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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

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.     

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.     

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.     

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.     

Elevated Serum Uric Acid Concentrations Independently Predict Cardiovascular Mortality in Type 2 Diabetic Patients

OBJECTIVE

There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals.

RESEARCH DESIGN AND METHODS

The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders.

RESULTS

During follow-up, 329 (12.1%) patients died, 44.1% (n = 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 [95% CI 1.12–1.27], P < 0.001) and cardiovascular (1.25 [1.16–1.34], P < 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 [1.01–1.61], P = 0.046), whereas the association of serum uric acid with all-cause mortality did not.

CONCLUSIONS

Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures.Cardiovascular disease (CVD) represents the most common cause of morbidity and mortality in the type 2 diabetic population (1,2). Several biochemical parameters have been associated with increased risk for CVD in type 2 diabetes (3–5). Increased levels of serum uric acid are quite common in type 2 diabetic patients (6), and they might represent an additional CVD risk factor in these patients (7,8).Whereas several prospective studies have consistently demonstrated that elevated serum uric acid levels are an independent risk factor for CVD mortality in the general population (9–13), there is currently a paucity of available data on the association between serum uric acid levels and CVD mortality in the type 2 diabetic population. In a small retrospective study of 535 type 2 diabetic patients, it was found that higher serum uric acid levels were significantly associated with an increased risk of all-cause mortality (14). However, no information was available on specific causes of mortality in such studies, and no adjustment was made for important risk factors, such as diabetes duration and albuminuria. In another small study of 581 elderly type 2 diabetic patients, it was found that higher serum uric acid levels independently predicted cardiovascular mortality, but the authors did not adjust for glycemic control, use of medications, and albuminuria (15). In this respect, it is important to emphasize that the progressive decline in kidney function, which frequently occurs with aging and the course of type 2 diabetes, is also generally paralleled by progressive increases in serum uric acid levels (16). Thus, the presence of renal dysfunction, as assessed by glomerular filtration rate and albuminuria, should be always taken into account when the association of serum uric acid levels with mortality is explored, especially in the type 2 diabetic population.The aim of this prospective study was to investigate whether an association does exist between serum uric acid concentrations and all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals, independent of several baseline confounding factors, including markers of kidney function.     

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.     

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).     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Osteoprotegerin and mortality in type 2 diabetic patients

OBJECTIVE

Plasma osteoprotegerin (OPG) is an emerging strong and independent predictor of cardiovascular disease (CVD) in high-risk populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells, and increased plasma OPG levels may reflect arterial vascular damage. We aimed to investigate the prognostic value of OPG in relation to all-cause and cardiovascular mortality in a cohort of type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

In a prospective observational follow-up study, 283 type 2 diabetic patients (172 men; aged 53.9 ± 8.8 years) were followed for a median of 16.8 years (range 0.2–23.0). Baseline plasma OPG concentrations were determined by immunoassay.

RESULTS

During follow-up, 193 (68%) patients died. High versus low levels of OPG predicted all-cause mortality (covariate-adjusted for urinary albumin excretion rate [UAER], estimated glomerular filtration rate, and conventional risk factors); hazard ratio (HR) 1.81 [95% CI 1.21–2.69]. The all-cause predictive effect of OPG was independent of NH₂-terminal pro-brain natriuretic peptide (NT-proBNP) and was also useful within groups divided according to level of UAER. In total, 103 (73%) patients died because of CVD. High and medium versus low levels of OPG predicted cardiovascular mortality (unadjusted HR 1.86 [95% CI 1.07–3.23] and 3.51 [2.10–5.85], respectively). However, after adjustment for the covariates, HRs were no longer significant.

CONCLUSIONS

Elevated plasma OPG is a strong predictor of all-cause mortality in type 2 diabetic patients. The effect of OPG on all-cause mortality was independent of conventional cardiovascular risk factors, UAER, and NT-proBNP levels.Plasma osteoprotegerin (OPG) is a promising strong and independent predictor of cardiovascular disease (CVD) in high-risk individuals, such as type 1 diabetic patients with nephropathy and nondiabetic patients after kidney transplantation or myocardial infarction (1–4). OPG is a member of the tumor necrosis factor receptor superfamily acting as a soluble decoy receptor for the receptor activator of nuclear factor-κβ ligand (RANKL) to prevent osteoclast activation and bone resorption (5). OPG mRNA has been detected in a variety of human tissues, including the lung, heart, and kidney (5). This bone-related glycoprotein is present in the arterial wall, and plasma OPG has been suggested to reflect the increased OPG content in arterial tissue observed in diabetic patients (6). OPG is upregulated in calcified coronary plaques (7) and associated with angiographic disease severity and cardiovascular events independent of conventional risk factors (8,9). Therefore, increased plasma OPG levels are suggested to be a marker of arterial vascular damage.CVD is the major determinant of morbidity and mortality in patients with type 2 diabetes and, in particular, patients with an elevated urinary albumin excretion rate (UAER) (10). Increased OPG levels are associated with diabetes (11). Recently, an elevated plasma OPG level was shown to predict increased mortality in patients with type 1 diabetes and diabetic nephropathy (4) and also to predict increased incidence of cardiovascular events among patients with uncomplicated type 2 diabetes who were followed for 18 months (12). However, the prognostic importance of OPG in type 2 diabetic patients with long follow-up and elevated UAER is unknown. Therefore, this study examines the predictive value of plasma OPG in relation to all-cause and cardiovascular mortality in a large cohort of type 2 diabetic patients followed prospectively for 17 years.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Circulating Vascular Progenitor Cells in Patients With Type 1 Diabetes and Microalbuminuria

OBJECTIVE

Patients with type 1 diabetes and microalbuminuria are at increased risk of cardiovascular disease (CVD). Abnormalities in vascular progenitor cells, which participate in vascular repair, may be implicated in this susceptibility.

RESEARCH DESIGN AND METHODS

We studied the number and function of vascular progenitor cells in 22 type 1 diabetic patients with history of microalbuminuria (MA⁺) and 22 type 1 diabetic patients without history of microalbuminuria (MA⁻), of similar age, diabetes duration, glycemic control, renal function, and no history of CVD.

RESULTS

MA⁺ patients had lower circulating CD34⁺ and CD34⁺/CD133⁺ cell numbers compared with MA⁻ patients (P < 0.006). In in vitro functional assays, MA⁺ patients had a significantly lower number of colony-forming units and impaired vascular endothelial growth factor (VEGF)-A–mediated tube formation, when compared with MA⁻ patients (P < 0.01).

CONCLUSIONS

In type 1 diabetic patients with microalbuminuria, a marker of microvascular injury and a risk factor for CVD, circulating vascular progenitor cell number is reduced and function is impaired.The number of circulating endothelial progenitor cells inversely relates to cardiovascular disease (CVD) (1–3); microalbuminuria is one of the earliest manifestations of diabetic nephropathy and a marker of CVD (4). A subset of patients with type 1 diabetes is susceptible to diabetic nephropathy, a condition characterized by a higher risk of cardiovascular morbidity and mortality (4,5). Type 1 diabetic patients without complications have a lower number of circulating progenitor cells than healthy control subjects (6,7). To gain insight into the susceptibility to CVD in type 1 diabetes, we studied circulating vascular progenitor cell number and function in type 1 diabetic patients with and without microalbuminuria.     

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.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Effect of diabetes on severity and hospital mortality in patients with acute pancreatitis: a national population-based study

OBJECTIVE

Diabetes may increase the risk of acute pancreatitis (AP). We aimed to further investigate whether diabetes may also adversely affect outcomes of patients with AP.

RESEARCH DESIGN AND METHODS

In this retrospective cohort study, we compared 18,990 first-attack AP with diabetes to 37,980 matched control subjects from Taiwan’s National Health Insurance Research Database between 2000 and 2009. Primary outcomes were development of severe AP, defined by a modified Atlanta classification scheme, and hospital mortality. Analyses were performed using univariable and multivariable logistic regression model with generalized estimating equations accounting for hospital clustering effect.

RESULTS

After baseline characteristics were adjusted, AP patients with diabetes had a higher risk of a severe attack than their nondiabetic counterparts (adjusted odds ratio [OR] 1.21, 95% CI 1.16–1.26). When severity criteria were analyzed individually, diabetic AP patients had a 58% higher risk of intensive care unit admission and a 30% higher risk of local complications, but a 16% lower risk of gastrointestinal bleeding, than AP patients without diabetes. The risk of organ failure at least one system) was similar between the two groups. Conversely, AP patients with diabetes were associated with a lower risk of hospital mortality (adjusted OR 0.77, 95% CI 0.65–0.91).

CONCLUSIONS

Although diabetes may adversely affect the disease process of AP, it seems to protect patients from AP-related mortality.Acute pancreatitis (AP) is an acute inflammatory disease of the pancreas. The local inflammation is usually self-limited within a few days, but it can be destructive and cause a severe local complication and/or systemic reaction leading to organ failures and death. Although the case-fatality rate has been decreasing over the decades (1,2), severe cases still carry a high mortality (20–50%) and consume nearly half of the resources and costs incurred by all patients with AP (3). Accordingly, many efforts have been made to identify correlates of severity and predictors for mortality in patients with AP (4–6).In addition to older people (7), patients with certain comorbidities, such as obesity (8), hypertriglyceridemia (9), chronic renal failure (10), and systemic lupus erythematosus (11), are shown to be associated with greater risk of not only the incidence but also the severity and mortality of AP. Among various comorbidities, diabetes mellitus is relatively common in patients with AP; the prevalence was 11% in Japan (12), 17.7% in California (U.S.), (13) and 19.3% in Taiwan (3). These figures are expected to continuously increase in the future because diabetic patients not only are at risk for developing AP (14–16) but also are growing in prevalence worldwide (17). Nonetheless, the effect of diabetes on outcomes of patients with AP has not been adequately studied, and the results of available reports are inconsistent (13,18). For example, Frey and colleagues examined the effect of comorbidities on patients with AP and found that diabetes was not associated with early mortality (13), whereas Graham and coworkers assessed the effect of diabetes on critically ill patients and showed a reduced risk of hospital mortality in a subgroup patients with AP (18). In both studies, however, the effect of diabetes was not specifically examined and detailed analyses were not performed (13,18).In a recent national population-based study on Taiwanese patients with first-attack AP, we found that the prevalence of diabetes increased from 15.6% in 2000 to 2001 to 19.7% in 2008 to 2009 (1). In this study, we used the same cohort (1) to further investigate the effect of diabetes on outcomes of these patients. Because diabetic patients are likely to have a higher comorbid burden and hence a poorer reserve for acute illnesses, we hypothesized that diabetes is associated with a higher risk of severe attacks and hospital mortality in adult patients with first-attack AP.     

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.     

Sex Differences in All-Cause and Cardiovascular Mortality,Hospitalization for Individuals With and Without Diabetes,and Patients With Diabetes Diagnosed Early and Late

OBJECTIVE

To compare risk of all-cause mortality, cardiovascular disease (CVD) mortality, acute myocardial infarction (AMI) mortality, stroke mortality, and hospitalizations for males and females with and without diabetes and those with diabetes diagnosed early and late.

RESEARCH DESIGN AND METHODS

We conducted a population-based retrospective cohort study including 73,783 individuals aged 25 years or older in Newfoundland and Labrador, Canada (15,152 with diabetes; 9,517 with late diagnoses).

RESULTS

Males and females with diabetes had an increased risk of all-cause mortality, CVD mortality, AMI mortality, and CVD hospitalizations compared with individuals without diabetes, and the risk was stronger in females than in males. For females, risks of all-cause mortality (hazard ratio [HR] 1.85 [95% CI 1.74–1.96]) and CVD hospitalizations (2.57 [2.24–2.94]) were significantly higher compared with their male counterparts (1.59 [1.51–1.69] and 1.92 [1.72–2.14]). Females with diabetes diagnosed late had an increased risk of CVD mortality (6.54 [4.80–8.91]) and CVD hospitalizations (5.22 [4.31–6.33]) compared with females without diabetes, and both were significantly higher compared with their male counterparts (3.44 [2.47–4.79]) and (3.33 [2.80–3.95]).

CONCLUSIONS

Females with diabetes have a greater risk of mortality than males with diabetes. CVD has a greater impact on females with diabetes than males, especially when diagnosed at a later stage. Different management strategies should be considered for males and females and those with early and late diagnoses of diabetes.Diabetes has become a health problem of increasing significance in the past two decades. The number of individuals with diabetes will reach 366 million in 2011 and will increase to 552 million by 2030 (1). In Canada, the age-standardized incidence and prevalence of diabetes have been increasing in recent years (2).A challenge with type 2 diabetes is the late diagnosis of the disease because many individuals who meet the criteria are often asymptomatic. Approximately 183 million people, or half of those who have diabetes, are unaware they have the disease (1). Furthermore, type 2 diabetes can be present for 9 to 12 years before being diagnosed and, as a result, complications are often present at the time of diagnosis (3). Insulin resistance and β-cell dysfunction are largely responsible for the development of diabetes and its related complications, and both are present very early in the natural history of diabetes (4). However, the potential does exist to prevent or at least delay the onset of type 2 diabetes because several randomized control trials have shown that both lifestyle and pharmacologic interventions in adults are effective (5–8). In addition to preventing diabetes, it is also possible to reduce diabetes-related complications through intensive blood glucose control. Results from the UK Prospective Diabetes Study (UKPDS) have shown that intensive blood glucose control reduces diabetes-related complications (6–9). Early detection of type 2 diabetes is critical because effective and active management is essential for those with newly diagnosed diabetes who have not developed complications.Cardiovascular disease (CVD) is the most common comorbidity associated with diabetes, and with 50% of those with diabetes dying of CVD it is the most common cause of death (1). Acute myocardial infarction (AMI) and stroke are other common comorbidities associated with diabetes. Individuals with diabetes have an increased risk of all-cause mortality and morbidity related to CVD, AMI, and stroke compared with individuals without diabetes (9–12). Although studies consistently have found that individuals with diabetes have a higher risk of mortality and hospitalizations compared with those without diabetes, results have been inconsistent when comparing males and females. Most studies have found that females with diabetes have a greater risk of mortality and hospitalizations than males with diabetes (9,10,12–17). Two previous meta-analyses found that diabetes is a stronger risk factor for CVD mortality in females than in males; however, studies that did not adjust for major CVD risk factors were included in these meta-analyses (18,19). A meta-analysis conducted by Kanaya et al. (20), which included studies that controlled for CVD risk factors, found that the risks associated with diabetes for coronary heart disease mortality, nonfatal myocardial infarction, and CVD were higher among females than males. However, the differences were not statistically significant.Newfoundland and Labrador has the highest age-standardized prevalence of diabetes in Canada (2), and the age-standardized mortality and hospitalization rates for CVD, AMI, and stroke are some of the highest in the country (21,22). A better understanding of mortality and hospitalizations associated with diabetes for males and females is important to support diabetes prevention and management. Therefore, the objectives of this study were to compare the risk of all-cause, CVD, AMI, and stroke mortality and hospitalizations for males and females with and without diabetes and those with early and late diagnoses of diabetes.     

Nationwide study on trends in hospital admissions for major cardiovascular events and procedures among people with and without diabetes in England, 2004-2009

OBJECTIVE

It is unclear whether people with and without diabetes equally benefitted from reductions in cardiovascular disease (CVD). We aimed to compare recent trends in hospital admission rates for angina, acute myocardial infarction (AMI), stroke, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) among people with and without diabetes in England.

RESEARCH DESIGN AND METHODS

We identified all patients aged >16 years with cardiovascular events in England between 2004–2005 and 2009–2010 using national hospital activity data. Diabetes- and nondiabetes-specific rates were calculated for each year. To test for time trend, we fitted Poisson regression models.

RESULTS

In people with diabetes, admission rates for angina, AMI, and CABG decreased significantly by 5% (rate ratio 0.95 [95% CI 0.94–0.96]), 5% (0.95 [0.93–0.97]), and 3% (0.97 [0.95–0.98]) per year, respectively. Admission rates for stroke did not significantly change (0.99 [0.98–1.004]) but increased for PCI (1.01 [1.005–1.03]) in people with diabetes. People with and without diabetes experienced similar proportional changes for all outcomes, with no significant differences in trends between these groups. However, diabetes was associated with an ~3.5- to 5-fold risk of CVD events. In-hospital mortality rates declined for AMI and stroke, remained unchanged for CABG, and increased for PCI admissions in both groups.

CONCLUSIONS

This national study suggests similar changes in admissions for CVD in people with and without diabetes. Aggressive risk reduction is needed to further reduce the high absolute and relative risk of CVD still present in people with diabetes.The incidence and mortality from cardiovascular disease (CVD) have declined markedly during the last several decades in the U.K. and other Western societies (1–3). Advances in understanding and control of major cardiovascular risk factors and medical care of CVD have contributed to these reductions (4). However, although previous reports from different populations and study settings have emphasized favorable trends in adults without diabetes, conflicting findings were reported in people with diabetes. Some data indicate similar reductions in CVD rates in these groups, whereas other data report that adults with diabetes had lower declines in their CVD event rates compared with the improvement experienced by people without diabetes (5–8). Some studies found no evidence that people with diabetes, particularly women, benefited from the reductions in CVD incidence (7,9). In the U.K., the considerable recent increases in obesity and diabetes, particularly among young and middle-aged adults, could increase CVD rates (10). A study showed increased coronary heart disease (CHD) mortality rates in young men in 2002 in England and Wales and explained this finding by adverse trends in CHD risk factors (11).As part of a national strategy to reduce CVD mortality, a number of quality-improvement initiatives were introduced in the U.K. health system during the last decade, with a major emphasis on secondary prevention (12–14). However, there are no data available on whether these reforms have had a significant effect on the clinical outcomes of diabetes, such as cardiovascular events.Although CVD remains the leading cause of death and hospitalization for CVD is one of the main users of health resources, data on recent national trends in CVD among people with and without diabetes in England are lacking. The objective of this study was to describe the trends in the rate of major cardiovascular events requiring hospital admission (myocardial infarction [MI], angina, and stroke) and cardiovascular interventions (percutaneous coronary intervention [PCI] and coronary artery bypass graft [CABG]) among people with and without diabetes between 2004 and 2009 in England. We also aimed to describe the relative risk of these events in people with diabetes.     

Fasting Glucose Level and the Risk of Incident Atherosclerotic Cardiovascular Diseases

OBJECTIVE

Although diabetes increases the risk of cardiovascular disease (CVD) and mortality, the dose-response relationship between fasting glucose levels below those diagnostic of diabetes with cardiovascular events has not been well characterized.

RESEARCH DESIGN AND METHODS

A prospective cohort study of more than one million Koreans was conducted with a mean follow-up of 16 years. A total of 1,197,384 Korean adults with no specific medical conditions diagnosed were classified by baseline fasting serum glucose level. Associations of fasting glucose level with CVD incidence and mortality, stroke incidence and mortality, and all-cause mortality were analyzed using multivariate proportional hazards regression.

RESULTS

The relationships between fasting glucose levels and CVD risks generally followed J-shape curves, with lowest risk in the glucose range of 85–99 mg/dL. As fasting glucose levels increased to >100 mg/dL, risks for CVD, ischemic heart disease, myocardial infarction, and thrombotic stroke progressively increased, but risk for hemorrhagic stroke did not. Fasting glucose levels <70 mg/dL were associated with increased risk of all stroke (hazard ratio 1.06, 95% CI 1.01–1.11) in men and (hazard ratio 1.11, 1.05–1.17) in women.

CONCLUSIONS

Both low glucose level and impaired fasting glucose should be considered as predictors of risk for stroke and coronary heart disease. The fasting glucose level associated with the lowest cardiovascular risk may be in a narrow range.Diabetes is a well-established risk factor for cardiovascular disease (CVD) and all-cause mortality (1–3). Impaired fasting glucose (IFG), defined by the American Diabetes Association as having a fasting plasma glucose level of 100–125 mg/dL (5.6–7.0 mmol/L) or a 2-h value on the oral glucose tolerance test of 140–199 mg/dL (7.8–11.1 mmol/L) (4) was associated with CVD risk in several studies (1,5–7). The evidence is inconsistent, however, and the clinical relevance of IFG as a predictor of CVD is still unclear (8–11). In addition, the shape of the dose-response relationship between CVD risk and fasting glucose level has not been well characterized across the full range of fasting blood glucose values.It is unclear whether there is an optimum fasting glucose level associated with the lowest level of CVD risk (12,13), or whether risk increases at very low fasting glucose levels (14). Several studies have shown J-shape or U-shape relationships between fasting glucose levels and mortality (3,5,14,15).The Korean Cancer Prevention Study (16,17) (KCPS) is a cohort study of >1.3 million Korean adults designed to evaluate major risk factors for chronic diseases and mortality. The large sample size of this cohort facilitated detailed characterization of the dose-response relationship of fasting glucose level with the incidence of clinical CVD end points.