The Role of Adjunctive Exenatide Therapy in Pediatric Type 1 Diabetes

OBJECTIVE

Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 μg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal.

RESULTS

Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004).

CONCLUSIONS

Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.Intensive insulin therapy delays/prevents complications associated with type 1 diabetes (1,2). However, insulin monotherapy fails to achieve normoglycemia (3). Postprandial hyperglycemia and hypoglycemia (4,5) continue to create impediments to management. Even the closed-loop system fails to normalize postprandial hyperglycemia (6). Additional therapies to insulin are needed to achieve optimal glycemic control.Glucagon-like peptide (GLP)-1 is an incretin secreted in response to nutrient ingestion (7). Physiological GLP-1 enhances insulin secretion, delays gastric emptying, and suppresses glucagon. But because of its short half-life (8), it is unsuitable for clinical application.Exenatide is a long-acting GLP-1 receptor agonist and acts similarly to native GLP-1 (9). Exenatide is effective in decreasing postprandial hyperglycemia in type 2 diabetes (10). However, there are few studies using exenatide in type 1 diabetes and none in adolescents. The objective of our study was to examine the effect of adjuvant premeal exenatide and insulin on postprandial glucose in type 1 diabetes and establish an effective and safe glucose-lowering dose.     

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).     

DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks

OBJECTIVE

In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.

RESEARCH DESIGN AND METHODS

In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.

RESULTS

Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.

CONCLUSION

Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.Type 2 diabetes is a complex and increasingly prevalent disease associated with interrelated comorbidities, including obesity, dyslipidemia, and hypertension. The importance of treating not only hyperglycemia, but also the associated comorbidities, is recognized as necessary to reduce the risk of complications, particularly cardiovascular disease (1). Lifestyle modification can improve glycemic control as well as body weight, blood pressure, and lipid profiles; however, behavioral modifications are inherently difficult, and most patients eventually require multiple medications (2–6). Although several classes of antihyperglycemic medications are currently indicated for the treatment of type 2 diabetes, most of them do not improve the comorbidities and several are associated with weight gain.Exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, improves glycemic control in patients with type 2 diabetes through multiple mechanisms of action: increased glucose-dependent insulin secretion, attenuated postprandial glucagon secretion, slowed gastric emptying, and increased satiety (7,8). The twice-daily formulation of exenatide (exenatide BID) improves both fasting and postprandial glucose control, resulting in A1C reductions of roughly 0.8–1.0% in placebo-controlled trials (9–12) and 1.0–1.4% in open-label trials (13–15). These improvements in glucose control were maintained in patients completing 3 years of treatment (−1.0%) (16). Exenatide therapy is also associated with weight loss and improvement in cardiovascular risk factors, including blood pressure and serum lipid profiles (16). Furthermore, the glucose-dependent mechanisms of action of exenatide minimize the risk of hypoglycemia. GLP-1R agonists have recently been added to the American Diabetes Association and European Association for the Study of Diabetes consensus algorithm for the treatment of type 2 diabetes as an option after the addition of metformin in patients in whom body weight and hypoglycemia risk are concerns (1).Exenatide BID is administered within the 60-min period before the morning and evening meals and primarily exerts its pharmacodynamic effects on glucose concentrations during the postprandial period. A long-acting once-weekly formulation of exenatide (exenatide QW) has been developed. Weekly administration of 2 mg exenatide QW results in therapeutic plasma exenatide concentrations within 2 weeks and steady-state plasma exenatide concentrations within the therapeutic target range 6–7 weeks after initiation of therapy (17,18).The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) trial was designed as a two-stage protocol. We previously reported the first stage, a randomized open-label comparison of exenatide QW to exenatide BID in patients with type 2 diabetes over 30 weeks (17). Both therapies improved glycemic control, and the improvement in A1C observed with exenatide QW treatment was significantly greater than that observed with exenatide BID (−1.9 vs. −1.5%, respectively). Similar improvements in body weight, blood pressure, and fasting lipids were demonstrated with both forms of exenatide therapy. We now describe 52-week results from the second phase of the DURATION-1 trial which examined the safety and efficacy of 1) switching from exenatide BID to exenatide QW after 30 weeks of treatment and 2) continuing exenatide QW treatment for an additional 22 weeks (52 weeks total).     

Postchallenge Glucose, A1C, and Fasting Glucose as Predictors of Type 2 Diabetes and Cardiovascular Disease: A 10-year prospective cohort study

OBJECTIVE

A1C has been proposed as a new indicator for high risk of type 2 diabetes. The long-term predictive power and comparability of elevated A1C with the currently used high-risk indicators remain unclear. We assessed A1C, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) as predictors of type 2 diabetes and cardiovascular disease (CVD) at 10 years.

RESEARCH DESIGN AND METHODS

This prospective population-based study of 593 inhabitants from northern Finland, born in 1935, was conducted between 1996 and 2008. An oral glucose tolerance test (OGTT) was conducted at baseline and follow-up, and A1C was determined at baseline. Those with a history of diabetes were excluded from the study. Elevated A1C was defined as 5.7–6.4%. Incident type 2 diabetes was confirmed by two OGTTs. Cardiovascular outcome was measured as incident CVD or CVD mortality. Multivariate log-binomial regression models were used to predict diabetes, CVD, and CVD mortality at 10 years. Receiver operating characteristic curves compared predictive values of A1C, IGT, and IFG.

RESULTS

Incidence of diabetes during the follow-up was 17.1%. Two of three of the cases of newly diagnosed diabetes were predicted by a raise in ≥1 of the markers. Elevated A1C, IGT, or IFG preceded diabetes in 32.8, 40.6, and 21.9%, respectively. CVD was predicted by an intermediate and diabetic range of 2-h glucose but only by diabetic A1C levels in women.

CONCLUSIONS

A1C predicted 10-year risk of type 2 diabetes at a range of A1C 5.7–6.4% but CVD only in women at A1C ≥6.5%.Early detection of high risk for type 2 diabetes is fundamental for prevention of diabetes and associated cardiovascular complications. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are currently used for diagnosis of high-risk glucose levels below the diabetic range. The International Expert Committee proposed A1C ≥6.5% as a diagnostic tool for diabetes in 2009 (1) and in January 2010 an intermediate range of A1C 5.7–6.4% (elevated A1C) was proposed by the American Diabetes Association (ADA) to detect individuals at high risk for developing type 2 diabetes (2).To date, however, limited data exist to support the use of A1C in predicting type 2 diabetes (3–8). Importantly, the long-term predictive power of elevated A1C as defined above has not yet been investigated. Previous data on the association between A1C and incident type 2 diabetes in unselected populations have relied on self-reporting, fasting glucose measurements, and use of antidiabetes medication to determine the outcomes. An oral glucose tolerance test (OGTT) has not been used to determine the outcome (3–8).Deterioration of glucose homeostasis reflects a continuum of glycemia, some of which is reversible if detected early (9,10). Importantly, the risk of cardiovascular disease is increased already before glycemia reaches the levels of diabetes, and 2-h glucose appears to be a better predictor of cardiovascular disease (CVD) than fasting glucose (11). Recently, A1C was shown to be a better predictor of CVD than fasting glucose (12).Data directly comparing 2-h glucose and A1C as long-term predictors of new-onset cardiovascular disease are scarce, and results are controversial (13,14). Therefore, we compared A1C, 2-h glucose, and fasting glucose as predictors of type 2 diabetes, CVD, and CVD mortality during a prospective population-based study with a 10-year follow-up.     

Metabolic Syndrome and Diabetes, Alone and in Combination, as Predictors of Cardiovascular Disease Mortality Among Men

OBJECTIVE

To examine cardiovascular disease (CVD) mortality risk in men with diabetes only, metabolic syndrome only, and concurrent metabolic syndrome and diabetes.

RESEARCH DESIGN AND METHODS

We examined CVD mortality risk by metabolic syndrome and diabetes status in men from the Aerobics Center Longitudinal Study (ACLS) (mean ± SD age 45.1 ± 10.2 years). Participants were categorized as having neither diabetes nor metabolic syndrome (n = 23,770), metabolic syndrome only (n = 8,780), diabetes only (n = 532), or both (n = 1,097). The duration of follow-up was 14.6 ± 7.0 years with a total of 483,079 person-years of exposure and 1,085 CVD deaths.

RESULTS

Age-, examination year–, and smoking-adjusted CVD death rates (per 1,000 man-years) in men with neither metabolic syndrome nor diabetes, metabolic syndrome only, diabetes only, and both were 1.9, 3.3, 5.5, and 6.5, respectively. CVD mortality was higher in men with metabolic syndrome only (hazard ratio 1.8 [95% CI 1.5–2.0]), diabetes only (2.9 [2.1–4.0]), and both (3.4 [2.8–4.2]) compared with men with neither. The presence of metabolic syndrome was not associated (1.2 [0.8–1.7]) with higher CVD mortality risk in individuals with diabetes. In contrast, the presence of diabetes substantially increased (2.1 [1.7–2.6]) CVD mortality risk in individuals with metabolic syndrome.

CONCLUSIONS

The presence of diabetes was associated with a threefold higher CVD mortality risk, and metabolic syndrome status did not modify this risk. Our findings support the fact that physicians should be aggressive in using CVD risk–reducing therapies in all diabetic patients regardless of metabolic syndrome status.Approximately 7.8% of the U.S. population has diabetes, and it is estimated that the number of adults with diabetes will increase to 48.3 million by 2050 in the U.S. and to 300 million worldwide in the year 2025, representing a 122% rise compared with 1995 (1–3). The public health importance is great, considering that individuals with diabetes have more than twice the risk for premature death, heart disease, and stroke compared with individuals without diabetes (1). Although clinical definitions differ slightly, metabolic syndrome is generally characterized as a clustering of abnormal levels of blood lipids (low HDL and high triglycerides), impaired fasting glucose, elevated blood pressure, and excess abdominal obesity (4–7). Approximately 25% of Americans and >50% of those aged >50 years meet the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III definition of metabolic syndrome (8). Similar to individuals with diabetes, individuals with metabolic syndrome have an increased risk for premature death, heart disease, and stroke (9–12).Metabolic syndrome and diabetes share many common characteristics, so it is not surprising that 65–85% of individuals with diabetes also have metabolic syndrome (13–15). However, relativity few studies have examined the effect of the combination of metabolic syndrome and diabetes on cardiovascular disease (CVD) risk (11,13,14). A cross-sectional study using National Health and Nutrition Examination Survey data reported that the prevalence of coronary heart disease (CHD) among individuals with diabetes and without metabolic syndrome was similar to that in those without diabetes or metabolic syndrome (7.5 vs. 8.7%, respectively) (14). However, individuals with concurrent diabetes and metabolic syndrome had a substantially greater prevalence (19.2%) compared with these groups. This finding suggests that in individuals with diabetes there is an increased risk for CHD only when metabolic syndrome also is present. Similarly, in a prospective study Hunt et al. (16) reported that within individuals with diabetes, those with metabolic syndrome have an increased risk for CVD mortality, whereas individuals with diabetes but not metabolic syndrome do not. However, this study was relatively small (n = 2,815) with only 117 CVD deaths. Finally, the UK Prospective Diabetes Study (UKPDS) reported that in individuals with type 2 diabetes, the presence of metabolic syndrome (NCEP) increased the risk of CVD events (17). However, it was noted from a clinical perspective that the presence of metabolic syndrome in individuals with diabetes provided little information for detecting who has an increased risk of CVD.Given the high prevalence of both metabolic syndrome and diabetes, it is of great clinical and public health importance that we develop a better understanding of the interactions of diabetes and metabolic syndrome on the risk of CVD. The primary aim of the current investigation is to examine the risk of CVD mortality in individuals with metabolic syndrome only, diabetes only, and concurrent metabolic syndrome and diabetes in a large prospective study population.     

Risk of cardiovascular and all-cause mortality: impact of impaired health-related functioning and diabetes: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study

OBJECTIVE

There is an established link between health-related functioning (HRF) and cardiovascular disease (CVD) mortality, and it is known that those with diabetes predominantly die of CVD. However, few studies have determined the combined impact of diabetes and impaired HRF on CVD mortality. We investigated whether this combination carries a higher CVD risk than either component alone.

RESEARCH DESIGN AND METHODS

The Australian Diabetes, Obesity and Lifestyle (AusDiab) study included 11,247 adults aged ≥25 years from 42 randomly selected areas of Australia. At baseline (1999–2000), diabetes status was defined using the World Health Organization criteria and HRF was assessed using the SF-36 questionnaire.

RESULTS

Overall, after 7.4 years of follow-up, 57 persons with diabetes and 105 without diabetes had died from CVD. In individuals with and without diabetes, HRF measures were significant predictors of increased CVD mortality. The CVD mortality risks among those with diabetes or impaired physical health component summary (PCS) alone were similar (diabetes only: hazard ratio 1.4 [95% CI 0.7–2.7]; impaired PCS alone: 1.5 [1.0–2.4]), while those with both diabetes and impaired PCS had a much higher CVD mortality (2.8 [1.6–4.7]) compared with those without diabetes and normal PCS (after adjustment for multiple covariates). Similar results were found for the mental health component summary.

CONCLUSIONS

This study demonstrates that the combination of diabetes and impaired HRF is associated with substantially higher CVD mortality. This suggests that, among those with diabetes, impaired HRF is likely to be important in the identification of individuals at increased risk of CVD mortality.Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for >20% of all deaths (1). Biological and behavioral variables, such as diabetes, obesity, smoking, and physical inactivity, are robust risk factors for the development of CVD and mortality (2). As well as these established risk factors, subjective health status markers, such as health-related functioning (HRF), have been shown to be associated with an increased risk of cardiovascular mortality (3). It has been shown that psychosocial risk factors exert an association similar in strength to that of biological risk factors for CVD (4), and yet the two types of risk factors are rarely assessed concurrently.HRF refers to how well an individual functions in their daily life, physically and socially, and their perceived physical and mental well-being (5,6). Most of the literature to date examines HRF as an outcome in patient populations, providing an important indicator of the impact of chronic disease (3,5,7). However, there is increasing evidence to suggest that poor HRF may predict the development of disease, e.g., in type 2 diabetes (T2DM) (8) and CVD (9). Because of the burden of the daily management of T2DM and the development of complications, HRF is particularly important for people with T2DM, with levels of health status shown to be compromised in these populations (5,7,10). Findings from previous studies show that in samples of patients with T2DM, persons reporting low levels of HRF have higher risk of mortality compared with those reporting high functioning (11,12). It is likely, therefore, that exposure to T2DM and poor HRF has an additive, if not synergistic, effect on the risk of cardiovascular mortality; however, the impact of this combined relationship on mortality has not been examined. It is important to understand whether the effects of each disorder simply have an additive impact or whether their combined effects exert a synergistic effect (i.e., greater than the sum of two independent effects) on mortality.Using longitudinal data from a population-based, national study in Australia, these analyses aimed to examine the combined impact of HRF and T2DM on cardiovascular mortality compared with either risk factor alone.     

Racial/ethnic- and education-related disparities in the control of risk factors for cardiovascular disease among individuals with diabetes

OBJECTIVE

There is limited information on whether recent improvements in the control of cardiovascular disease (CVD) risk factors among individuals with diabetes have been concentrated in particular sociodemographic groups. This article estimates racial/ethnic- and education-related disparities and examines trends in uncontrolled CVD risk factors among adults with diabetes. The main racial/ethnic comparisons made are with African Americans versus non-Latino whites and Mexican Americans versus non-Latino whites.

RESEARCH DESIGN AND METHODS

The analysis samples include adults aged ≥20 years from the National Health and Nutrition Examination Survey (NHANES) 1988–1994 and the NHANES 1999–2008 who self-reported having diabetes (n = 1,065, NHANES 1988–1994; n = 1,872, NHANES 1999–2008). By use of logistic regression models, we examined the correlates of binary indicators measuring 1) high blood glucose, 2) high blood pressure, 3) high cholesterol, and 4) smoking.

RESULTS

Control of blood glucose, blood pressure, and cholesterol improved among individuals with diabetes between the NHANES 1988–1994 and the NHANES 1999–2008, but there was no change in smoking prevalence. In the NHANES 1999–2008, racial/ethnic minorities and individuals without some college education were more likely to have poorly controlled blood glucose compared with non-Latino whites and those with some college education. In addition, individuals with diabetes who had at least some college education were less likely to smoke and had better blood pressure control compared with individuals with diabetes without at least some college education.

CONCLUSIONS

Trends in CVD risk factors among individuals with diabetes improved over the past 2 decades, but racial/ethnic- and education-related disparities have emerged in some areas.Diabetes is a leading cause of morbidity and mortality in the U.S., and the prevalence of this disease is rising (1). The Centers for Disease Control and Prevention, based on data from the National Health Interview Survey, estimated that the age-adjusted prevalence of diagnosed diabetes increased from 3.7% in 1980 to 7.7% in 2008 (2). The total direct and indirect costs associated with diabetes in the U.S. were estimated to be $174 billion in 2007, with ~33% ($58 billion) of the total cost being attributed to treatment of medical complications (3). Cardiovascular disease (CVD) is a widely documented potential complication of diabetes and a leading cause of mortality among individuals with diabetes (4–6). Although rates of CVD events have declined in recent decades among both individuals with and without diabetes, people with diabetes still are twice as likely as those without diabetes to experience a CVD event (4), and individuals with diabetes have heart disease mortality rates that are two to four times greater than those without diabetes (6).To prevent CVD and other complications of diabetes, the American Diabetes Association (ADA) in 2009 published updated standards for diabetes screening, diagnosis, and therapeutic care (7). These guidelines, which reflect new evidence from epidemiological studies and randomized controlled trials, included targets for glycemic control, blood pressure control, lipid control, and smoking (7). The ADA recommends that most adults with diabetes maintain an HbA_1c (a measure of blood glucose) level below or around 7.0%, blood pressure under 130/80 mmHg, and LDL cholesterol under 100 mg/dL (2.6 mmol/L) (7). All patients with diabetes are advised not to smoke. In addition, the National Cholesterol Education Program Adult Treatment Panel III recommends that individuals with diabetes keep their LDL under 100 mg/dL and total cholesterol under 200 mg/dL (8).Given that successful management of diabetes requires a coordinated team of health care providers (7) and access to health insurance (9), continuity of care (10), and patient knowledge and self-management skills (11), there may be differences in control of CVD risk factors across sociodemographic groups within the population of people with diabetes. On the basis of data from the National Health and Nutrition Examination Survey (NHANES) 1999–2000, previous researchers reported that only 7.3% of those with diagnosed diabetes achieve all three of the ADA (2009) targets for control of blood glucose, blood pressure, and total cholesterol (12). Between the NHANES 1988–1994 and the NHANES 1999–2000, trends in the control of blood cholesterol among individuals with diagnosed diabetes improved, but there was no change in the control of blood glucose and blood pressure levels (12). Poor glycemic control generally is more prevalent among African Americans and Mexican Americans with diabetes compared with non-Latino whites with diabetes (13–15), but these differences have been small in some studies (13) and limited to certain sex/race-ethnicity subgroups in other studies (14). Recent research based on individuals with diabetes interviewed in the NHANES 1999–2008 shows an overall trend of improvement in CVD risk factors and, notably, reductions in the predicted 10-year risk of coronary heart disease (16), but some findings show that socioeconomic status and racial/ethnic disparities persist (14–18).Using data from the NHANES 1988–1994 and the NHANES 1999–2008, we built on these important new results by 1) examining trends in the prevalence of diagnosed diabetes and the sociodemographic characteristics of the diagnosed diabetic population and 2) testing for racial/ethnic- and education-related disparities in poorly controlled risk factors for CVD among individuals with diagnosed diabetes. Given the mounting body of evidence showing the importance of controlling CVD risk factors (7) and the increasing focus on prevention in the 2010 health care reform law (19), it is critical to document current trends in the control of CVD risk factors among individuals with diabetes and to examine whether any improvements have been concentrated in particular sociodemographic groups.     

GHb Level and Subsequent Mortality Among Adults in the U.S.

OBJECTIVE

To examine the association of hyperglycemia, as measured by GHb, with subsequent mortality in a nationally representative sample of adults.

RESEARCH DESIGN AND METHODS

We included adults aged ≥20 years who participated in Third National Health and Nutrition Examination Survey (1988–1994) and had complete information, including baseline diabetes status by self-report and measured GHb (n = 19,025) and follow-up through the end of 2000 for mortality.

RESULTS

In the overall population, higher levels of GHb were associated with increased risk of mortality from all causes, heart disease, and cancer. After adjustment for potential risk factors, the relative hazard (RH) for adults with GHb ≥8% compared with adults with GHb <6% was 2.59 (95% CI 1.88–3.56) for all-cause mortality, 3.38 (1.98–5.77) for heart disease mortality, and 2.64 (1.17–5.97) for cancer mortality. Among adults with diagnosed diabetes, having GHb ≥8% compared with GHb <6% was associated with higher all-cause mortality (RH 1.68, 95% CI 1.03–2.74) and heart disease mortality (2.48, 1.09–5.64), but there was no increased risk of cancer mortality by GHb category. Among adults without diagnosed diabetes, there was no significant association of all-cause, heart disease, or cancer mortality and GHb category.

CONCLUSIONS

These results highlight the importance of GHb levels in mortality risk among a nationally representative sample of adults with and without diagnosed diabetes and indicate that higher levels are associated with increased mortality in adults with diabetes.Hperglycemia has been associated with a wide range of adverse outcomes for individuals with glucose values both above and below the threshold for diabetes, including increased cardiovascular disease (CVD) and mortality (1). Studies have consistently found undiagnosed diabetes to be associated with increased risk of mortality (2–4), and many studies have also shown levels of glucose that are elevated, but not enough for a diagnosis of diabetes, such as impaired fasting glucose, to be associated with increased mortality (2–4).However, most of these studies are based on fasting or postprandial glucose (1–4), and few are based on GHb levels (3,5–8). The GHb level may be a better indicator of hyperglycemia because it provides a measure of an individual''s average glucose levels for the previous 3 months. Thus, it may provide a more stable snapshot of glucose levels when used in prospective cohort studies to examine the association of subsequent risk. Currently, GHb is monitored in the treatment of diabetes, and GHb targets for prevention of complications among individuals with diabetes have been established (9). Interest in the use of GHb for the diagnosis of diabetes is increasing (10), and an international effort is underway to standardize the measurement of GHb (11). This focus of GHb in clinical care measures (12) raises important questions about the long-term predictability of GHb.Examination of the relationship of GHb with mortality reveals several areas of uncertainty, including whether the relationship of GHb with mortality is similar among individuals with and without diabetes from both prospective cohort studies and clinical trials. A few prospective cohort studies have examined the association of GHb with risk of mortality (5–8) and shown an increased risk of mortality with increasing GHb level. Only two studies included individuals with diabetes, but these studies did not examine GHb levels by diabetes status, and none were representative of the general U.S. population.Recently published findings from three clinical trials among adults with diabetes have added to this uncertainty. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that lower GHb levels increased risk of mortality and did not decrease CVD events (13). Whereas the Action in Diabetes and Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study showed that lowering of GHb levels was associated with a decrease in micro- and macrovascular events and deaths from CVD (14) and the Veterans Administration Diabetes Trial reported that lower GHb levels were not associated with a reduction in cardiovascular events (15). These findings have not led to any changes in glycemic control recommendations (16).The Third National Health and Nutrition Examination Survey (NHANES III) is the first nationally representative survey to include a measure of GHb and has mortality status available through linkage to the National Death Index. The objective of this study was to examine the association of GHb with subsequent mortality in a nationally representative sample of U.S. adults.     

Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes: A randomized controlled trial exploring weekly, biweekly, and monthly dosing

OBJECTIVE

To evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy.

RESEARCH DESIGN AND METHODS

In this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m², A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16.

RESULTS

Dose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P < 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.

CONCLUSIONS

Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.Early intervention to improve glycemic control reduces microvascular complications in type 2 diabetes (1–4) and may provide long-term macrovascular benefits (5). Despite numerous available therapies, over half of patients with type 2 diabetes are unable to achieve the American Diabetes Association (ADA) target A1C level (<7%) (6–8). Moreover, weight gain and treatment-induced hypoglycemic episodes (9,10) are major barriers to achieving glycemic control (10).Antidiabetic therapies based on glucagon-like peptide-1 (GLP-1) retain the ability of native GLP-1 to stimulate glucose-dependent insulin secretion and suppress inappropriately elevated glucagon secretion (11,12). Native GLP-1 also slows gastric emptying and reduces food intake, which leads to modest weight loss (11). However, native GLP-1 is rapidly inactivated (half-life 1–2 min) by dipeptidyl peptidase-4 (DPP-4), limiting its therapeutic potential (13). Exenatide (half-life 2.4 h) improves glycemic control in combination with metformin, a sulfonylurea, or a thiazolidinedione (14–18). Despite modest weight loss and improved glycemic control, gastrointestinal (GI) intolerability and twice-daily administration may lead to discontinuation (19).Albiglutide (formerly known as albugon) is a GLP-1 receptor agonist developed through the fusion of two repeats of human GLP-1 (7–36) molecules to recombinant human albumin (20). The GLP-1 dimer was used to avoid potential reductions of the interaction of the GLP-1 moiety of the monomer with its receptor in the presence of albumin. A single amino acid substitution (ala8→gly) renders the molecule resistant to DPP-4. The structure of albiglutide provides an extended half-life (∼5 days), which may allow weekly or less frequent dosing. Furthermore, albiglutide is relatively impermeant to the central nervous system (21), which may have implications for GI tolerability. In nonclinical studies, albiglutide stimulated cAMP production through the GLP-1 receptor and induced insulin secretion from INS-1 cells in vitro and in animal models (21–22). It also delayed gastric emptying and reduced food intake in rodents (21–23).This study was designed to explore a wide range of doses (4–100 mg) and schedules (weekly to monthly) to assess glycemic control and adverse event profiles for albiglutide. Exenatide was included as an open-label reference to provide clinical perspective for a GLP-1 receptor agonist.     

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.     

Derivation and Validation of a New Cardiovascular Risk Score for People With Type 2 Diabetes: The New Zealand Diabetes Cohort Study

OBJECTIVE

To derive a 5-year cardiovascular disease (CVD) risk equation from usual-care data that is appropriate for people with type 2 diabetes from a wide range of ethnic groups, variable glycemic control, and high rates of albuminuria in New Zealand.

RESEARCH DESIGN AND METHODS

This prospective open-cohort study used primary-care data from 36,127 people with type 2 diabetes without previous CVD to derive a CVD equation using Cox proportional hazards regression models. Data from 12,626 people from a geographically different area were used for validation. Outcome measure was time to first fatal or nonfatal cardiovascular event, derived from national hospitalization and mortality records. Risk factors were age at diagnosis, diabetes duration, sex, systolic blood pressure, smoking status, total cholesterol–to–HDL ratio, ethnicity, glycated hemoglobin (A1C), and urine albumin-to-creatinine ratio.

RESULTS

Baseline median age was 59 years, 51% were women, 55% were of non-European ethnicity, and 33% had micro- or macroalbuminuria. Median follow-up was 3.9 years (141,169 person-years), including 10,030 individuals followed for at least 5 years. At total of 6,479 first cardiovascular events occurred during follow-up. The 5-year observed risk was 20.8% (95% CI 20.3–21.3). Risk increased with each 1% A1C (adjusted hazard ratio 1.06 [95% CI 1.05–1.08]), when macroalbuminuria was present (2.04 [1.89–2.21]), and in Indo-Asians (1.29 [1.14–1.46]) and Maori (1.23 [1.14–1.32]) compared with Europeans. The derived risk equations performed well on the validation cohort compared with other risk equations.

CONCLUSIONS

Renal function, ethnicity, and glycemic control contribute significantly to cardiovascular risk prediction. Population-appropriate risk equations can be derived from routinely collected data.Ethnic and socioeconomic disparities in cardiovascular disease (CVD) outcomes exist around the world. Locally derived or ethnic-specific CVD risk equations to guide management may be appropriate to help redress these disparities. Including glycemic control, albuminuria, current management, and socioeconomic status in risk equations may also improve prediction and outcomes, particularly for people with type 2 diabetes, a group at high risk of CVD (1).The Framingham equation has been extremely useful for assessing CVD risk for the past 40 years worldwide (2). However, it does not include renal function, albuminuria, or ethnicity, which are often potent predictors of CVD (3–6). Although it includes diabetes as a dichotomous variable, risk increases continuously with increasing glycemia (7,8). The UK Prospective Diabetes Study (UKPDS) risk equations, also widely used, include glycemia and diabetes duration but not measures of renal function or treatment and only two ethnic categories (9). Several other CVD equations exist, many derived regionally, but few have included measures of glycemia, renal function, and ethnicity together to improve risk prediction (6,10–13). The Strong Heart Study equation includes albuminuria but includes diabetes only as a dichotomous variable and is specific to a single ethnicity (14). The DECODE equation did not include renal function or ethnicity, although it provided “multiplying factors” based on nationality (15). The Swedish National Diabetes Register was used to produce a prediction equation for 5-year CVD risk but without renal function or ethnicity (16). Other variations include the Systematic Coronary Risk Evaluation (SCORE) equation, which did not include diabetes, ethnicity, or renal function (17); a stroke prediction equation for Hong Kong Chinese with type 2 diabetes (18); and a “clinical grouping” approach from Norway in which people were placed into broad groups by a count of basic risk factors (one of which was self-reported diabetes) (19).This study demonstrates how routinely collected data can be used to derive an appropriate risk equation to use when making treatment decisions within a specific population, which may lead to more equitable outcomes. This study aimed to derive a 5-year CVD risk equation for people with type 2 diabetes that included these important prognostic risk factors such as glycemia, albuminuria, and ethnic groups relevant to New Zealand.     

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.     

Thoracoabdominal Calcifications Predict Cardiovascular Disease Mortality in Type 2 Diabetic and Nondiabetic Subjects: 18-year follow-up study

OBJECTIVE

To evaluate cardiovascular disease (CVD) and total mortality associated with thoracoabdominal calcifications.

RESEARCH DESIGN AND METHODS

Thoracoabdominal calcifications of native radiograms were evaluated in 833 subjects with type 2 diabetes and 1,292 subjects without diabetes, aged 45–64 years, without prior evidence of CVD. The type 2 diabetic and nondiabetic study cohorts were followed up for 18 years.

RESULTS

After adjustment for conventional risk factors, marked thoracoabdominal calcifications predicted CVD/total mortality with hazard ratio (HR) (95% CI) of 1.5 (0.8–3.0)/1.8 (1.1–2.9) in type 2 diabetic men, 3.0 (1.6–5.7)/3.1 (1.9–5.0) in type 2 diabetic women, 5.0 (2.2–12)/4.0 (2.2–7.4) in nondiabetic men, and 7.8 (1.8–34)/3.0 (1.3–7.0) in nondiabetic women and in the presence of C-reactive protein below/over 3 mg/l with HR of 2.4 (1.3–4.4)/3.0 (1.4–6.1) in type 2 diabetic subjects and 4.0 (1.5–10.8)/6.6 (2.7–16.0) in nondiabetic subjects.

CONCLUSIONS

Thoracoabdominal calcifications in native radiograms are significant predictors of CVD and total mortality, especially in type 2 diabetic and nondiabetic women with elevated high-sensitivity C-reactive protein level.Vascular calcification is initiated by metabolic, mechanical, infectious, or inflammatory injury to vasculature. Its progression is mainly determined by inflammatory response to vascular injury (1). It may precede cardiovascular disease (CVD) morbidity and mortality by years or decades in subjects with type 2 diabetes (2) and in the general population (3–6). Medial calcification has been associated with CVD morbidity and mortality in diabetic subjects (7) and in subjects with end-stage renal disease (8). Calcifications can be divided into intimal type, medial type of arterial calcification, cardiac valve calcification, and vascular calciphylaxis (9). These four entities of calcifications are consequences of distinct but overlapping pathophysiological mechanisms, which can occur simultaneously. Calcifications may function as a limiting factor for intimal plaque growth and represent a biological response to this process (10). A new perspective to the question of clinical significance of calcification has evolved from the practical need to evaluate CVD effects of medications targeted to bone formation and the bone density effects of medications targeted to vascular welfare (11,12).Although inflammation is involved in the initiation and progression of vascular calcification, inflammation and calcification may reflect partly independent processes. A combination of markers of calcification and inflammation might therefore be a good predictor CVD mortality. This study evaluates thoracoabdominal calcifications, and their combination with elevated high-sensitivity C-reactive protein (hs-CRP), in prediction of CVD mortality in a cohort of two diabetic and nondiabetic subjects without prior evidence of CVD during an 18-year follow-up.     

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.     

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).     

Meta-analysis of the significance of asymptomatic bacteriuria in diabetes

OBJECTIVE

To evaluate whether asymptomatic bacteriuria (ASB) is more common in patients with diabetes than among control subjects. In addition, we wanted to clarify the clinical significance of ASB in patients with diabetes.

RESEARCH DESIGN AND METHODS

We conducted a systematic review and meta-analysis of published data since 1966. Twenty-two studies fulfilled the inclusion criteria of the meta-analysis.

RESULTS

ASB was present in 439 of 3,579 (12.2%) patients with diabetes and in 121 of 2,702 (4.5%) healthy control subjects. ASB was more common both in patients with type 1 diabetes (odds ratio 3.0 [95% CI 1.1–8.0]) and type 2 diabetes (3.2 [2.0–5.2]) than in control subjects. The point prevalence of ASB was higher in both women (14.2 vs. 5.1%; 2.6 [1.6–4.1]) and men (2.3 vs. 0.8%; 3.7 [1.3–10.2]) as well as in children and adolescents (12.9 vs. 2.7%; 5.4 [2.7–11.0]) with diabetes than in healthy control subjects. Albuminuria was more common in patients with diabetes and ASB than those without ASB (2.9 [1.7–4.8]). History of urinary tract infections was associated with ASB (1.6 [1.1–2.3]).

CONCLUSIONS

We were able to show that the prevalence of ASB is higher in all patients with diabetes compared with control subjects. We also found that diabetic subjects with ASB more often had albuminuria and symptomatic urinary tract infections.As the prevalence of both type 1 diabetes and type 2 diabetes increases world wide, factors associated with diabetes and its complications become more important (1,2). Asymptomatic bacteriuria (ASB) refers to the presence of bacteria in bladder urine in an asymptomatic individual. Usually, samples are collected indirectly by clean-voided midstream urine, and growth of the same uropathogen (≥10⁵ cfu/ml) in two consecutive specimens is considered to be a significant indication of the presence of bacteria in bladder urine (3). ASB is found in 2–5% of healthy adult women, is quite unusual in healthy men, and has been claimed to be three to four times more common in women with diabetes than in healthy women (3). A prevalence as high as 30% in diabetic women has been reported (4).ASB is considered clinically significant and worth treating during pregnancy because treatment effectively reduces the risk of pyelonephritis and preterm delivery (5,6). Although ASB has been found to associate with increased risk of hospitalization for urosepsis in a prospective observational study among women with diabetes (7), the treatment of ASB in one randomized controlled trial did not reduce the risk of symptomatic urinary tract infection (8). Associations between ASB, metabolic control of diabetes, and impaired renal function have been brought up repeatedly (9–15). To evaluate whether ASB is truly more common in patients with diabetes than among control subjects and to clarify the clinical significance of ASB in diabetic subjects we did a systematic literature search and performed a meta-analysis of the published data.     

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.     

Further Improvement in Postprandial Glucose Control With Addition of Exenatide or Sitagliptin to Combination Therapy With Insulin Glargine and Metformin: A proof-of-concept study

OBJECTIVE

To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5–10 μg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET).

RESEARCH DESIGN AND METHODS

This was a single-center, randomized, open-label, active comparator–controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose ≤100 mg/dl).

RESULTS

The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 ± 104 vs. 612 ± 133 vs. 728 ± 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P < 0.0001), with the greatest reduction of −1.9 ± 0.7 under GLAR + MET + EXE (GLAR + MET + SITA −1.5 ± 0.7; GLAR + MET −1.2 ± 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose <50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (−0.9 ± 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 ± 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377).

CONCLUSIONS

EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings.The UK Prospective Diabetes Study (UKPDS) demonstrated that good glycemic control in type 2 diabetes is associated with a reduced risk of diabetes complications (1). After lifestyle modifications (diet and exercise) and oral hypoglycemic agents (OHAs) the addition of basal insulin to OHAs is common practice (2), because this kind of regimen requires only a single injection in most cases and can improve glycemic control. Its use, however, may not adequately control postprandial hyperglycemia or may be associated with hypoglycemia and/or weight gain (3,4). Because obesity is frequently present in subjects with type 2 diabetes (5) and represents a factor contributing to insulin resistance (5) and cardiovascular risk (5), weight gain may be particularly undesirable.A significant advance in basal insulin therapy was the introduction of insulin glargine, a long-acting insulin analog with an extended duration of action of ∼24 h without exhibiting a pronounced peak (6,7). In subjects with type 2 diabetes, insulin glargine was shown to confer glycemic control at least equivalent to that of NHP insulin with a lower incidence of hypoglycemia (3,8,9). However, insulin glargine still has the drawbacks of insulin treatment such as weight gain (3,8,9) and a lower effect on postprandial glucose excursions (8) than on fasting glucose values.Exenatide is the first-in-class glucagon-like peptide 1 (GLP-1) receptor agonist (or incretin mimetic) approved in the U.S. and Europe (10). Compared with placebo, exenatide statistically reduced A1C, whereas there was no difference in A1C improvement between exenatide and insulin glargine or biphasic insulin aspart (11–14). However, postprandial glycemia as well as weight was further reduced with exenatide compared with insulin glargine or biphasic insulin, with a similar risk of hypoglycemia (12,13).Sitagliptin is an approved once-daily, potent, and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor (15). When added to metformin, sitagliptin, given at a dose of 100 mg once daily over 24 weeks, led to significant reductions in A1C, fasting, and 2-h postprandial plasma glucose and was weight-neutral (16).With this background, a therapy controlling both fasting blood glucose (FBG) and postprandial glucose excursions seems to be a promising approach for subjects with type 2 diabetes (17–21). Therefore, in the present study we investigated the influence of a 4-week adjunctive therapy of either a GLP-1 receptor agonist (exenatide) or a DPP-4 inhibitor (sitagliptin) to titrated basal insulin (insulin glargine) plus metformin versus the continuation with titrated insulin glargine plus metformin alone as active comparator in subjects with type 2 diabetes.     

Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes

OBJECTIVE

Interleukin (IL)-1 impairs insulin secretion and induces β-cell apoptosis. Pancreatic β-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and β-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses.

RESEARCH DESIGN AND METHODS

Among 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m² and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in β-cell function after anakinra withdrawal. Analysis was done by intention to treat.

RESULTS

Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by −0.07 [95% CI −0.14 to −0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (−3.2 mg/l [−6.2 to −1.1], P = 0.014) and in IL-6 (−1.4 ng/l [−2.6 to −0.3], P = 0.036) were maintained until the end of study.

CONCLUSIONS

IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.Type 2 diabetes is caused by inability of the functional β-cell mass to compensate for increased insulin needs due to insulin resistance (1). During the course of the disease, β-cell function progressively declines irrespective of treatment with glucose-lowering drugs (2–4). β-Cell mass is reduced through apoptosis (5) and type 2 diabetes is associated with a low-grade systemic inflammation (6), but the mechanisms underlying β-cell failure and destruction in type 2 diabetes remain elusive.In vitro, long-term exposure to high glucose and the peptide hormone leptin secreted by adipose tissue induce β-cell apoptosis and production of the proinflammatory cytokine interleukin (IL)-1 in β-cells and pancreatic islets, respectively (7,8). IL-1 inhibits the function and induces apoptosis of β-cells (9) and has been implicated as a mediator of the β-cell destruction leading to type 1 diabetes (10). Exogenous addition of interleukin-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1 signaling, protects the β-cells from the deleterious effects of high glucose and leptin exposure (7,8).Both β-cell expression and serum levels of IL-1Ra are reduced in patients with type 2 diabetes (8,11). This inadequate IL-1 antagonism seems to be a genetic trait because genetic polymorphisms in the gene encoding IL-1Ra are associated with altered serum levels of IL-1Ra (12–15).We showed previously that 13 weeks of IL-1Ra treatment improved β-cell function and reduced A1C and markers of systemic inflammation in patients with type 2 diabetes (16). The aim of this 39-week follow-up study was to investigate the durability of these effects.     

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.