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).     

��-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.     

Cardiovascular Disease Mortality in Europeans in Relation to Fasting and 2-h Plasma Glucose Levels Within a Normoglycemic Range

OBJECTIVE

To study mortality in relation to fasting plasma glucose (FPG) and 2-h plasma glucose levels within the normoglycemic range.

RESEARCH DESIGN AND METHODS

Data from 19 European cohorts comprising 12,566 men and 10,874 women who had FPG <6.1 mmol/l and 2-h plasma glucose <7.8 mmol/l at baseline examination were analyzed. Multivariate-adjusted hazard ratios (HRs) and 95% CIs for deaths from cardiovascular disease (CVD), non-CVD, and all causes were estimated for individuals whose 2-h plasma glucose > FPG (group II) compared with those whose 2-h plasma glucose ≤ FPG (group I).

RESULTS

A total of 827 (246) CVD and 611 (351) non-CVD and 1,438 (597) all-cause deaths occurred in men (women). Group II was older and had higher BMI, blood pressure, and fasting insulin than group I. The multivariate-adjusted HRs (95% CIs) for CVD, non-CVD, and all-cause mortality were 1.22 (1.05–1.41), 1.09 (0.92–1.29), and 1.16 (1.04–1.30) in men and 1.40 (1.03–1.89), 0.99 (0.79–1.25), and 1.13 (0.94–1.35) in women, respectively, for group II as compared with group I. HRs were 1.25 (1.05–1.50), 1.09 (0.89–1.34), and 1.18 (1.03–1.35) in men and 1.60 (1.03–2.48), 1.05 (0.78–1.42), and 1.18 (0.93–1.51) in women, respectively, after additional adjustment for fasting insulin in a subgroup of individuals.

CONCLUSIONS

In individuals with both FPG and 2-h plasma glucose within the normoglycemic range, high 2-h plasma glucose was associated with insulin resistance and increased CVD mortality.It is well known that type 2 diabetes (1,2) and nondiabetic hyperglycemia such as impaired glucose tolerance are risk factors for cardiovascular disease (CVD) mortality (3–5). The relations of fasting plasma glucose (FPG) and 2-h plasma glucose with CVD mortality and morbidity have been extensively investigated during the last few decades (6–9). Evidence has shown that 2-h plasma glucose is a stronger risk predictor than FPG for incident coronary heart disease (6) and CVD mortality (7), but little is known about the impact of FPG versus 2-h plasma glucose in the normoglycemic range. It has been suggested that individuals with normoglycemia, whose 2-h plasma glucose did not return to the FPG levels during an oral glucose tolerance test (OGTT) had a significantly higher risk of developing type 2 diabetes (10) and a worse cardiovascular risk factor profile (11) than individuals whose 2-h plasma glucose returned to the FPG levels. In the current study, based on the data of the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study, we compared CVD mortality in individuals whose 2-h plasma glucose was higher than FPG with those whose 2-h plasma glucose was equal to or lower than FPG.     

Matrix Gla Protein Species and Risk of Cardiovascular Events in Type 2 Diabetic Patients

OBJECTIVE

To investigate the relationship of circulating matrix Gla protein (MGP) species with incident cardiovascular disease (CVD) or coronary heart disease (CHD) in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

EPIC-NL is a prospective cohort study among 40,011 Dutch men and women. At baseline (1993–1997), 518 participants were known to have type 2 diabetes. MGP levels were measured by ELISA techniques in baseline plasma samples. The incidence of fatal and nonfatal CVD and CVD subtypes—CHD, peripheral arterial disease (PAD), heart failure, and stroke—were obtained by linkage to national registers. Cox proportional hazard models were used to calculate hazard ratios (HRs), adjusted for sex, waist-to-hip ratio, physical activity, and history of CVD.

RESULTS

During a median 11.2 years of follow-up, 160 cases of CVD were documented. Higher circulating desphospho-uncarboxylated MGP (dp-ucMGP) levels were significantly associated with higher risk of CVD, with an HR per SD (HR_SD) of 1.21 (95% CI 1.06–1.38), PAD (HR_SD 1.32 [95% CI 1.07–1.65]), and heart failure (HR_SD 1.75 [95% CI 1.42–2.17]) after adjustment. Higher circulating dp-ucMGP levels were not related to risk of CHD (HR_SD 1.12 [95% CI 0.94–1.34]) or stroke (HR_SD 1.05 [95% CI 0.73–1.49]). Circulating desphospho-carboxylated MGP and circulating total-uncarboxylated MGP levels were not associated with CVD or CVD subtypes.

CONCLUSIONS

High dp-ucMGP levels were associated with increased CVD risk among type 2 diabetic patients, especially with the subtypes PAD and heart failure, while other MGP species were not related to CVD risk. These results suggest that a poor vitamin K status is associated with increased CVD risk.Coronary artery calcification is an independent predictor of cardiovascular disease (CVD) (1). Matrix Gla protein (MGP) is a vitamin K–dependent protein and a potent inhibitor of vascular calcification (2). The importance of MGP for vascular health has been demonstrated in MGP-deficient animals, who all died of massive arterial calcification within 6–8 weeks after birth (3). The cellular and molecular mechanisms by which MGP prevents ectopic calcium deposition are multifaceted, including 1) regulation of calcification by vascular smooth muscle cell (VSMC)-derived matrix vesicles and apoptotic body, 2) inhibition of calcium-phosphate precipitation, and 3) inhibition of VSMC trans differentiation (4). Vitamin K is required for the function of MGP through its role as a cofactor for the enzyme γ-glutamyl carboxylase, catalyzing the carboxylation of glutamic acid residues (Glu) into γ-carboxyglutamate (Gla) at five well-defined places in the protein (5). Human studies showed that high vitamin K intake is associated with reduced coronary artery calcification and reduced risk of CVD (6–9). These effects are thought to be mediated by increased activation of MGP (10).MGP exists as various species, which differ in their state of phosphorylation or carboxylation: phosphorylated, nonphosphorylated (desphospho-MGP [dpMGP]), carboxylated (cMGP), or uncarboxylated (ucMGP). Total uncarboxylated MGP (t-ucMGP) is thought to be the sum of desphospho-uncarboxylated MGP (dp-ucMGP) and phosphorylated-uncarboxylated MGP (p-ucMGP) and mainly consists of p-ucMGP.Development of assays to measure circulating MGP species enabled the investigation of these species in the circulation (11). These studies have shown that dp-ucMGP is a marker for vitamin K status, with high dp-ucMGP level reflecting a low vitamin K status (12–17). In line with these results, several studies indeed showed that high dp-ucMGP levels were associated with more calcification, though not consistently (13,16,18,19). Theoretically, dp-cMGP forms the mirror image of dp-ucMGP and is hypothesized to be associated with lower calcification, but results from human, observational studies are inconsistent (16,20). Finally, in cross-sectional studies, high t-ucMGP has been associated with decreased calcification (16,21–23).Although vascular calcification may not be causally related to CVD, it has emerged as a strong and independent risk marker for CVD (1), but the association of MGP species with CVD events has not been investigated to date. Diabetes is associated with severe cardiovascular complications, including vascular calcification and accelerated atherosclerosis, leading to increased morbidity and mortality in diabetic patients (24–27) Therefore, we performed a prospective study to investigate the association between circulating MGP species and CVD or coronary heart disease (CHD) risk among a high-risk population, i.e., type 2 diabetic patients.     

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.     

Educational Disparities in Mortality Among Adults With Diabetes in the U.S.

OBJECTIVE

To measure relative and absolute educational disparities in mortality among U.S. adults with diabetes and to compare their magnitude with disparities observed within the nondiabetic population.

RESEARCH DESIGN AND METHODS

A total of 85,867 individuals (5,007 with diabetes), aged 35–84 years, who participated in the National Health Interview Survey from 1986 to 1996 were followed for mortality through 31 December 2002. Relative and absolute educational disparities in all-cause, cardiovascular disease (CVD), and non-CVD mortality were measured.

RESULTS

In relative terms, the risk of all-cause mortality was 28% higher in diabetic adults with the lowest versus the highest position on the educational scale (relative index of inequality 1.28 [95% CI 1.08–1.53]). This inverse relationship reflected marked disparities in CVD mortality and was found in all age, sex, and race/ethnicity groups except Hispanics. Although substantial, this relative educational gradient in mortality among adults with diabetes was smaller than in the nondiabetic population. In absolute terms, diabetic adults with the lowest position on the educational scale suffered 503 excess deaths per 10,000 person-years of follow-up compared with those with the highest position. These absolute disparities were stronger than in the nondiabetic population. The results were even more striking for CVD mortality.

CONCLUSIONS

The risk of mortality differs substantially according to educational level among individuals with diabetes in the U.S. Although relative educational disparities in mortality are weaker in adults with versus without diabetes, their absolute impact is greater and translates into a major mortality burden.In the U.S., >20 million adults have diabetes, and the prevalence is expected to rise substantially in the coming decades (1,2). Diabetes complications impose an enormous burden on public health, and people with diabetes have an age-adjusted mortality rate approximately twice as high as those without (3).The public health burden of diabetes is unevenly distributed across socioeconomic strata. First, diabetes is more common in ethnic minorities and people of low education and income level (4,5). Second, in people with diabetes, socioeconomic position (SEP) may influence major determinants of health, such as access to care, quality of care, and health behaviors (6). Correspondingly, SEP may have a profound impact on the morbidity and mortality associated with diabetes. In Europe, socioeconomic health disparities have been reported among people with diabetes in various settings (5,6); though, two large record linkage studies (7,8) found that the magnitude of socioeconomic differentials in survival was weaker in people with diabetes than in the general population, a result that has remained largely unexplained. In the U.S., only few studies have focused on SEP-related disparities among people with diabetes and then only in selected subpopulations (9–12), making it difficult to determine the impact of such disparities at the population level and their public health importance.To fully monitor health disparities, the general consensus is that both relative and absolute measures are required (13,14). The objective of this study was to quantify relative and absolute educational disparities in mortality within the U.S. diabetic population according to cause of death and across age, sex, and race/ethnicity strata and to compare the magnitude of these disparities to those found in the nondiabetic population.     

Aortic and mitral annular calcifications are predictive of all-cause and cardiovascular mortality in patients with type 2 diabetes

OBJECTIVE

To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals.

RESEARCH DESIGN AND METHODS

We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992–2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality.

RESULTS

At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1–4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9–17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality.

CONCLUSIONS

Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.Aortic valve sclerosis (AVS) is a common finding at echocardiography in the elderly population (1). AVS is defined as focal or diffuse calcification and thickening of a trileaflet aortic valve in the absence of obstruction of ventricular outflow. Approximately 30% of adults >65 years of age have AVS in Western countries. Until recently, AVS was considered an incidental echocardiographic finding of no clinical significance, as it does not significantly obstruct left ventricular outflow. However, AVS shows epidemiologic and histopathologic similarities to coronary atherosclerosis (2,3). In addition, recent large prospective studies have suggested a strong association between AVS and cardiovascular disease (CVD) outcomes both in the general population (1,4–6) and in nondiabetic high-risk patient populations such as patients with hypertension (7), coronary artery disease (8), and chronic kidney disease (9).Mitral annulus calcification (MAC) is also a common echocardiographic finding in the elderly (10). Similar to AVS, MAC is strongly associated with an increased risk of CVD morbidity and mortality, mainly in nondiabetic populations (11,12). Notably, a recent large community-based cohort study involving 2,081 German individuals aged ≥45 years (∼11% of patients with diabetes) showed that AVS and MAC were associated with a fourfold to fivefold increased risk of all-cause and CVD mortality and that the combination of AVS and MAC with a heart valve sclerosis score improved the predictability with respect to mortality (5). Similarly, patients with AVS were approximately four times more likely to develop incident coronary heart events than were those without AVS among the 2,279 middle-aged African American participants of the Jackson Atherosclerosis Risk in Community cohort (6), whereas AVS was found to be independently associated with an increase of ~50–60% in the risk of CVD events and death among the 5,621 elderly participants of the Cardiovascular Heart Study (1).To our knowledge, no large observational studies are available on the relationship of AVS and MAC with the risk of all-cause and CVD mortality in patients with type 2 diabetes. The aim of this observational study was to evaluate the association of AVS and MAC, singly or in combination, with the risk of all-cause and CVD mortality in a sample of type 2 diabetic individuals referred for clinically indicated echocardiograms.     

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.     

Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease

OBJECTIVE

Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD).

RESEARCH DESIGN AND METHODS

We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes–PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes–non-PAD) were examined.

RESULTS

Type 2 diabetes–PAD subjects (399 ± 155 μg/ml) had significantly higher fetuin-A levels than type 2 diabetes–non-PAD subjects (247 ± 42; P < 0.001). In NGM-PAD subjects (376 ± 144), fetuin-A was significantly higher than in type 2 diabetes–non-PAD subjects (P < 0.001). Type 2 diabetes–PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes–PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1–3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0–1.7, P = 0.039) for the prevalence of myocardial infarction.

CONCLUSIONS

In contrast to previous findings, fetuin-A was higher in type 2 diabetes–PAD patients than in type 2 diabetes–non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes–non-PAD patients. In type 2 diabetes–PAD patients, fetuin-A was inversely associated with mediasclerosis—the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease.Patients suffering from type 2 diabetes and peripheral artery disease (PAD) (type 2 diabetes–PAD) have a five times higher risk for cardiovascular mortality than patients with one disease alone (1–3). Furthermore, the risk of lower-extremity amputation is higher than in patients without diabetes (3).Fetuin-A, also known as α2-Schmid Heremans glycoprotein (ASHG), is a potent systemic calcification inhibitor (4). Fetuin-A knockout mice develop severe calcification of various organs (4). In a cross-sectional study, low levels of fetuin-A were associated with cardiovascular mortality in patients on dialysis (5). In addition, low fetuin-A has been linked to vascular calcification (6) and flow-limiting aortic stenosis (7).Fetuin-A interacts with the insulin receptor tyrosine kinase and induces insulin resistance in rodents (8,9). Stefan et al. (10) demonstrated in a prospective case-cohort study that elevated fetuin-A is an independent risk factor for developing diabetes. Contrariwise to renal (dialysis) patients, several studies showed that high levels of fetuin-A were associated with atherosclerosis and its manifestations in non-renal patients (11–13). Likewise, high levels of fetuin-A were linked to myocardial infarction and ischemic stroke (12). This possible involvement of fetuin-A in the pathogenesis of cardiovascular disease has been confirmed by a recent trans-European cohort study with 2,520 patients (13). Thus, it seems that high levels of fetuin-A are associated with atherosclerosis and its manifestations in non-renal patients.In contrast to the latter findings, a recent article (14) suggested that fetuin-A levels in a non-dialysis condition are lower in type 2 diabetes–PAD patients (n = 38) than in patients with diabetes alone.However, the role of fetuin-A and its involvement in atherosclerosis seems to be very complex and yet not understood. The situation is even more complex in patients with type 2 diabetes–PAD, who generally suffer from advanced/systemic atherosclerosis (1–3,15). In those high-risk patients, up to 30% show mediasclerosis (2,15). The aim of this study was to investigate fetuin-A levels in patients with type 2 diabetes with or without PAD in comparison with PAD patients with diabetes.     

Prothrombotic State, Cardiovascular, and Metabolic Syndrome Risk Factors in Prepubertal Children Born Large for Gestational Age

OBJECTIVE

To evaluate metabolic syndrome and cardiovascular disease risk factors in prepubertal children born large for gestational age (LGA) to nondiabetic, nonobese mothers.

RESEARCH DESIGN AND METHODS

At 6–7 years of age, the comparison of various factors was made between 31 LGA and 34 appropriate-for-gestational-age (AGA) children: fibrinogen, antithrombin III, protein C and S, fasting insulin, glucose, homeostasis assessment model of insulin resistance (HOMA-IR) index, adiponectin, leptin, visfatin, IGF-1, IGF-binding protein (IGFBP)-1, IGFBP-3, lipids, and the genetic factors V Leiden G1691A mutation, prothrombin 20210A/G polymorphism, and mutation in the enzyme 5,10-methylenetetrahydrofolate-reductase gene (MTHFR-C677T).

RESULTS

LGA children had higher levels of leptin (P < 0.01), fasting insulin (P < 0.01), and HOMA-IR (P < 0.01), but lower IGFBP-3 (P = 0.0001), fibrinogen (P = 0.0001), and lipoprotein(a) (P < 0.001) than AGA children. Significantly more LGA children were homozygous for the MTHFR-C677T mutation (P = 0.0016).

CONCLUSIONS

Being born LGA to nondiabetic, nonobese mothers is associated with diverse effects on cardiometabolic risk factors at prepuberty.Large-for-gestational-age (LGA) infants may be at risk for the development of obesity and insulin resistance (1–4). A relationship between excess birth weight and metabolic syndrome (MetS) and cardiovascular disease (CVD) risk factors (1–4) has not yet been clearly demonstrated.The aim of this study was to evaluate markers of the prothrombotic state and other MetS and CVD risk factors in prepubertal children born LGA to nondiabetic, nonobese mothers.     

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.     

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.     

Impaired Fasting Glucose and Risk of Cardiovascular Disease in Korean Men and Women: The Korean Heart Study

OBJECTIVE

The relationship between impaired fasting glucose (IFG) and risk of cardiovascular disease (CVD) or ischemic heart disease (IHD) varies widely according to sex and ethnicity. We evaluated the relationship between IFG and CVD or IHD among Korean men and women.

RESEARCH DESIGN AND METHODS

A total of 408,022 individuals who underwent voluntary private health examinations in 17 centers in South Korea were followed for 10 years. Data regarding CVD or IHD events were obtained from the Korean National Health Insurance database. IFG was categorized as grade 1 (fasting glucose 100–109 mg/dL) or grade 2 (110–125 mg/dL).

RESULTS

Incidence rates of CVD (per 100,000 person-years) were 2,203 for diabetes. Age-adjusted hazard ratios (HRs) for CVD were 1.17 (95% CI 1.13–1.20) for grade 1 IFG, 1.30 (1.24–1.35) for grade 2 IFG, and 1.81 (1.75–1.86) for diabetes. The increased risk for women was similar to that of men. Age-adjusted HRs for IHD and ischemic stroke were also significantly increased for men and women with IFG and diabetes. After multivariate adjustment of conventional risk factors (hypertension, dyslipidemia, smoking, obesity, and family history of CVD), the overall risk of CVD was greatly attenuated in all categories. However, the HRs for IHD and ischemic stroke remained significantly increased in men for grade 2 IFG but not in women.

CONCLUSIONS

In Korea, grade 2 IFG is associated with increased risk of IHD and ischemic stroke, independent of other conventional risk factors, in men but not in women.It is well-established that type 2 diabetes is associated with a marked increase in the risk of cardiovascular disease (CVD) and ischemic heart disease (IHD) (1–4). Studies suggest that atherosclerosis develops before the onset of clinical diabetes (5,6). Supporting this possibility, many studies have reported that impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality (7,8). However, the association between impaired fasting glucose (IFG) and risk of CVD and/or IHD remains unclear (7–18). Although some studies have reported that IFG was associated with a greater risk of IHD/CVD in women than in men (17,19), others have reported similar risks for men and women (18).There has also been considerable debate regarding the threshold glucose level associated with increased CVD risk. In 2003, the American Diabetes Association (ADA) lowered the fasting plasma glucose (FPG) cutoff point for IFG from 110 to 100 mg/dL (20). Some studies have reported that FPG levels of 110–125 mg/dL were associated with significantly higher rates CVD morbidity or mortality, but that FPG levels of 100–109 mg/dL were not (12,13). However, other investigators reported that the relationship between CVD risk and fasting glucose was continuous or J-shaped rather than showing a threshold effect at high glucose levels (18,21). However, most studies were based mainly on Caucasian populations, and only a few studies have assessed the relationship between IFG and CVD risk in Asian populations (13,14,18). Furthermore, most of these studies analyzed IHD and stroke together as CVD, whereas few studies have analyzed IHD, ischemic stroke, and hemorrhagic stroke separately (14,22).The primary purpose of this study was to determine whether IFG is associated with increased risk of CVD, IHD, and/or stroke in the Korean population. We also assessed potential sex differences, which have been shown in some previous studies (17,19). Finally, we evaluated whether the CVD risk associated with fasting serum glucose (FSG) levels of 100–109 mg/dL is similar to the risk associated with FSG levels of 110–125 mg/dL (the 1997 ADA definition of IFG).     

Trends in death rates among U.S. adults with and without diabetes between 1997 and 2006: findings from the National Health Interview Survey

OBJECTIVE

To determine whether all-cause and cardiovascular disease (CVD) death rates declined between 1997 and 2006, a period of continued advances in treatment approaches and risk factor control, among U.S. adults with and without diabetes.

RESEARCH DESIGN AND METHODS

We compared 3-year death rates of four consecutive nationally representative samples (1997–1998, 1999–2000, 2001–2002, and 2003–2004) of U.S. adults aged 18 years and older using data from the National Health Interview Surveys linked to National Death Index.

RESULTS

Among diabetic adults, the CVD death rate declined by 40% (95% CI 23–54) and all-cause mortality declined by 23% (10–35) between the earliest and latest samples. There was no difference in the rates of decline in mortality between diabetic men and women. The excess CVD mortality rate associated with diabetes (i.e., compared with nondiabetic adults) decreased by 60% (from 5.8 to 2.3 CVD deaths per 1,000) while the excess all-cause mortality rate declined by 44% (from 10.8 to 6.1 deaths per 1,000).

CONCLUSIONS

Death rates among both U.S. men and women with diabetes declined substantially between 1997 and 2006, reducing the absolute difference between adults with and without diabetes. These encouraging findings, however, suggest that diabetes prevalence is likely to rise in the future if diabetes incidence is not curtailed.Diabetes has been associated with an average 10 years of life lost for individuals diagnosed during middle age (1). Fortunately, numerous evidence-based interventions exist, ranging from glycemic and cardiovascular disease (CVD) risk factor control to early screening for diabetes complications (2). These have been paralleled by population-wide improvements in glycemic control, CVD risk factors, and rates of several diabetes complications (3–5). Despite these improvements, it remains unclear whether longevity has increased uniformly among diabetic populations. Studies in specific diabetic cohorts in Framingham, Minnesota, and North Dakota suggest mortality declined during the 1990s (6–8). Analyses of consecutive cohorts of the U.S. population from the 1970s through the 1990s, however, found that all-cause and CVD death rates declined among diabetic men but not diabetic women (9,10). However, no national studies have examined mortality trends among the U.S. diabetic population since the 1990s, and the intervening years have been a period of continued advances in treatment approaches and risk factor levels. Newly available mortality follow-up data linked to the National Health Interview Survey (NHIS) provide a unique opportunity to determine whether CVD and all-cause mortality has improved among the U.S. population during recent decades as well as whether the excess mortality associated with diabetes has declined (11,12).     

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.     

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.     

Osteoprotegerin Is an Independent Predictor of Vascular Events in Finnish Adults With Type 1 Diabetes

OBJECTIVEOsteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D).RESULTSOnly patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01–1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13–1.88]; P = 0.004) during follow-up.CONCLUSIONSWe showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.Arterial calcification is strongly associated with the development and progression of vascular stiffening and arteriosclerosis leading to cardiovascular disease (CVD). This process is accelerated in patients with diabetes or chronic kidney disease (CKD) and especially in those with both (1). Many of the key regulators of bone mineralization also appear to be key mediators of osteogenic transformation of vascular smooth muscle cells and arterial calcification in diabetes (2,3). One of the most well known is osteoprotegerin (OPG) (4,5). OPG concentrations are positively correlated with coronary calcification (6), vascular stiffness (7), and the presence of unstable plaque (8) in nondiabetic individuals and an increased risk of cardiovascular (CV) mortality in patients with diabetes (9,10). In this study, we further explore the association between circulating concentrations of OPG and CV outcomes in a large well-characterized cohort of patients with type 1 diabetes (T1D) exploring mortality, coronary, stroke, and amputation events.     

Diabetes and risk of prostate cancer: a study using the National Health Insurance

OBJECTIVE

The link between diabetes and prostate cancer is rarely studied in Asians.

RESEARCH DESIGN AND METHODS

The trend of age-standardized prostate cancer incidence in 1995–2006 in the Taiwanese general population was calculated. A random sample of 1,000,000 subjects covered by the National Health Insurance in 2005 was recruited. A total of 494,630 men for all ages and 204,741 men ≥40 years old and without prostate cancer at the beginning of 2003 were followed to the end of 2005. Cumulative incidence and risk ratio between diabetic and nondiabetic men were calculated. Logistic regression estimated the adjusted odds ratios for risk factors.

RESULTS

The trend of prostate cancer incidence increased significantly (P < 0.0001). The cumulative incidence markedly increased with age in either the diabetic or nondiabetic men. The respective risk ratio (95% CI) for all ages and age 40–64, 65–74, and ≥75 years was 5.83 (5.10–6.66), 2.09 (1.60–2.74), 1.35 (1.07–1.71), and 1.39 (1.12–1.71). In logistic regression for all ages or for age ≥40 years, age, diabetes, nephropathy, ischemic heart disease, dyslipidemia, living region, and occupation were significantly associated with increased risk, but medications including insulin and oral antidiabetic agents were not.

CONCLUSIONS

Prostate cancer incidence is increasing in Taiwan. A positive link between diabetes and prostate cancer is observed, which is more remarkable in the youngest age of 40–64 years. The association between prostate cancer and comorbidities commonly seen in diabetic patients suggests a more complicated scenario in the link between prostate cancer and diabetes at different disease stages.The association between diabetes and prostate cancer has been inconsistently reported, even though two meta-analyses suggested that diabetic patients have a lower risk of prostate cancer of 9% (1) and 16% (2), respectively.While the two meta-analyses were examined, many studies were case-control and only three focused on the follow-up of cohorts of diabetic patients (3–5). Among the three cohorts, the cases of prostate cancer were 9 (3), 498 (4), and 2,455 (5), respectively; and only the last (5) showed a significant 9% risk reduction in diabetic patients. Except for the first study being conducted in residents with diabetes in Rochester, Minnesota (3), the diabetic patients in the other two were from hospitalized patients in Denmark (4) and Sweden (5), respectively. The meta-analyses have limitations including a mixture of case-control and cohort designs, a mixture of incident and dead cases, a small number of prostate cancer in most studies, and different sources of subjects with potential selection bias. Although the contamination of type 1 diabetes is possibly minimal because >90% of overall patients have type 2 diabetes, residual confounding could not be excluded if the two types of diabetes are not differentiated.Although some recent studies still suggested a lower risk of prostate cancer in diabetic patients including Caucasians (6,7), Iranians (8), Israelis (9), African Americans, Native Hawaiians, and Japanese Americans (6), the lower risk in African Americans and Native Hawaiians (6) was not significant. Two Japanese studies did not find any significant association (10,11). The Ohsaki Cohort Study suggested that diabetes was not predictive for total prostate cancer, but diabetic patients did show a higher risk of advanced cancer (11).Because diabetic patients are prone to develop cancer involving pancreas, liver, breast, colorectum, bladder, and endometrium (12–15) and the protective effect of diabetes on prostate cancer requires confirmation, this study evaluated the possible link between diabetes and prostate cancer, and the potential risk factors, by using the reimbursement database of the National Health Insurance (NHI) in Taiwan.