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.     

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.     

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).     

Sex and Racial/Ethnic Differences in Cardiovascular Disease Risk Factor Treatment and Control Among Individuals With Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

To examine sex and racial/ethnic differences in cardiovascular risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).

RESEARCH DESIGN AND METHODS

This study was an observational study examining mean levels of cardiovascular risk factors and proportion of subjects achieving treatment goals.

RESULTS

The sample included 926 individuals with diabetes. Compared with men, women were 9% less likely to achieve LDL cholesterol <130 mg/dl (adjusted prevalence ratio 0.91 [0.83–0.99]) and systolic blood pressure (SBP) <130 mmHg (adjusted prevalence ratio 0.91 [0.85–0.98]). These differences diminished over time. A lower percentage of women used aspirin (23 vs. 33%; P < 0.001). African American and Hispanic women had higher mean levels of SBP and lower prevalence of aspirin use than non-Hispanic white women.

CONCLUSIONS

Women with diabetes had unfavorable cardiovascular risk factor profiles compared with men. African American and Hispanic women had less favorable profiles than non-Hispanic white women.Population-based health survey data suggest that sex and racial/ethnic disparities are present in diabetes process of care measures and cardiovascular risk factor control (1–9). Available data also indicate that sex-specific race/ethnicity differences are present in cardiovascular risk factor control, but these data are limited to Medicare and Veterans'' Hospital patient populations (5,10–13). We therefore performed analyses of participants with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine sex and sex-specific racial/ethnic differences in cardiovascular risk factor treatment and control.     

Effect of Ranolazine on A1C and Glucose Levels in Hyperglycemic Patients With Non-ST Elevation Acute Coronary Syndrome

OBJECTIVE

We determined the relationships between glycemia at randomization, concurrent antidiabetic therapy, and change in A1C and fasting plasma glucose (FPG) in patients with diabetes receiving standard treatment for diabetes and randomized to ranolazine or placebo within the MERLIN-TIMI-36 (MERLIN) study. Ranolazine is a novel first-in-class drug approved for treating angina pectoris.

RESEARCH DESIGN AND METHODS

Randomization and 4-month glycemic and antidiabetes drug usage data from MERLIN were analyzed using Spotfire and SAS version 9.1 software.

RESULTS

In patients with diabetes and A1C of ≥8–10% at randomization (n = 171), there was an absolute A1C reduction in the ranolazine group of 1.2% (95% CI −1.4 to −1.0), and the placebo-adjusted (n = 182) decrease in A1C by ranolazine was 0.59% (95% CI −0.99 to −0.20, P < 0.001). In patients with FPG of 150–400 mg/dl at randomization, ranolazine (n = 131) compared with placebo (n = 147) reduced FPG by 25.7 mg/dl (95% CI −43.3 to −8.1, P = 0.001). When changes in either A1C or FPG were correlated to A1C or FPG at randomization, the slopes were significantly steeper for ranolazine than placebo (A1C, P = 0.046; FPG, P < 0.001), indicating that lowering of A1C and FPG by ranolazine is related to hyperglycemia at randomization. Ranolazine, compared with placebo, was not associated with serious hypoglycemic events, associated with significant changes in concurrent antidiabetic therapy, or dependent on a history of angina.

CONCLUSIONS

Ranolazine, when added to concurrent antidiabetes treatment, lowers FPG and A1C in patients with cardiovascular disease and poorly controlled diabetes.Diabetes is an established risk factor for cardiovascular disease, and the risk of cardiovascular disease increases with worsening hyperglycemia (1–3). Furthermore, coronary artery disease is the most common cause of death in patients with diabetes (4). Patients with coronary artery disease and a recent myocardial infarction or acute coronary syndrome (ACS) have an increased incidence of impaired fasting plasma glucose (FPG) and new-onset diabetes (5–7). Management of diabetes in patients with cardiovascular disease is complicated by the fact that the cardiovascular safety of some oral glucose–lowering agents has been questioned, and outcome data are lacking (8).Ranolazine is a first-in-class anti-anginal drug with cardioprotective properties without effects on heart rate or blood pressure (9). The drug inhibits the cardiac late sodium current (10,11). The late sodium current is enhanced during ischemia and in the failing heart and contributes to the Na+-dependent cellular calcium overload associated with these pathological conditions (10,11). Ranolazine has been shown effective in treating chronic angina both as a monotherapy (MARISA trial) and in combination with commonly prescribed cardiovascular drugs (CARISA and ERICA trials) (12–14), with no increase in mortality in patients with established coronary artery disease, including those with diabetes (15,16).Post hoc analysis of data from the CARISA study demonstrated that ranolazine lowered A1C, a long-term biomarker of glucose control, in patients with chronic angina and diabetes, in a dose-dependent manner (17). While the mechanism of glycemic improvement remains incompletely understood, preliminary studies using isolated rat and human pancreatic islets suggest ranolazine may promote glucose-stimulated insulin secretion (18).In the MERLIN-TIMI-36 (MERLIN) study, the effects of ranolazine to lower A1C and glucose were confirmed using prespecified glycemic end points (16). In this study, patients with diabetes were receiving standard of care treatment for diabetes with mean A1C levels of 7.5% at randomization. Despite the relatively low mean A1C at randomization, ranolazine was found to significantly reduce A1C in patients with diabetes and to reduce the incidence of newly elevated A1C in initially normoglycemic patients (16). The mean placebo-corrected reductions in A1C with ranolazine treatment at 4 months were 0.42% (P < 0.001) and 0.18% (P < 0.001) for patients with and without diabetes, respectively. There were no differences in the reported incidence of hypoglycemia between placebo and ranolazine.The glucose-lowering response to multiple antidiabetic therapies is greater in patients with higher baseline A1C and glucose values (19). Therefore, the current analysis of the MERLIN data was undertaken to evaluate the effects of ranolazine on FPG and A1C in diabetic patients with moderate or severe hyperglycemia, defined as an A1C of 6 to <8% or ≥8–10%, or FPG <150 or ≥150–400 mg/dl, respectively, at randomization. Additionally, MERLIN data were assessed as to whether effects of ranolazine on glycemia were influenced by concurrent antidiabetic therapy.     

Peri-Conceptional A1C and Risk of Serious Adverse Pregnancy Outcome in 933 Women With Type 1 Diabetes

OBJECTIVE

To study the association between peri-conceptional A1C and serious adverse pregnancy outcome (congenital malformations and perinatal mortality).

RESEARCH DESIGN AND METHODS

Prospective data were collected in 933 singleton pregnancies complicated by type 1 diabetes.

RESULTS

The risk of serious adverse outcome at different A1C levels was compared with the background population. The risk was significantly higher when peri-conceptional A1C exceeded 6.9%, and the risk tended to increase gradually with increasing A1C. Women with A1C exceeding 10.4% had a very high risk of 16%. Congenital malformation rate increased significantly at A1C above 10.4%, whereas perinatal mortality was increased even at A1C below 6.9%.

CONCLUSIONS

These results support recent guidelines of preconceptional A1C levels <7% in women with type 1 diabetes.Recently, guidelines for management of pregnancy in women with pregestational diabetes have recommended pregestational A1C values <7.0% (1,2) and <6.1% (3). Previous studies have reported information of early A1C including 116–691 pregnancies (4–10). We aimed to study whether there is a threshold value for peri-conceptional A1C in women with type 1 diabetes below which the risk of serious adverse pregnancy outcome (congenital malformation and perinatal mortality) is not increased.     

Rosiglitazone Decreases C-Reactive Protein to a Greater Extent Relative to Glyburide and Metformin Over 4 Years Despite Greater Weight Gain: Observations from A Diabetes Outcome Progression Trial (ADOPT)

OBJECTIVE

C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown.

RESEARCH DESIGN AND METHODS

In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years.

RESULTS

Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by −47.6% relative to glyburide and by −30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and −2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = −0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups.

CONCLUSIONS

Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone.C-reactive protein (CRP) has been traditionally viewed as one of the acute-phase reactants and is a sensitive systemic marker of inflammation and tissue damage. This acute-phase inflammatory protein is predominantly secreted in hepatocytes, its release being regulated by interleukin-6 and other inflammatory cytokines (1). Other studies have shown that extrahepatic sources of CRP production from adipocytes could point to a more systemic generation of CRP in the body after stimulation by inflammatory cytokines and more specifically, by the adipokine, resistin (1).Both population-based and prospective studies have demonstrated a clear association between CRP and an increased risk of cardiovascular disease (CVD) and stroke (2). The magnitude of the CRP prediction for future CVD events is similar to that of other traditional CVD risk factors (cholesterol, hypertension, and smoking status) (2). CRP also may be a mediator of atherosclerosis (1,3–6). However, there is no available evidence from clinical trials that a reduction in CRP directly reduces or prevents further CVD events.The production of CRP by adipocytes may partially explain why CRP levels are elevated in patients with the metabolic syndrome (1), in whom CVD risk is increased. The strong association between CRP and body adiposity has been observed in both diabetic (7) and nondiabetic subjects (8–11) and was only moderately attenuated by adjustment of insulin sensitivity. These results suggest that obesity, insulin resistance, and the metabolic syndrome are interconnected in a proinflammatory state that may be mediated by cytokines and subsequently cause elevated levels of CRP. Elevated CRP concentrations have been shown to predict an increased risk of diabetes (9,12,13). Therefore, CRP may play an active role in the causal relationship among obesity, diabetes, and the high risk of future CVD events. Statins (14) and weight loss (15–17), which can reduce CRP levels and improve other CVD risk factors, also show benefits in reducing CVD events.Glucose-lowering agents have different effects on CRP, weight, insulin sensitivity, and glycemic control in the treatment of type 2 diabetes. The thiazolidinediones (TZDs) rosiglitazone and pioglitazone, insulin-sensitizing oral antidiabetic agents, have been shown to be effective in reducing CRP in several short-term (≤6 months) studies (18–21). However, it is not clear whether the weight gain associated with TZDs could attenuate the effect on CRP reduction over larger periods of time. In short-term studies, metformin moderately decreases CRP (16,18), increases insulin sensitivity, and produces weight loss (16). The longer-term relationships among the three commonly used oral antidiabetic agents (TZDs, sulfonylureas, and metformin) with CRP, insulin sensitivity, weight, and glycemic control have not been investigated previously.A Diabetes Outcome Progression Trial (ADOPT) provided the opportunity to evaluate the effects of members of these three classes of oral agents in a randomized, double-blind, controlled trial involving >4,000 patients, treated for a median time of 4 years (22,23). This study compared the efficacy and safety of rosiglitazone, glyburide, and metformin in drug-naive patients with newly diagnosed (≤3 years) type 2 diabetes. We have previously reported the association of CRP, obesity, and insulin resistance in the baseline examination of the ADOPT study (7). We discuss here a subgroup analysis of ADOPT, in which we examined prospectively the long-term effects of rosiglitazone, glyburide, and metformin on CRP reduction and the relationship among CRP, insulin sensitivity, weight, and glycemic variables.     

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.     

��-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.     

Elevated A1C in Adults Without a History of Diabetes in the U.S.

OBJECTIVE

The purpose of this study was to examine the prevalence and correlates of elevated A1C in a large, nationally representative sample of adults without diabetes in the U.S.

RESEARCH DESIGN AND METHODS

We analyzed data from 15,934 participants aged ≥20 years without diagnosed diabetes who had A1C measurements in the 1999–2006 National Health and Nutrition Examination Survey, a cross-sectional and nationally representative sample of the U.S. population.

RESULTS

The overall prevalence of A1C >6% was 3.8%, corresponding to 7.1 million adults without diabetes in the U.S. population. Approximately 90% of these individuals had fasting glucose ≥100 mg/dl. Older age, male sex, non-Hispanic black race/ethnicity, hypercholesterolemia, higher BMI, and lower attained education were significantly associated with having a higher A1C level even among individuals with normal fasting glucose (<100 mg/dl) and after multivariable adjustment.

CONCLUSIONS

A single elevated A1C level (A1C >6%) is common in the general population of adults without a history of diabetes and is highly reliable for the detection of elevated fasting glucose. Nondiabetic adults with elevated A1C are likely to have impaired fasting glucose and an array of other risk factors for type 2 diabetes and cardiovascular disease.A1C is an integrated measure of circulating glucose levels and tracks well in individuals over time. Epidemiological studies have shown that A1C values in nondiabetic adults predict incident diabetes (1–5), cardiovascular disease morbidity and mortality (6–10), and total mortality (7). In these studies, A1C values well within in the “normal” range (i.e., A1C <6%) were independently associated with clinical outcomes. There is currently renewed interest in using A1C for diagnosis and/or screening for diabetes (11); however, there have been few epidemiological investigations of A1C in nondiabetic adults. The objective of the present study was to examine the prevalence and correlates of elevated A1C in a large, nationally representative sample of U.S. adults without diagnosed diabetes who participated in the National Health and Nutrition Examination Survey (NHANES) (1999–2006). We hypothesized that 1) elevated A1C levels (e.g., A1C >6%) are common in the general population of nondiabetic adults in the U.S. and 2) A1C levels would be associated with risk factors for type 2 diabetes and its complications even in the absence of elevated glucose levels.     

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.     

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.     

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.     

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).     

Control of glycemia and cardiovascular risk factors in patients with type 2 diabetes in primary care in Catalonia (Spain)

OBJECTIVE

The objective of this study was to analyze the clinical characteristics and levels of glycemic and cardiovascular risk factor control in patients with type 2 diabetes that are in primary health care centers in Catalonia (Spain).

RESEARCH DESIGN AND METHODS

This was a cross-sectional study of a total population of 3,755,038 individuals aged 31–90 years at the end of 2009. Clinical data were obtained retrospectively from electronic clinical records.

RESULTS

A total of 286,791 patients with type 2 diabetes were identified (7.6%). Fifty-four percent were men, mean (SD) age was 68.2 (11.4) years, and mean duration of disease was 6.5 (5.1) years. The mean (SD) A1C value was 7.15 (1.5)%, and 56% of the patients had A1C values ≤7%. The mean (SD) blood pressure (BP) values were 137.2 (13.8)/76.4 (8.3) mmHg, mean total cholesterol concentration was 192 (38.6) mg/dL, mean HDL cholesterol concentration was 49.3 (13.2) mg/dL, mean LDL cholesterol (LDL-C) concentration was 112.5 (32.4) mg/dL, and mean BMI was 29.6 (5) kg/m². Thirty-one percent of the patients had BP values ≤130/80 mmHg, 37.9% had LDL-C values ≤100 mg/dL, and 45.4% had BMI values ≤30 kg/m². Twenty-two percent were managed exclusively with lifestyle changes. Regarding medicated diabetic patients, 46.9, 22.9, and 2.8% were prescribed one, two, or three antidiabetic drugs, respectively, and 23.4% received insulin therapy.

CONCLUSIONS

The results from this study indicate a similar or improved control of glycemia, lipids, and BP in patients with type 2 diabetes when compared with previous studies performed in Spain and elsewhere.Type 2 diabetes is a chronic disease with a prevalence of 13.8% in people over 18, with up to 6% of the population remaining undiagnosed, according to a recent Spanish study (1). Because diabetic patients have a higher risk of developing microvascular disease and a two- to fourfold higher risk of developing macrovascular disease than the general population, type 2 diabetes is considered to be among the top conditions with the greatest health and economic impact (2). Many studies have shown that the occurrence of these complications depends largely on the degree of glycemic control and intensive control of cardiovascular risk factors (CVRFs) (3–5).In the last few decades, a consensus toward the implementation of a multidisciplinary approach to prevention and control of patients with type 2 diabetes in primary care has been reached. Since 1993, the Spanish Group of Study of Diabetes in Primary Health Care (Gedaps) has published up-to-date guidelines with the main recommendations for diagnosis, control, and treatment of diabetes. The Catalan Health Institute has subsequently incorporated these recommendations into its own guidelines (6). Current targets include an A1C value ≤7%, blood pressure (BP) values ≤130/80 mmHg, a total cholesterol (TC) value ≤200 mg/dL, and an LDL cholesterol (LDL-C) value ≤100 mg/dL (7).Despite scientific evidence and the publication of international (8,9) and national guidelines (6,7), adequate control of these patients’ health remains beset with challenges. A number of observational studies performed in Spain (10–14) and elsewhere (15–22) have shown that there is a gap between recommendations and daily clinical practice. Several studies have indicated that only 7–9% of diabetic patients achieve optimal control of all CVRFs (11,13,23). The current generalization of electronic clinical records systems in Spain allowed us to access the data of the entire diabetic population registered in the public health care system for our study, unlike previous studies that were based on population samples. The analyses of these data more accurately reflect the actual control of patients with type 2 diabetes in our setting. Previous publications on population registers in other countries have indicated the relevance of these types of data (15–22). Consequently, this cross-sectional study aimed to determine the clinical features and the glycemic and CVRF control of patients with type 2 diabetes in primary care centers of the Catalan Health Institute in Catalonia (Spain).     

Plasma 25-Hydroxyvitamin D Concentration and Metabolic Syndrome Among Middle-Aged and Elderly Chinese Individuals

OBJECTIVE

To evaluate the association between 25-hydroxyvitamin D [25(OH)D] and metabolic syndrome in the Chinese population.

RESEARCH DESIGN AND METHODS

Plasma 25(OH)D was measured in a cross-sectional sample of 1,443 men and 1,819 women aged 50–70 years from Beijing and Shanghai. Metabolic syndrome was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. Fasting plasma glucose, insulin, lipid profile, A1C, and inflammatory markers were measured.

RESULTS

The geometric mean of plasma 25(OH)D was 40.4 nmol/l, and percentages of vitamin D deficiency [25(OH)D <50 nmol/l] and insufficiency [50 ≤ 25(OH)D <75 nmol/l] were 69.2 and 24.4%, respectively. Compared with the highest 25(OH)D quintile (≥57.7 nmol/l), the odds ratio for metabolic syndrome in the lowest quintile (≤28.7 nmol/l) was 1.52 (95% CI 1.17–1.98, P_trend = 0.0002) after multiple adjustment. Significant inverse associations also existed between 25(OH)D and individual metabolic syndrome components plus A1C. Moreover, we observed significant inverse associations of 25(OH)D with fasting insulin and the insulin resistance index (homeostasis model assessment of insulin resistance [HOMA-IR]) in overweight and obese individuals (BMI ≥24 kg/m²) but not in their normal-weight counterparts (test for interaction: P = 0.0363 and 0.0187 for insulin and HOMA-IR, respectively).

CONCLUSIONS

Vitamin D deficiency is common in the middle-aged and elderly Chinese population, and a low 25(OH)D level is significantly associated with an increased risk of having metabolic syndrome and insulin resistance. Prospective studies and randomized clinical trials are warranted to determine the role of 25(OH)D in the development of metabolic syndrome and related metabolic diseases.Vitamin D deficiency is now recognized as a worldwide concern (1). A growing body of evidence suggests that 25-hydroxyvitamin D [25(OH)D], a generally accepted indicator of vitamin D status, is inversely associated with adiposity, glucose homeostasis, lipid profiles, and blood pressure along with its classic role in calcium homeostasis and bone metabolism (1–6). Even though the underlying mechanism has not been well understood, vitamin D appears to exert effects through direct modulation of gene expression via vitamin D receptors (VDRs) (1) and through regulation of extra- and intracellular calcium (1,7).Metabolic syndrome, a constellation of cardiometabolic disease risk factors, has become a global epidemic (8). Several epidemiologic studies (5,6,9,10) have suggested that 25(OH)D status is inversely associated with metabolic syndrome in western populations, although data for morbidly obese individuals are inconsistent (11,12). Nevertheless, evidence from the Asian population is limited. Because of ethnic differences in vitamin D metabolism and its nutritional status indicated by previous studies (3,13), it is not clear whether the findings from western populations could be extrapolated directly to Asian individuals. With rapid nutrition and lifestyle transitions in the last 20 years, metabolic syndrome has become one of the most widespread health problems in Asian countries (8). However, little is known regarding whether vitamin D deficiency plays an important role in the heightened prevalence of metabolic syndrome and other metabolic disorders among Asian individuals. Therefore, the aim of our study was to evaluate the plasma 25(OH)D concentration and its association with metabolic syndrome among Chinese individuals aged 50–70 years.     

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.     

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.     

Pediatric Endocrinologists' Management of Children With Type 2 Diabetes

OBJECTIVE

To understand physician behaviors and attitudes in managing children with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A survey was mailed to a nationwide sample of pediatric endocrinologists (PEs).

RESULTS

A total of 40% of PEs surveyed responded (211 of 527). Concordance with current monitoring guidelines varied widely, ranging from 36% (foot care) to 93% (blood pressure monitoring). Given clinical vignettes addressing hyperlipidemia, hypertension, and microalbuminuria, only 34% of PEs were fully concordant with current treatment guidelines. Reported barriers included concerns about patient adherence, insufficient scientific evidence about treatment, and lack of familiarity with current recommendations. Providers aged ≤45 years or in clinical practice <10 years reported significantly more aggressive management behaviors and had higher concordance with guidelines.

CONCLUSIONS

Screening and management of pediatric type 2 diabetes varied widely among PEs, suggesting opportunities for quality improvement. More aggressive management of type 2 diabetes among younger providers may be related to recent training when type 2 diabetes was more common.The incidence of type 2 diabetes in children is increasing (1), and children with type 2 diabetes are at high risk to develop diabetes-related complications, including hyperlipidemia, hypertension, and microalbuminuria (2–4). Despite limited scientific evidence, several consensus statements on the assessment and management of pediatric type 2 diabetes have been developed (4–6). Current understanding of physician management of pediatric type 2 diabetes is limited (7–10). We conducted a survey to better understand pediatric endocrinologists'' (PEs'') behaviors and attitudes related to the management of pediatric type 2 diabetes.