) than in men (0.92 [0.83–1.02], P_trend = 0.04).

CONCLUSIONS

Foods high in meat and fat appear to confer a higher diabetes risk in all ethnic groups, whereas the effects of other dietary patterns vary by sex and ethnicity.Native Hawaiians have extremely high rates of obesity and diabetes, but despite their relatively low body weight, individuals with Japanese ancestry are also disproportionately affected by diabetes (1). Among the >44,000 Japanese Americans, 14,000 Native Hawaiians, and 35,000 Caucasians in the Hawaii component of the Multiethnic Cohort (MEC), a previous analysis had found diabetes incidence rates of 15.5, 12.5, and 5.8 per 1,000 person-years, respectively, that could not be explained by BMI (2). Dietary patterns have been identified as additional predictors of disease but have only rarely been investigated prospectively among non-Caucasian populations (3–5). The most commonly identified patterns are the so-called “western,” “unhealthy,” or “conservative” pattern (3–11), which is high in meat, high-fat foods, and sweets, and the “prudent” or “healthy” pattern, rich in fruit and vegetables (3–8,10,12,13). With the goal to contribute to the prevention of diabetes, we examined the effect of three dietary patterns, “fat and meat,” “vegetables,” and “fruit and milk,” which had been previously identified in the MEC, on diabetes risk (14).     

Gestational Diabetes Mellitus: Simplifying the International Association of Diabetes and Pregnancy diagnostic algorithm using fasting plasma glucose

OBJECTIVE

To determine the impact of the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria on 1) gestational diabetes mellitus (GDM) diagnosis compared with the American Diabetes Association (ADA) criteria and 2) the fasting plasma glucose (FPG) to predict GDM.

RESEARCH DESIGN AND METHODS

In 10,283 pregnant women undergoing a 75-g oral glucose tolerance test (OGTT) for universal screening of GDM, two FPG thresholds (of the OGTT) were used to rule in and to rule out GDM.

RESULTS

The IADPSG and ADA criteria identified GDM in 3,875 (37.7%) women and 1,328 (12.9%) women, respectively (P < 0.0005). FPG thresholds of ≥5.1 mmol/l ruled in GDM in 2,975 (28.9%) women with 100% specificity, while <4.4 mmol/l ruled out GDM in 2,228 (21.7%) women with 95.4% sensitivity. FPG independently could have avoided the OGTT in 5,203 (50.6%) women.

CONCLUSIONS

The IADPSG criteria increased GDM prevalence nearly threefold. By circumventing a significant number of OGTTs, an initial FPG can greatly simplify the IADPSG diagnostic algorithm.The scourge of gestational diabetes mellitus (GDM) is the lack of an international agreement on the screening and diagnosis among the pre-eminent diabetes, obstetric, and health care organizations (1). Therefore, without a globally accepted guideline, the diagnosis of GDM causes a great deal of clinical confusion (2). In March 2010, the International Association of Diabetes and Pregnancy Study Group (IADPSG) issued consensus guidelines to potentially attain a single approach for GDM diagnosis worldwide (3).The inconsistency in GDM diagnosis is evident in the United Arab Emirates (UAE), which has the second highest prevalence of type 2 diabetes (18.7%) in the world (4). GDM in the UAE varies from 7.9 to 24.9%, depending on which of the six well-accepted criteria are used for diagnosis (2). The popular American Diabetes Association (ADA) criteria (5) demonstrates a prevalence of 10.6–14.7% (2,6–8). In this population, multiple studies have confirmed that the initial fasting plasma glucose (FPG) result of the oral glucose tolerance test (OGTT) is excellent in determining the need to continue with the OGTT (6,9–10); however, its efficiency depends on the criteria used for GDM diagnosis (6). The aim of this study was to determine, in this high-risk population, the impact of the new IADPSG criteria on 1) the diagnosis of GDM compared with the ADA criteria and 2) the FPG to predict GDM in order to decide whether to proceed with the OGTT.     

Comparison of near-patient capillary glucose measurement and a risk assessment questionnaire in screening for type 2 diabetes in a high-risk population in rural India

OBJECTIVE

To assess the utility of a point-of-care (POC) capillary blood glucose measurement as compared with routine clinical parameters in predicting undiagnosed diabetes in a low-resource rural India setting.

RESEARCH DESIGN AND METHODS

Nine hundred and ninety-four participants aged >30 years and stratified by age and sex were randomly selected from 20 villages in India. A clinical questionnaire, sampling for laboratory venous fasting plasma glucose (FPG), and POC capillary blood glucose assay were performed simultaneously. Diabetes diagnosis was based on the World Health Organization (WHO) definition using FPG. The capacity of the POC glucose to predict the presence of diabetes was assessed and compared with the questionnaire using area under the receiver operating characteristic curves (AUCs).

RESULTS

The AUC for POC glucose alone in predicting diabetes was 0.869 (95% CI 0.810–0.929). This was significantly better (P < 0.001 for AUC comparison) than the models based upon clinical variables alone (AUC for the best clinical model including age, BMI, hypertension, waist circumference: 0.694 [95% CI 0.621–0.766]). POC glucose appropriately reclassified the risk of up to one-third of participants ranked according to the clinical models. Adding the clinical variables to the POC glucose assay did not significantly improve the discriminatory capability beyond that achieved with the POC glucose measurement alone (all P > 0.37).

CONCLUSIONS

POC glucose testing appears to be a simple and reliable tool for identifying undiagnosed diabetes in a high-risk, resource-poor rural population. However, studies evaluating the cost effectiveness of introducing POC glucose testing are needed prior to widespread implementation.The prevalence of type 2 diabetes is rapidly increasing around the world (1). Developing countries are facing the largest increases both in absolute and relative terms (1). It is predicted that this will have devastating consequences on the economies and health systems of these countries. Successful prevention and early management of diabetes is therefore a major health priority (1,2).In many regions, up to 50% of people with diabetes remain undiagnosed (1,3,4). Failure to improve these levels of detection will mean that the opportunity to improve health outcomes with early intervention will be lost. Early treatment with successful glucose control significantly reduces the morbidity and mortality associated with diabetes (5,6). Earlier detection of diabetes also allows for the implementation of other treatments that reduce the vascular complications of diabetes (5,6).Universal screening for diabetes is not currently recommended due to a lack of good evidence for an accurate test. However, targeted screening is advocated in certain ethnic groups deemed at increased risk of diabetes (2). For some ethnic groups, implementation of targeted screening may require the entire population to be screened. This applies for instance to Asian Indian populations, which are at greater risk of developing diabetes (7) and have a high prevalence of diabetes both in urban (4) and rural settings (3). However to successfully apply screening to such populations requires accurate, safe, and low-cost diagnostic strategies that are easy to implement (8).In resource-poor settings, clinical variables–based risk assessment questionnaires or point-of-care (POC) glucose analysis may be reasonable screening tools (9). Both require little expertise and allow an individual''s risk of having undiagnosed diabetes to be immediately determined so that only those at high risk require a confirmatory diagnostic test. However, the value of risk assessment questionnaires (9–13) and POC glucose analysis (14–16) in resource-poor settings remains unclear. Additionally the performance of these different screening methods has not been compared in rural Asian Indian populations.The aim of this study was to quantify and compare the accuracy of strategies based on POC glucose, clinical variables, and the combination of both in predicting undiagnosed diabetes in an asymptomatic, resource-poor rural Asian Indian population.     

Glycemic Control and Cardiovascular Disease in 7,454 Patients With Type 1 Diabetes: An observational study from the Swedish National Diabetes Register (NDR)

OBJECTIVE

We assessed the association between A1C and cardiovascular diseases (CVDs) in an observational study of patients with type 1 diabetes followed for 5 years.

RESEARCH DESIGN AND METHODS

A total of 7,454 patients were studied from the Swedish National Diabetes Register (aged 20–65 years, diabetes duration 1–35 years, followed from 2002 to 2007).

RESULTS

Hazard ratios (HRs) for fatal/nonfatal coronary heart disease (CHD) per 1% unit increase in baseline or updated mean A1C at Cox regression analysis were 1.31 and 1.34 and 1.26 and 1.32, respectively, for fatal/nonfatal CVD (all P < 0.001 after adjustment for age, sex, diabetes duration, blood pressure, total and LDL cholesterol, triglycerides, BMI, smoking, and history of CVD). HRs were only slightly lower for CHD (P = 0.002) and CVD (P = 0.002–0.007) after also adjusting for albuminuria. Adjusted 5-year event rates of CHD and CVD increased progressively with higher A1C, ranging from 5 to 12%, as well as when subgrouped by shorter (1–20 years) or longer (21–35 years) duration of diabetes. A group of 4,186 patients with A1C 5–7.9% (mean 7.2) at baseline showed risk reductions of 41% (95% confidence intervals: 15–60) (P = 0.005) for fatal/nonfatal CHD and 37% (12–55) (P = 0.008) for CVD, compared with 3,268 patients with A1C 8–11.9% (mean 9.0), fully adjusted also for albuminuria.

CONCLUSIONS

This observational study of patients in modern everyday clinical practice demonstrates progressively increasing risks for CHD and CVD with higher A1C, independently of traditional risk factors, with no J-shaped risk curves. A baseline mean A1C of 7.2% showed considerably reduced risks of CHD and CVD compared with A1C 9.0%, emphasizing A1C as a strong independent risk factor in type 1 diabetes.Patients with type 1 diabetes have long been considered to have increased risks of cardiovascular disease (CVD) and mortality (1,2), and this has recently been confirmed in two studies (3,4) from the General Practice Research Database in the U.K. Based on data from 1992 to 1999, risks of CVD and mortality were four to eight times higher in men and women with type 1 diabetes than nondiabetic individuals (3,4).While the association between glycemia and microvascular complications is established (5,6), there have been no long-term randomized clinical studies satisfactorily examining the relationship with macrovascular complications in type 1 diabetes, and epidemiological studies have shown conflicting results (7–14). The Epidemiology of Diabetes Interventions and Complications (EDIC) Study showed that patients who had previously been subjected to intensive glucose control during the Diabetes Control and Complications Trial (DCCT) had a considerably lower risk of CVD than patients receiving standard treatment (1983–1993) (7). A small study from Finland on late-onset type 1 diabetic patients without albuminuria showed increased risk of coronary heart disease (CHD) with poor glycemic control (9), but the EURODIAB Prospective Complications Study (PCS), the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study, and the Wisconsin Epidemiologic Study of Diabetic Retinopathy did not demonstrate a significant relationship between glycemia and CHD after controlling for other cardiovascular risk factors (10–13). However, a recent study (14) from the Pittsburgh EDC showed that change in A1C was related to coronary artery disease, whereas baseline A1C was not.With this background, we assessed the association between A1C and CHD, stroke, and CVD in a large cohort of patients with type 1 diabetes, aged 20–65 years, treated in everyday clinical practice from 2002 to 2007. Data were used from the Swedish National Diabetes register (NDR), a quality-assurance tool in diabetes care with nationwide coverage with recently published reports regarding type 1 and type 2 diabetes (15–17).     

Physical Activity, Adiposity, and Diabetes Risk in Middle-Aged and Older Chinese Population: The Guangzhou Biobank Cohort Study

OBJECTIVE

Physical activity may modify the association of adiposity with type 2 diabetes. We investigated the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose, and type 2 diabetes in a Chinese population.

RESEARCH DESIGN AND METHODS

Middle-aged and older Chinese (n = 28,946, ≥50 years, 72.4%women) from the Guangzhou Biobank Cohort Study were examined in 2003–2008. Multivariable regression was used in a cross-sectional analysis.

RESULTS

BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with type 2 diabetes after multiple adjustment, most strongly for WHR with odds ratio (OR) of 3.99 (95% CI 3.60–4.42) for highest compared with lowest tertile. Lack of moderate-to-vigorous physical activity, but not walking, was associated with diabetes with an OR of 1.29 (1.17–1.41). The association of moderate-to-vigorous activity with fasting glucose varied with WHR tertiles (P = 0.01 for interaction). Within the high WHR tertile, participants who had a lack of moderate-to-vigorous activity had an OR of 3.87 (3.22–4.65) for diabetes, whereas those who were active had an OR of 2.94 (2.41–3.59).

CONCLUSIONS

In this population, WHR was a better measure of adiposity-related diabetes risk than BMI or waist circumference. Higher moderate-to-vigorous activity was associated with lower diabetes risk, especially in abdominally obese individuals.Type 2 diabetes is a worldwide cause of morbidity and mortality. Adiposity, especially abdominal adiposity, seems to be at the core of development of hyperglycemia and type 2 diabetes (1). Increased physical activity may mitigate some of the diabetogenic impact of adiposity (2–4). Individuals who are obese but fit could even have a lower risk of mortality than those who are normal weight but unfit (5,6). However, being physically active does not completely abolish the obesity-related risk for cardiovascular disease and associated mortality (7). Adiposity is still the main risk factor for the development of type 2 diabetes (2–4,8). Although increased physical activity has been shown to be associated with reduced type 2 diabetes risk independent of adiposity, the protective effects may differ by the level of adiposity. However, the group that could benefit most from physical activity for the prevention of diabetes is still unclear (2–4,8–10).Understanding the relationship between adiposity and physical activity is important to stratify risk groups for the development of effective diabetes prevention strategies from public health and clinical perspectives. Most of the studies relate to Caucasians (2–4,8–10), whereas Asians, including Chinese and Indians, are possibly more vulnerable to insulin resistance (11). The number of Chinese adults with type 2 diabetes was estimated to be ∼28.1 million in 2000 and may double by 2030, with China being second only to India (12). The purpose of this study was to investigate the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose (IFG), and type 2 diabetes in 28,946 middle-aged and older Chinese participants in the Guangzhou Biobank Cohort Study.     

Lifestyle counseling in routine care and long-term glucose, blood pressure, and cholesterol control in patients with diabetes

OBJECTIVE

In clinical trials, diet, exercise, and weight counseling led to short-term improvements in blood glucose, blood pressure, and cholesterol levels in patients with diabetes. However, little is known about the long-term effects of lifestyle counseling on patients with diabetes in routine clinical settings.

RESEARCH DESIGN AND METHODS

This retrospective cohort study of 30,897 patients with diabetes aimed to determine whether lifestyle counseling is associated with time to A1C, blood pressure, and LDL cholesterol control in patients with diabetes. Patients were included if they had at least 2 years of follow-up with primary care practices affiliated with two teaching hospitals in eastern Massachusetts between 1 January 2000 and 1 January 2010.

RESULTS

Comparing patients with face-to-face counseling rates of once or more per month versus less than once per 6 months, median time to A1C <7.0% was 3.5 versus 22.7 months, time to blood pressure <130/85 mmHg was 3.7 weeks versus 5.6 months, and time to LDL cholesterol <100 mg/dL was 3.5 versus 24.7 months, respectively (P < 0.0001 for all). In multivariable analysis, one additional monthly face-to-face lifestyle counseling episode was associated with hazard ratios of 1.7 for A1C control (P < 0.0001), 1.3 for blood pressure control (P < 0.0001), and 1.4 for LDL cholesterol control (P = 0.0013).

CONCLUSIONS

Lifestyle counseling in the primary care setting is strongly associated with faster achievement of A1C, blood pressure, and LDL cholesterol control. These results confirm that the findings of controlled clinical trials are applicable to the routine care setting and provide evidence to support current treatment guidelines.Diabetes is increasingly common in the U.S. and worldwide (1,2). Elevated blood glucose, blood pressure, and LDL cholesterol are associated with increased risk for micro- and macrovascular complications, and their reduction decreases the risk (3–8). Nevertheless, most patients with diabetes do not have A1C, blood pressure, and LDL cholesterol under control (9,10).American and European guidelines widely recommend diet, exercise, and weight counseling with follow-up for patients with diabetes (11,12). Many short-term randomized clinical trials have shown that intensive lifestyle counseling interventions of up to 1 year in duration can lead to lower blood glucose (13–16) and blood pressure (17–21), but long-term data on the efficacy of lifestyle counseling are lacking (22–24). Furthermore, clinical trials typically involve resource-intensive interventions that may not be feasible in routine care, and the efficacy of lifestyle counseling in everyday clinical practice remains questionable (25–27). Consequently, further evidence is needed to establish that lifestyle counseling as practiced in routine care improves the outcomes of patients with diabetes.We therefore conducted a retrospective study of over 30,000 patients with diabetes and hyperglycemia, hypertension, and/or hyperlipidemia who received care in a primary care setting to test the hypothesis that higher rates of lifestyle counseling in routine care are associated with better diabetes control.     

Serum 25-hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study)

OBJECTIVE

To examine whether serum 25-hydroxyvitamin D (25OHD) and dietary calcium predict incident type 2 diabetes and insulin sensitivity.

RESEARCH DESIGN AND METHODS

A total of 6,537 of the 11,247 adults evaluated in 1999–2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004–2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted for multiple potential confounders, including fasting plasma glucose (FPG).

RESULTS

During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58 vs. 65 nmol/L; P < 0.001) and calcium intake (mean 881 vs. 923 mg/day; P = 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63–0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-S at 5 years.

CONCLUSIONS

Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adult men and women.Accumulating evidence suggests that vitamin D deficiency is associated with an increased risk of developing type 2 diabetes (1–3). Animal and human studies indicate that vitamin D can have a direct (via activation of the vitamin D receptor on pancreatic β-cells and insulin-sensitive organs) and indirect (via regulation of calcium homeostasis) positive effect on insulin secretion and sensitivity (3,4). Several prospective studies also support the hypothesis that low vitamin D status is a risk factor for the development of type 2 diabetes (1–3,5,6); however, these studies were limited by small study sample sizes (3), indirect measures of vitamin D status as a surrogate marker (6,7), and incomplete identification of incident diabetes cases (1,2,5). In addition, most did not include an assessment of dietary calcium, which may have an independent or synergistic effect with vitamin D on lowering type 2 diabetes risk (7). The aim of this study was to examine the relationship between serum 25-hydroxyvitamin D (25OHD), dietary calcium, and risk of developing type 2 diabetes as assessed by an oral glucose tolerance test (OGTT) in a large national, population-based prospective study: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study.     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

Impact of Metabolic Syndrome Compared With Impaired Fasting Glucose on the Development of Type 2 Diabetes in a General Japanese Population: The Hisayama study

OBJECTIVE

We examined whether metabolic syndrome predicts incident type 2 diabetes more effectively than impaired fasting glucose (IFG) in a general Japanese population.

RESEARCH DESIGN AND METHODS

A total of 1,935 nondiabetic subjects aged 40–79 years were followed-up prospectively for a mean of 11.8 years.

RESULTS

During the follow-up, 286 subjects developed type 2 diabetes. Compared with those without metabolic syndrome, the multivariate-adjusted hazard ratio (HR) for incident type 2 diabetes was significantly higher in subjects of both sexes with metabolic syndrome, even after adjustment for confounding factors, age, family history of diabetes, total cholesterol, alcohol intake, smoking habits, and regular exercise (men: HR 2.58 [95% CI 1.85–3.59]; women: 3.69 [2.58–5.27]). The multivariate-adjusted HR of metabolic syndrome for type 2 diabetes was slightly lower in men and similar in women compared with that of IFG. The multivariate-adjusted HR for type 2 diabetes rose progressively as the number of metabolic syndrome components increased in both subjects with and without IFG. In stratified analysis, the multivariate-adjusted risk of type 2 diabetes was significantly higher in subjects with metabolic syndrome alone (2.37 [1.45–3.88]) or IFG alone (3.49 [2.57–4.74]) and markedly increased in subjects with both metabolic syndrome and IFG (6.76 [4.75–9.61]) than in subjects with neither metabolic syndrome nor IFG. Furthermore, the multivariate-adjusted risk for type 2 diabetes was also significantly higher in subjects with both metabolic syndrome and IFG than in those with either one alone (both P < 0.001).

CONCLUSIONS

Our findings suggest that metabolic syndrome significantly increases the risk of incident type 2 diabetes, independent of IFG, and is therefore a valuable tool to identify individuals at high risk of type 2 diabetes.Metabolic syndrome consists of a clustering of cardiovascular risk factors, such as central obesity, elevated blood pressure, glucose intolerance, and dyslipidemia, and individuals with this condition have an elevated risk of developing cardiovascular diseases (1–5) and type 2 diabetes in different ethnic populations (1–4,6–11). Thus, the concept of metabolic syndrome could be used to reduce the incidence of these diseases worldwide. However, a number of experts in the field of diabetes have questioned whether the idea of metabolic syndrome is useful and valuable (12–14). Because all of the criteria sets for metabolic syndrome have included the component of impaired fasting glucose (IFG), which is a powerful predictor of type 2 diabetes, detractors have questioned whether the more complex definition of metabolic syndrome is better than a simple measurement of fasting plasma glucose (FPG). However, reported findings concerning this issue are controversial: a cohort study has shown that the ability of metabolic syndrome to predict type 2 diabetes was superior to that of IFG alone (3), whereas in other studies, the value of metabolic syndrome was comparable or inferior to that of IFG alone (2,6,7). Furthermore, most of these epidemiological studies were performed in Western populations, and this subject has not been assessed sufficiently in Asian populations.The purpose of the present study was to investigate the association between metabolic syndrome and the development of type 2 diabetes in a prospective study of a defined Japanese population, taking into account comprehensive risk factors. In addition, we compared which of the two measures, metabolic syndrome or IFG, better predicted incident type 2 diabetes.     

Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes

OBJECTIVE

To compare the efficacy and safety of adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a 24-week open-label, multicenter study, 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 μg) or a titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving <50 units/day basal insulin for <6 months. The basal insulin dosage was titrated from day 1, seeking fasting plasma glucose (FPG) ≥70–<100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The proportion of patients achieving A1C ≤7.0% without weight gain or severe hypoglycemia at week 24 was the primary end point.

RESULTS

More pramlintide- than RAIA-treated patients achieved the primary end point (30 vs. 11%, P = 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded similar mean ± SEM values for FPG and A1C at 24 weeks (122 ± 7 vs. 123 ± 5 mg/dl and 7.2 ± 0.2 vs. 7.0 ± 0.1%, respectively) and similar least squares mean reductions from baseline to end point (−31 ± 6 vs. −34 ± 6 mg/dl and −1.1 ± 0.2 vs. −1.3 ± 0.2%, respectively). RAIAs but not pramlintide caused weight gain (+4.7 ± 0.7 vs. +0.0 ± 0.7 kg, P < 0.0001). Fewer patients reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group.

CONCLUSIONS

In patients taking basal insulin and OADs, premeal fixed-dose pramlintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen sometimes caused nausea but no weight gain and less hypoglycemia.Adding basal insulin therapy to oral agents improves glycemic control for many patients with type 2 diabetes, but up to 50% of patients continue to have A1C values >7% (1,2,3,4,5). Persistent after-meal hyperglycemia is generally observed in such patients (6). The usual next step in treatment is addition of mealtime insulin injections, but this approach increases risks of weight gain and hypoglycemia (4,6).Previous studies have shown that defects in addition to insulin deficiency contribute to after-meal hyperglycemia. Both insulin and amylin are secreted by β-cells, and, in individuals with abnormal β-cell function, glucose- and mixed meal–stimulated secretion of both hormones is delayed and reduced (7,8,9). Insulin deficiency impairs suppression of hepatic glucose production and enhancement of glucose uptake by tissues that normally limit postmeal hyperglycemia. Amylin deficiency accelerates gastric emptying, increases glucagon secretion, and alters satiety mechanisms (10,11).Pramlintide, an injectable synthetic analog of amylin, slows gastric emptying, attenuates postprandial glucagon secretion, enhances satiety, and reduces food intake (12,13,14). Pramlintide is approved as adjunctive treatment for patients with diabetes who use mealtime insulin with or without oral antihyperglycemic drugs (OADs) and have not achieved desired glucose control. Recently, a 16-week, double-blind, placebo-controlled study of patients with type 2 diabetes showed that pramlintide reduces A1C and weight without increasing insulin-induced hypoglycemia when added to basal insulin ± OADs without mealtime insulin (15).Pramlintide may offer an additional therapeutic option for mealtime use by patients with type 2 diabetes already using basal insulin. Rapid-acting insulin analogs (RAIAs) and pramlintide have different mechanisms of action and different patterns of desired and unwanted effects. Although both can limit after-meal hyperglycemia, RAIAs often cause weight gain and hypoglycemia (6), whereas pramlintide is associated with weight loss and nausea (15,16). This study was designed to compare the efficacy and side effects of pramlintide versus RAIAs when added to basal insulin to intensify treatment of type 2 diabetes.     

Relationship between A1C and fasting plasma glucose in dysglycemia or type 2 diabetes: an analysis of baseline data from the ORIGIN trial

OBJECTIVE

A1C measurement has advantages over measures of plasma glucose. Few studies have evaluated the A1C–fasting plasma glucose (FPG) relationship and whether oral antidiabetes drugs (OADs) and ethnic or geographic variations affect the relationship. Baseline A1C and FPG data from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial participants were analyzed to 1) elucidate the relationship between A1C and FPG in people with moderate dysglycemia (A1C 5.6–9.0% [38–75 mmol/mol]) and additional risk factors for cardiovascular disease, 2) determine whether this relationship is altered by use of an OAD, and 3) study whether geographic and ethnic differences exist.

RESEARCH DESIGN AND METHODS

Analysis was performed of 12,527 participants with dysglycemia or early type 2 diabetes recruited in North America, South America, Europe, Australia, and Asia who comprised white, Latin American, Asian, black, and other ethnicities. The A1C-FPG relationships were analyzed using cubic B spline curves in all participants and in subgroups not using an OAD or using an OAD and comprising persons of different ethnic or geographic origin.

RESULTS

A strong relationship between FPG in the range of 5.6–9.0 mmol/L and the corresponding A1C was seen across different geographic regions and ethnic groups. A smaller increase in A1C per unit increase in FPG occurred for persons taking an OAD versus those not taking an OAD.

CONCLUSIONS

The strong relationship between A1C and FPG in moderate dysglycemia is not significantly affected by ethnic or geographic differences. Use of an OAD alters the relationship and should be considered when interpreting A1C level.A1C is widely used in the management of diabetes both as a measure of long-term glycemic control and as a risk factor for diabetes complications (1–3). Many studies have demonstrated that A1C is correlated with and reflects other measures of glycemic control including FPG and 2-h plasma glucose (4,5). A1C has several advantages over direct measures of plasma glucose including greater reproducibility and sample stability, less intrapersonal variation, and measurability in random versus fasting or postprandial blood samples (6,7). Limitations of A1C as a measure of glycemic control include genetically determined variations of hemoglobin structure that may alter the rate of glycation of the molecule or the lifespan of erythrocytes, thus altering the relationship between glucose and A1C. These observations, together with known ethnic and regional variations of dietary habits, suggest that A1C and glucose levels may differ by ethnicity (8–10) or geographic location (11). However, little is known about the relationship between A1C and glucose levels in different populations. Furthermore, few studies have evaluated whether the relationship between A1C and glucose levels is affected by the use of glucose-lowering agents (4,8,12).The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial is a global trial testing whether targeting normal FPG levels with basal insulin glargine reduces cardiovascular outcomes compared with standard care in people taking 0 or 1 oral antidiabetes drugs (OADs) (13). Baseline A1C and FPG data collected from participants were analyzed in order to 1) elucidate the relationship between A1C and FPG in persons with moderate dysglycemia (A1C 5.6–9.0% [38–75 mmol/mol]) and additional risk factors for cardiovascular disease, 2) determine whether this relationship is altered by use of an OAD, and 3) study whether the relationship differs in persons from different geographic regions or of different ethnicity.     

Translating the A1C assay into estimated average glucose values

OBJECTIVE

The A1C assay, expressed as the percent of hemoglobin that is glycated, measures chronic glycemia and is widely used to judge the adequacy of diabetes treatment and adjust therapy. Day-to-day management is guided by self-monitoring of capillary glucose concentrations (milligrams per deciliter or millimoles per liter). We sought to define the mathematical relationship between A1C and average glucose (AG) levels and determine whether A1C could be expressed and reported as AG in the same units as used in self-monitoring.

RESEARCH DESIGN AND METHODS

A total of 507 subjects, including 268 patients with type 1 diabetes, 159 with type 2 diabetes, and 80 nondiabetic subjects from 10 international centers, was included in the analyses. A1C levels obtained at the end of 3 months and measured in a central laboratory were compared with the AG levels during the previous 3 months. AG was calculated by combining weighted results from at least 2 days of continuous glucose monitoring performed four times, with seven-point daily self-monitoring of capillary (fingerstick) glucose performed at least 3 days per week.

RESULTS

Approximately 2,700 glucose values were obtained by each subject during 3 months. Linear regression analysis between the A1C and AG values provided the tightest correlations (AG_mg/dl = 28.7 × A1C − 46.7, R² = 0.84, P < 0.0001), allowing calculation of an estimated average glucose (eAG) for A1C values. The linear regression equations did not differ significantly across subgroups based on age, sex, diabetes type, race/ethnicity, or smoking status.

CONCLUSIONS

A1C levels can be expressed as eAG for most patients with type 1 and type 2 diabetes.The A1C assay is widely accepted and used as the most reliable means of assessing chronic glycemia (1–3). Its close association with risk for long-term complications, established in epidemiologic studies and clinical trials (4–6), has lead to the establishment of specific A1C targets for diabetes care with the goal of preventing or delaying the development of long-term complications (2,7–9). Diabetes treatment is adjusted based on the A1C results, expressed as the percentage of hemoglobin that is glycated. The vast majority of assays have been standardized worldwide, through the National Glycohemoglobin Standardization Program (10), to the assay used in the Diabetes Control and Complications Trial (DCCT), which established the relationship between A1C levels and risk for long-term diabetes complications (4,5).A new, more stable and specific method of standardization of the A1C assay, which is not intended for use in routine assays, has been developed and proposed to be used for global standardization by the International Federation of Clinical Chemists (11,12). However, the new method results in values that are 1.5–2.0 percentage points lower than current National Glycohemoglobin Standardization Program values (13), potentially causing confusion for patients and health care providers. Moreover, the International Federation of Clinical Chemists results would be expressed in new units (millimoles per mole), which would add to the confusion. Chronic glycemia (A1C) is usually expressed as a percentage of hemoglobin that is glycated, whereas the day-to-day monitoring and therapy of diabetes are based on acute glucose levels expressed as milligrams per deciliter or millimoles per liter. This discrepancy has always been problematic. If we could reliably report chronic metabolic control and long-term management goals as average glucose (AG), i.e., in the same units of measurement as acute glycemia, it would eliminate these potential sources of confusion.The relationship between A1C and chronic glycemia has been explored in several studies that have supported the association of A1C with AG levels over the preceding 5–12 weeks (14–21). However, the older studies have been limited, including relatively small homogeneous cohorts of patients, usually with type 1 diabetes (14–19). Moreover, almost all of the prior studies have relied on infrequent measures of capillary glucose levels, calling into question the validity of their assessment of chronic glycemia. We performed an international multicenter study to examine the relationship between average glucose, assessed as completely as possible with a combination of continuous glucose monitoring and frequent fingerstick capillary glucose testing, and A1C levels over time to estimate the relationship between the two.     

A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers: Applicability of a novel insulin-independent treatment

OBJECTIVE

To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).

RESULTS

At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.

CONCLUSIONS

In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.Treatment of hyperglycemia in patients with type 2 diabetes remains a challenge, particularly in those who require insulin as the disease progresses (1,2). Various combinations of insulin with oral antidiabetic agents (OADs) have been investigated (2–8). Often, these combination therapies become less effective in controlling hyperglycemia over time, particularly as a result of weight gain and worsening insulin resistance as well as progressive failure of insulin secretion.Hypoglycemia, weight gain, and subsequent increased insulin resistance are significant factors that limit optimal titration and effectiveness of insulin (2). Weight gain with insulin therapy, used alone or with OADs (7–9), is in part a consequence of reducing glucosuria (10,11). Among commonly used OADs, thiazolidinediones (TZDs) and sulfonylureas intrinsically contribute to weight gain, whereas metformin causes weight loss and dipeptidyl peptidase-4 inhibitors are weight neutral. Overall, there is a need for novel agents that can be safely administered to help achieve glycemic targets without increasing the risks of weight gain or hypoglycemia.A novel approach to treating hyperglycemia targets receptors for renal glucose reabsorption (12). Agents that selectively block sodium-glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, inhibit glucose reabsorption and induce its elimination through urinary excretion (13). Preclinical models have shown that SGLT2 inhibition lowers blood glucose independently of insulin (14–17). Dapagliflozin, a highly selective inhibitor of SGLT2, has demonstrated efficacy, alone or in combination with metformin, in reducing hyperglycemia in patients with type 2 diabetes (18,19) but has not been tested in patients requiring insulin. This study was designed to determine whether dapagliflozin is effective in lowering blood glucose in patients with type 2 diabetes who have not responded adequately to insulin combined with oral therapies that act through insulin-dependent mechanisms.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

Screening for Diabetes and Pre-Diabetes With Proposed A1C-Based Diagnostic Criteria

OBJECTIVE

An International Expert Committee (IEC) and the American Diabetes Association (ADA) proposed diagnostic criteria for diabetes and pre-diabetes based on A1C levels. We hypothesized that screening for diabetes and pre-diabetes with A1C measurements would differ from using oral glucose tolerance tests (OGTT).

RESEARCH DESIGN AND METHODS

We compared pre-diabetes, dysglycemia (diabetes or pre-diabetes), and diabetes identified by the proposed criteria (A1C ≥6.5% for diabetes and 6.0–6.4% [IEC] or 5.7–6.4% [ADA] for high risk/pre-diabetes) with standard OGTT diagnoses in three datasets. Non-Hispanic white or black adults without known diabetes who had A1C and 75-g OGTT measurements were included from the prospective Screening for Impaired Glucose Tolerance study (n = 1,581), and from the National Health and Nutrition Examination Survey (NHANES) III (n = 2014), and NHANES 2005–2006 (n = 1,111).

RESULTS

OGTTs revealed pre-diabetes in 35.8% and diabetes in 5.2% of combined study subjects. A1C provided receiver operating characteristic (ROC) curve areas for diabetes of 0.79–0.83, but ROC curve areas were ≤0.70 for dysglycemia or pre-diabetes. The proposed criteria missed 70% of individuals with diabetes, 71–84% with dysglycemia, and 82–94% with pre-diabetes. Compared with the IEC criteria, the ADA criteria for pre-diabetes resulted in fewer false-negative and more false-positive result. There were also racial differences, with false-positive results being more common in black subjects and false-negative results being more common in white subjects. With use of NHANES 2005–2006 data, ∼5.9 million non-Hispanic U.S. adults with unrecognized diabetes and 43–52 million with pre-diabetes would be missed by screening with A1C.

CONCLUSIONS

The proposed A1C diagnostic criteria are insensitive and racially discrepant for screening, missing most Americans with undiagnosed diabetes and pre-diabetes.Diabetes affects >21 million American adults (1,2), with a lifetime risk ranging from 20 to 50+%, depending on sex and race (3). Identification of diabetes and its precursor, pre-diabetes, can permit management to prevent complications or delay progression from pre-diabetes to diabetes. Because most U.S. health care systems do not have systematic screening programs, many Americans have undiagnosed diabetes and pre-diabetes, and, therefore, these individuals are not initiating programs targeted at prevention (2).An International Expert Committee (IEC) recently proposed new diagnostic criteria based on measurement of A1C, with A1C ≥6.5% for diabetes and 6.0–6.4% for “high risk” of progression to diabetes (4). The American Diabetes Association (ADA) subsequently proposed A1C ≥6.5% for the diagnosis of diabetes and 5.7–6.4% for the highest risk to progress to diabetes (5).Because A1C testing is readily available in the U.S., is relatively well standardized, exhibits low intraindividual variation, and does not require fasting or restriction to certain times of the day (6), many clinicians might wish to use A1C measurements to screen for diabetes and pre-diabetes. However, the proposed diagnostic criteria were based largely on identification of diabetic retinopathy, and use of the proposed criteria as a screening test is not understood. The IEC A1C criteria have recently been compared with testing with fasting glucose or oral glucose tolerance tests (OGTTs) in various populations to diagnose diabetes (7–13) and high-risk/pre-diabetes (10,11,13), but the ADA A1C criteria have not been studied.We hypothesized that A1C diagnostic criteria would fail to identify many subjects with unrecognized diabetes or pre-diabetes. We evaluated the proposed criteria as screening tests in three populations, compared with the OGTT as a “gold standard” used for identification of diabetes and pre-diabetes around the world (14).     

Effect of Pharmacological Treatment of Depression on A1C and Quality of Life in Low-Income Hispanics and African Americans With Diabetes: A randomized, double-blind, placebo-controlled trial

OBJECTIVE

To determine whether pharmacological treatment of depression in low-income minorities with diabetes improves A1C and quality of life (QOL).

RESEARCH DESIGN AND METHODS

This was a 6-month, randomized, double-blind, placebo-controlled trial. Patients were screened for depression using Whooley''s two-question tool at a county diabetes clinic. Depression was confirmed (or not) with the Computerized Diagnostic Interview Survey (CDIS) software program, and the severity of depression was assessed monthly by the Hamilton Depression Scale (HAM-D). Depressed subjects with A1C levels ≥8.0% were randomly assigned to receive either sertraline or placebo. Diabetes care was provided by nurses following detailed treatment algorithms who were unaware of therapy for depression.

RESULTS

A total of 150 subjects answered positively to at least one question on Whooley''s questionnaire. The positive predictive value for depression diagnosed by CDIS was 69, 67, and 84% for positive answers to question 1 only, question 2 only, or both, respectively. Of the 89 subjects who entered the study, 75 completed. An intention-to-treat analysis revealed significant differences between baseline and 6 months in HAM-D and pain scores, QOL, and A1C and systolic blood pressure levels in both groups, with no differences between groups for the first three but a significantly greater decrease with sertraline in A1C and systolic blood pressure levels. Changes in HAM-D scores and A1C levels were significantly correlated in all subjects (P = 0.45 [P < 10⁻⁶]).

CONCLUSIONS

In this low-income minority population, pharmacological treatment of depression significantly improved A1C and systolic blood pressure levels compared with placebo.The prevalence of depression among people with diabetes is more than twice that of the general population (1). Coexistence of depression in persons with diabetes is associated with worse glycemic control (2), which may be due to less adherence to self-care behaviors and medications (3). Eventually, there is increased morbidity (4) and mortality (5) and higher medical costs (6).The prevalence of untreated depression in people with diabetes is higher in minorities (1). Yet, screening for and treating depression are less common in this population (7). Very little research has been published on diabetes and depression with a focus on minority populations, who have significant disparities in outcomes (8), such as higher A1C levels (9), increased rates of complications (10), and more severe depression (8).Depression is associated with worse glycemic control (2). Some studies have evaluated whether treatment of depression will improve A1C levels (11–20). However, these drug studies were open label, were of short duration, and/or were conducted in highly educated (more than high school education) Caucasian populations. Most showed that although depression was improved, A1C levels were not. We sought to determine whether use of antidepressants in a minority population with uncontrolled diabetes improved their A1C levels, quality of life (QOL), and depression compared with placebo.