Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study

OBJECTIVE

Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard.

RESEARCH DESIGN AND METHODS

Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models.

RESULTS

The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22–1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02–0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10–1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08–1.65]; P = 0.008), CAC (β 0.29 [0.08–0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05–1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08–1.96]; P = 0.01).

CONCLUSIONS

These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

Impact of Blood Lipids on 10-Year Cardiovascular Risk in Individuals Without Dyslipidemia and With Low Risk Factor Burden

ObjectiveTo determine the association of plasma lipids with the prevalence of subclinical atherosclerosis and 10-year risk of incident cardiovascular (CV) events among healthy individuals without dyslipidemia and with low risk factor burden.Patients and MethodsThe analysis (June 24, 2020, through June 12, 2021) included 1204 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) study who were current nonsmokers and did not have CV disease, hypertension (blood pressure ≥130/80 mm Hg or antihypertensive use), diabetes (fasting glucose ≥126 mg/dL or glucose-lowering medication use), and dyslipidemia (low-density-lipoprotein-cholesterol [LDL-C] ≥160 mg/dL, high-density-lipoprotein-cholesterol [HDL-C] <40 mg/dL, total cholesterol [TC] ≥240 mg/dL, triglycerides [TGs] ≥150 mg/dL, or lipid-lowering medication use) at baseline. Associations of lipids with baseline atherosclerosis (presence of carotid plaque and/or coronary calcification) and incident CV events over 10 years were examined using multivariable relative risk regression and Cox regression, respectively.ResultsAt baseline, participants’ median age was 54 (IQR, 49 to 62) years, and 10-year CV risk was 2.7% (IQR, 1.0% to 6.6%); 43.4% had subclinical atherosclerosis. A 1-SD higher LDL-C (23.4 mg/dL), TC (24.7 mg/dL), non–HDL-C (25.3 mg/dL), TC/HDL-C (0.75), and LDL-C/HDL-C (0.66) was associated with a higher prevalence of atherosclerosis of between 6% and 9% (P<.05). For every 1-SD higher LDL-C, non–HDL-C, TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C (0.49), the 10-year incidence of CV events was significantly increased by 40%, 44%, 51%, 49%, and 39%, respectively. For every 1-SD lower HDL-C (13.5 mg/dL), CV risk was increased by 37%. Triglycerides had no association with either outcome.ConclusionExcept for TGs, all lipid variables were associated with atherosclerosis and future risk of CV disease among persons without dyslipidemia and with low risk factor burden.     

Circulating Estrone Levels Are Associated Prospectively With Diabetes Risk in Men of the Framingham Heart Study

OBJECTIVE

In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS).

RESEARCH DESIGN AND METHODS

Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998–2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography–tandem mass spectrometry, and free estradiol and estrone were calculated.

RESULTS

In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02–1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8.

CONCLUSIONS

Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol.Aging is associated with a decline in glucose tolerance, resulting in higher prevalence of type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) in older adults (1). Previous studies have suggested a role of endogenous sex hormones in the development of T2DM. Age-related decline in testosterone levels has been associated with an increased risk of T2DM in older men (2–5); however, the effects of low or high estrone and estradiol levels on T2DM risk in men are not clear.Epidemiologic studies (6,7) and randomized trials (8–10) in women have suggested that hormone therapy reduces the risk of T2DM in postmenopausal women. Furthermore, genetic disruption of estrogen receptor α (ERα) in mice is associated with adiposity and insulin resistance (11). Only a few cross-sectional studies in older men have addressed the relationships between estradiol and T2DM, and the data are conflicting; some studies have shown a positive correlation of estradiol levels with T2DM (12,13), whereas others have found no significant association (5,14). The relationship between estrone and T2DM has not been studied in men. Most studies used immunoassays for the measurement of estradiol levels, for which accuracy in the low range has been questioned (15–17).By using data from the Framingham Offspring Study, we determined whether circulating estrone and estradiol levels are associated with T2DM or IFG in community-dwelling older men. In longitudinal analyses restricted to nondiabetic men, we evaluated whether these hormones were predictive of incident T2DM during a follow-up period of approximately 7 years. This analysis is among the first population-based assessments of the association between estradiol and estrone—here measured with liquid chromatography–tandem mass spectrometry (LC-MS/MS), widely considered the reference method with the highest specificity and sensitivity—with T2DM risk in men (18).     

All-Cause Mortality Risk Among a National Sample of Individuals With Diabetes

OBJECTIVE

Little is known about the relative contributions of modifiable risk factors to overall diabetes mortality. The purpose of the current study is to 1) assess the association between modifiable risk factors and all-cause mortality among a nationally representative sample of individuals with diabetes and 2) determine the population-attributable risk percent (PAR%) for these factors.

RESEARCH DESIGN AND METHODS

We analyzed data from a nationally representative sample of 1,507 adults over the age of 17 years with a self-reported diagnosis of diabetes from the Third National Health and Nutrition Examination Survey (NHANES III) mortality study. Our main outcome measures were all-cause mortality and PAR%. We used the Cox proportional hazard analysis to determine hazard ratios (HRs) for known diabetes risks and calculated PAR%.

RESULTS

Among adults with diabetes, the HRs for all-cause mortality were significant for individuals who had an A1C ≥8% (HR 1.65, 95% CI 1.11–2.45) or reported no regular physical activity (1.58, 1.24–2.02) or current tobacco use (1.77, 1.15–2.73). The population-attributable risk was 15.3% for A1C value ≥8%, 16.4% for no regular physical activity, and 7.5% for current tobacco use.

CONCLUSIONS

Health systems may consider prioritizing care to include smoking cessation, increasing physical activity, and moderate glycemic control among patients with diabetes. This study suggests that focusing on these areas may result in significant reductions in mortality in individuals with diabetes.Optimal disease management for individuals with diabetes often involves significant lifestyle modifications (including diet, physical activity, and smoking cessation) in addition to complex medication regimens to control blood glucose, blood pressure, and serum lipid levels. These treatments have the potential to improve risk factors for morbidity and mortality among individuals with type 2 diabetes (1). Given the complexity of care for individuals with diabetes and the time limitations of health care providers (2), the relative association of each of these factors will be useful to inform policy and planning for appropriate diabetes care.The purpose of the current study was to determine the association of modifiable risk factors for all-cause mortality among a nationally representative sample of individuals with diabetes and to assess the population-attributable risk percent (PAR%) for death for risk factors including blood pressure, lipid and glycemic control, smoking, and physical activity. Previous studies using data from the National Health and Nutrition Examination Survey (NHANES) have not examined the relative contribution of lifestyle factors such as physical activity (3) or have relied on older data that did not include information on glycemic control (4). In addition, previous studies have presented relative risk estimates for these factors, which do not necessarily give an indication of the public health implications of the exposure of interest or its effect on the population (3,5). In contrast, PAR% calculations are suitable in addressing public health policy questions regarding appropriate interventions, population-based treatment strategies, and quality improvement efforts (6).     

Risk Factors for Incident Fracture in Older Adults With Type 2 Diabetes: The Framingham Heart Study

OBJECTIVETo identify risk factors for fracture in type 2 diabetes.RESEARCH DESIGN AND METHODSThis prospective study included members of the Framingham Original and Offspring Cohorts. Type 2 diabetes was defined as fasting plasma glucose >125 mg/dL or use of type 2 diabetes therapy. We used repeated-measures Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for associations between potential predictors and incidence of fragility fracture.RESULTSParticipants included 793 individuals with type 2 diabetes. Mean ± SD age was 70 ± 10 years; 45% were women. A total of 106 incident fractures occurred over 1,437 observation follow-up intervals. Fracture incidence increased with age (adjusted HRs 1.00, 1.44 [95% CI 0.65, 3.16], and 2.40 [1.14, 5.04] for <60, 60–70, and >70 years, respectively; P_trend = 0.02), female sex (2.23 [1.26, 3.95]), HbA_1c (1.00, 2.10 [1.17, 3.75], and 1.29 [0.69, 2.41] for 4.45–6.46% [25–47 mmol/mol], 6.50–7.49% [48–58 mmol/mol], and 7.50–13.86% [58–128 mmol/mol]; P_trend =0.03), falls in past year (1.00, 1.87 [0.82, 4.28], and 3.29 [1.34, 8.09] for no falls, one fall, and two or more falls; P_trend =0.03), fracture history (2.05 [1.34, 3.12]), and lower grip strength (0.82 [0.69, 0.99] per 5-kg increase). Femoral neck bone mineral density, BMI, smoking, physical function, chronic diseases, medications, and physical function were not associated with fracture incidence.CONCLUSIONSPrior falls, fractures, low grip strength, and elevated HbA_1c are risk factors for fractures in older adults with type 2 diabetes. Evaluation of these factors may improve opportunities for early intervention and reduce fractures in this high-risk group.     

Sulfonylurea Use and Incident Cardiovascular Disease Among Patients With Type 2 Diabetes: Prospective Cohort Study Among Women

OBJECTIVE

Evidence is inconsistent for the association between sulfonylurea use and risk of cardiovascular disease among patients with diabetes. We aimed to prospectively evaluate this association using the Nurses’ Health Study (NHS), a well-established cohort of U.S. women with long-term follow-up.

RESEARCH DESIGN AND METHODS

We followed 4,902 women (mean age 68 years) with diabetes (mean duration 11 years), but without cardiovascular disease at baseline. The use of sulfonylureas and other medications was self-reported at baseline and during the follow-up period of up to 10 years. Cox proportional hazards regression models were used to estimate the relative risk (RR) and 95% CI for the association between the sulfonylurea use and incident cardiovascular disease while accounting for potential confounders, including age, diabetes duration, diabetes-related complications, other antihyperglycemic medications, BMI, lifestyle factors, family history of cardiovascular diseases, and present chronic conditions. We also applied the propensity score stratification method to address the possibility of residual confounding.

RESULTS

We identified 339 incident cases of cardiovascular disease, including 191 cases of coronary heart disease (CHD) and 148 cases of stroke. A longer duration of sulfonylurea use was significantly associated with a higher risk of CHD (P for trend = 0.002); the RRs for CHD were 1.24 (95% CI 0.85–1.81) for patients who used sulfonylurea therapy for 1–5 years, 1.51 (0.94–2.42) for 6–10 years, and 2.15 (1.31–3.54) for >10 years, compared with nonusers. Compared with users of metformin monotherapy, the RR for CHD was 3.27 (1.31–8.17) for those who were treated with the combination of metformin and sulfonylurea. The analysis using propensity score stratification yielded similar results. We did not observe a significant association between sulfonylurea therapy and stroke risk.

CONCLUSIONS

Long-term use of sulfonylureas was associated with a significantly higher risk of developing CHD among women with diabetes.     

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.     

Effect of the Look AHEAD Study Intervention on Medication Use and Related Cost to Treat Cardiovascular Disease Risk Factors in Individuals With Type 2 Diabetes

OBJECTIVE

To examine the effect of a lifestyle intervention to produce weight loss and increased physical fitness on use and cost of medications to treat cardiovascular disease (CVD) risk factors in people with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Look AHEAD is a multicenter randomized controlled trial of 5,145 overweight or obese individuals with type 2 diabetes, aged 45–76 years. An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition. Medications prescribed to treat diabetes, hypertension, and hyperlipidemia were compared at baseline and 1 year. Medication costs were conservatively estimated using prices from a national online pharmacy.

RESULTS

Participants randomized to an ILI had significantly greater improvements in CVD risk parameters and reduced medication use and cost compared with those assigned to DSE. At 1 year, average number of medications prescribed to treat CVD risk factors was 3.1 ± 1.8 for the ILI group and 3.6 ± 1.8 for the DSE group (P < 0.0001), with estimated total monthly medication costs of $143 and $173, respectively (P < 0.0001). DSE participants meeting optimal care goals at 1 year were taking an average of 3.8 ± 1.6 medications at an estimated cost of $194/month. ILI participants at optimal care required fewer medications (3.2 ± 1.7) at lower cost ($154/month) (P < 0.001).

CONCLUSIONS

At 1 year, ILI significantly improved CVD risk factors, while at the same time reduced medication use and cost. Continued intervention and follow-up will determine whether these changes are maintained and reduce cardiovascular risk.Type 2 diabetes is one of the most significant public health concerns in the U.S. due to its prevalence and adverse impact on life expectancy, quality of life, and cost. The increasing prevalence of obesity and type 2 diabetes in the U.S. further heightens the importance of diabetes as a chronic public health disease. Forecasts based on data from national health surveys ominously predict that continuation of current trends in obesity and diabetes will significantly and adversely impact the rate of future improvements in U.S. life expectancy and quality of life (1).The excess morbidity and mortality experienced by people with type 2 diabetes is primarily due to increased cardiovascular disease (CVD) risk, and this risk is in turn driven by the triad of hyperglycemia, hypertension, and hyperlipidemia (2). Appropriately, interventions to reduce the adverse health outcomes of type 2 diabetes are primarily directed at these three CVD risk factors, and specific patient goals for parameters of hyperglycemia (A1C), hypertension (blood pressure), and hyperlipidemia (primarily LDL cholesterol) have been promulgated by various professional organizations (2,3).Currently, only a minority of people with type 2 diabetes appear to be achieving optimal-care goals for CVD risk management (4). Lifestyle measures including weight loss and increased physical activity have been shown to improve CVD risk parameters and are therefore the initial interventions recommended for achieving glycemic, blood pressure, and lipid goals (5). However, in practice, most people are unable to implement significant lifestyle changes on a long-term basis and ultimately require multiple pharmacologic agents to achieve currently recommended treatment goals (6–8). Unfortunately, this polypharmacy is associated with decreased quality of life, increased risk of adverse medication effects, increased medication use, higher costs, and higher monitoring expenses (9,10).Several studies (11–13) of weight loss interventions in people with type 2 diabetes have reported reductions in medication use and/or cost. These studies have typically been uncontrolled weight loss interventions applied to small groups of patients. Benefits have primarily been seen in diabetes medication requirements, with usually smaller effects when assessed on medications prescribed for treatment of hypertension and hyperlipidemia. These studies support the premise that effective programs for people with type 2 diabetes that achieve long-term weight loss and increase physical activity hold the promise of improving cardiovascular risk parameters while minimizing the use of pharmacologic agents.Look AHEAD (Action for Health and Diabetes) is an National Institutes of Health–funded long-term (up to 11.5 years) clinical trial studying the effect of an intensive lifestyle intervention (ILI) on CVD morbidity and mortality in people with type 2 diabetes. The 1-year results of the Look AHEAD ILI on weight loss, glycemic control, blood pressure, lipid parameters, and medication use were recently reported (14). In this report, we examine the effect of the Look AHEAD intervention on medication requirements and estimated medication costs to treat CVD risk factors in the Look AHEAD cohort.     

Associations of Microvascular Complications With the Risk of Cardiovascular Disease in Type 1 Diabetes

OBJECTIVEWe examined whether the presence of microvascular complications was associated with increased subsequent risk of cardiovascular disease (CVD) among participants with type 1 diabetes in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study followed for >35 years.RESEARCH DESIGN AND METHODSStandardized longitudinal data collection included: 1) stereoscopic seven-field retinal fundus photography centrally graded for retinopathy stage and clinically significant macular edema; 2) urinary albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR); 3) cardiovascular autonomic neuropathy (CAN) reflex testing; and 4) adjudicated CVD events, including death from CVD, nonfatal myocardial infarction, stroke, subclinical myocardial infarction on electrocardiogram, confirmed angina, or coronary artery revascularization. Cox proportional hazards models assessed the association of microvascular complications with subsequent risk of CVD.RESULTSA total of 239 participants developed CVD, including 120 participants who suffered major adverse cardiovascular events (MACE) defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The presence of microvascular disease (diabetic retinopathy, kidney disease, or CAN) was associated with increased risk of subsequent CVD and MACE (hazard ratios 1.86 to 3.18 and 2.09 to 3.63, respectively), associations that remained significant after adjusting for age and HbA_1c. After adjustment for traditional CVD risk factors, however, only sustained AER ≥30 mg/24 h occurring alone and/or with eGFR <60 mL/min/1.73 m² and the presence of both retinal and kidney disease remained associated with CVD.CONCLUSIONSAdvanced microvascular disease, especially moderate to severe albuminuria or eGFR <60 mL/min/1.73 m², conveyed an increased risk of subsequent cardiovascular disease in the DCCT/EDIC cohort.     

Early Menopause and Cardiovascular Disease Risk in Women With or Without Type 2 Diabetes: A Pooled Analysis of 9,374 Postmenopausal Women

OBJECTIVEEarly menopause may be associated with higher cardiovascular disease (CVD) risk. Type 2 diabetes mellitus (T2DM), coupled with early menopause, may result in even greater CVD risk in women. We examined CVD risk in women with early compared with normal-age menopause, with and without T2DM overall, and by race/ethnicity.RESEARCH DESIGN AND METHODSWe pooled data from the Atherosclerosis Risk in Communities study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. We included women with data on menopausal status, menopausal age, and T2DM, excluding pre- or perimenopausal women and those with prevalent CVD. Outcomes included incident coronary heart disease (CHD), stroke, heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD) (CHD or stroke). We estimated the risk associated with early (<45 years) compared with normal-age menopause using Cox proportional hazards models. Covariates included age, race/ethnicity, education, BMI, blood pressure, cholesterol, smoking, alcohol consumption, antihypertensive medication, lipid-lowering medication, hormone therapy use, and pregnancy history.RESULTSWe included 9,374 postmenopausal women for a median follow-up of 15 years. We observed 1,068 CHD, 659 stroke, 1,412 HF, and 1,567 ASCVD events. T2DM significantly modified the effect of early menopause on CVD risk. Adjusted hazard ratios for early menopause and the outcomes were greater in women with T2DM versus those without (CHD 1.15 [95% CI 1.00, 1.33] vs. 1.09 [1.03, 1.15]; stroke 1.21 [1.04, 1.40] vs. 1.10 [1.04, 1.16]; ASCVD 1.29 [1.09, 1.51] vs. 1.10 [1.04, 1.17]; HF 1.18 [1.00, 1.39] vs. 1.09 [1.03, 1.16]). The modifying effect of T2DM on the association between early menopause and ASCVD was only statistically significant in Black compared with White women.CONCLUSIONSEarly menopause was associated with an increased risk for CVD in postmenopausal women. T2DM may further augment the risk, particularly in Black women.     

Risk of a Recurrent Cardiovascular Event in Individuals With Type 2 Diabetes or Intermediate Hyperglycemia: The Hoorn Study

OBJECTIVE

To investigate risk of a recurrent cardiovascular event and its predictors in a population-based cohort.

RESEARCH DESIGN AND METHODS

Participants of the Hoorn Study who had experienced a first cardiovascular event after baseline (n = 336) were followed with respect to a recurrent event. Absolute risk of a recurrent event was calculated for individuals with normal glucose metabolism, intermediate hyperglycemia, and type 2 diabetes. Cox regression models were used to investigate which variables, measured before the first vascular event, predicted a recurrent event using the stepwise backward procedure.

RESULTS

During a median follow-up of 4.1 years, 44% (n = 148) of the population developed a recurrent vascular event. The rate of recurrent events per 100 person-years was 7.2 (95% CI 5.8–8.7) in individuals with normal glucose metabolism, compared with 9.8 (6.6–14.0) in individuals with intermediate hyperglycemia and 12.5 (8.5–17.6) in individuals with type 2 diabetes. Higher age (hazard ratio 1.02 [95% CI 1.00–1.04]), male sex (1.56 [1.08–2.25]), waist circumference (1.02 [1.02–1.03]), higher systolic blood pressure (1.01 [1.01–1.02]), higher HbA_1c (%, 1.13 [0.97–1.31]/ mmol/mol, 1.01 [1.00–1.03]), and family history of myocardial infarction (1.38 [0.96–2.00]) predicted a recurrent cardiovascular event.

CONCLUSIONS

Individuals with type 2 diabetes, but not individuals with intermediate hyperglycemia, are at increased risk for a recurrent vascular event compared with individuals with normal glucose metabolism. In people with a history of cardiovascular disease, people at increased risk of a recurrent event can be identified based on the patient’s risk profile before the first event.Due to aging, the increasing prevalence of obesity and diabetes worldwide, and improved care after a first cardiovascular event, the number of people at risk for a recurrent cardiovascular event is increasing (1).High blood pressure levels, dyslipidemia, smoking, and type 2 diabetes are known risk factors for a first cardiovascular event in the general population, with addition of glycemic level (HbA_1c) in individuals with diabetes (2–4). Also, individuals in a prediabetic state (elevated glucose levels) are at increased risk for a first cardiovascular event compared with individuals with normal glucose metabolism (5).In 1998, the cumulative incidence of recurrent events in patients with and without type 2 diabetes was described (5). Since then, care after a first cardiovascular event has improved, which might have affected absolute risk of a recurrent event. Less is known about predictors of a recurrent cardiovascular event in the general population. In general, established risk factors for a first event have not been found to be predictive for a recurrent event regarding various outcomes (6–8).In the current study, we investigated whether people in a prediabetic state as well as people with type 2 diabetes are at increased risk of a recurrent cardiovascular event compared with people with normal glucose metabolism. To enable identification of individuals at high risk for a recurrent event and consequently effectively target screening, predictors of a recurrent cardiovascular event were determined, based on the patient’s risk profile before the first event.     

Maternal Family History of Diabetes Is Associated With a Reduced Risk of Cardiovascular Disease in Women With Type 2 Diabetes: The Fremantle Diabetes Study

OBJECTIVE

To investigate whether parental family history of diabetes influences cardiovascular outcomes in type 2 diabetes.

RESEARCH DESIGN AND METHODS

We studied 1,294 type 2 diabetic patients (mean age 64.1 years, 51.2% female) recruited to a community-based cohort study from 1993 to 1996 and followed until mid-2006. A data linkage system assessed all-cause and cardiac mortality, incident myocardial infarction, and stroke. Cox proportional hazards modeling was used to determine the influence of maternal or paternal family history on these outcomes.

RESULTS

A maternal family history of diabetes was reported by 20.4% of the cohort, 8.3% reported paternal family history, and 2.0% reported both parents affected. Maternal and paternal family history was associated with earlier age of diabetes onset, and maternal family history was associated with worse glycemic control. For all patients, maternal family history was significantly associated with reduced risk of all-cause mortality and cardiac mortality. When analyzed by sex, maternal family history had no effect on male patients, whereas female patients with diabetic mothers had significantly reduced hazard ratios for death from all causes (0.63 [95% CI 0.41–0.96]; P = 0.033), for death from cardiac causes (0.32 [0.14–0.72]; P = 0.006), and for first myocardial infarction (0.45 [0.26–0.76]; P = 0.003). Paternal family history status was not associated with these outcomes.

CONCLUSIONS

A maternal family history of diabetes confers relative protection against cardiovascular disease in female patients but not in male patients with type 2 diabetes. Paternal family history is associated with risks equivalent to those without a family history of diabetes. Some of the clinical heterogeneity of type 2 diabetes is related to maternal transmission effects with differential impact on male and female patients.The complex etiology of type 2 diabetes involves both genetic components and environmental exposures. In type 2 diabetes, there is a well documented association between a family history of the disease and its development (1,2). Maternal and paternal family histories of diabetes are both associated with an earlier age of onset (2–4), and this effect is more marked when multiple family members are affected (5). In addition, intrauterine exposure to diabetes increases the risk of diabetes in offspring (6), which may help explain the reported excess maternal transmission (7,8).Patients with familial diabetes have relatively poor glycemic control, but few other clinical differences have been reported (4,5,9,10). An early age of onset and poor glycemic control would both be expected to have a negative impact on the development of chronic complications, but no such longitudinal data have been published. In the present study, we examined relationships among parental diabetes and important clinical outcomes in type 2 diabetes, including incident coronary heart disease (CHD) and all-cause and cardiac mortality in a large community-based sample of patients with type 2 diabetes. We hypothesized that familial diabetes would indicate worse clinical outcomes. We investigated potential relationships in male and female patients separately, given the known differences in CHD incidence between men and women with diabetes (11).     

Trends in Diabetes Incidence: The Framingham Heart Study

OBJECTIVEObesity and type 2 diabetes continue to increase in prevalence in the U.S. Whether diabetes incidence continues to increase in recent times is less well documented. We examined trends in diabetes incidence over the previous four decades.RESULTSThe annualized rates of diabetes per 1,000 individuals were 2.6, 3.8, 4.7, and 3.0 (women) and 3.4, 4.5, 7.4, and 7.3 (men) in the 1970s, 1980s, 1990s, and 2000s, respectively. Compared with the 1970s, the age- and sex-adjusted relative risks of diabetes were 1.37 (95% CI 0.87–2.16; P = 0.17), 1.99 (95% CI 1.30–3.03; P = 0.001), and 1.81 (95% CI 1.16–2.82; P = 0.01) in the 1980s, 1990s, and 2000s, respectively. Compared with the 1990s, the relative risk of diabetes in the 2000s was 0.85 (95% CI 0.61–1.20; P = 0.36).CONCLUSIONSIn our community-based sample, the risk of new-onset diabetes continued to be higher in the 2000s compared with the 1970s. In the past decade, diabetes incidence remained steady despite the ongoing trend of rising adiposity.