History of Cardiovascular Disease, Intensive Lifestyle Intervention, and Cardiovascular Outcomes in the Look AHEAD Trial.

OBJECTIVE: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). METHODS: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. RESULTS: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. CONCLUSIONS: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

Effects of visceral adipose tissue reduction on CVD risk factors independent of weight loss: The Look AHEAD study.

OBJECTIVES: To determine if the reduction of visceral adipose tissue (VAT) volume by lifestyle intervention improved risk factors for cardiovascular disease (CVD) independent of weight loss amount. DESIGN: Ancillary study of randomized-controlled trial. SETTING: Data analysis using multivariable regression models. PARTICIPANTS: Participants of the Look AHEAD (Action for HEAlth in Diabetes) Fatty Liver Ancillary Study. MAIN OUTCOME MEASURES: Correlations between changes in VAT and in CVD risk factors, while adjusting for weight loss and treatment (intensive lifestyle intervention [ILI] vs. diabetes support and education [DSE]). RESULTS: Of 100 participants analyzed, 52% were women, and 36% were black, with a mean age of 61.1 years. In the DSE group, mean weight and VAT changed by 0.1 % (p=0.90) and 4.3% (p=0.39), respectively. In the ILI group, mean weight and VAT decreased by 8.0% (p<0.001) and 7.7% (p=0.01), respectively. Across both groups, mean weight decreased by 3.6% (p<0.001), and mean VAT decreased by 1.2% (p=0.22); the decrease in VAT was correlated with the increase in HDL-cholesterol (HDL-C; R=-0.37; p=0.03). There were no correlations between changes in VAT and blood pressure, triglycerides, LDL-C, glucose, or HbA1c. After adjusting for age, race, gender, baseline metabolic values, fitness, and treatment group, changes in HDL-C were not associated with changes in VAT, while weight changes were independently associated with decrease in glucose, HbA1c, and increase in HDL-C. CONCLUSIONS: VAT reduction was not correlated with improvements of CVD risk factors in a sample of overweight and obese adults with type 2 diabetes after adjusting for weight loss.

Access to Care, Treatment Ambivalence, Medication Nonadherence, and Long-Term Mortality Among Severely Hypertensive African Americans: A Prospective Cohort Study.

African Americans living in poor neighborhoods bear a high burden of illness and early mortality. Nonadherence may contribute to this burden. In a prospective cohort study of urban African Americans with poorly controlled hypertension, mortality was 47.6% over a median follow-up of 6.1 years. Patients with pill-taking nonadherence were more likely to die (hazard ratio, 1.80; 95% confidence interval [CI], 1.18-2.76) after adjustment for potential confounders. With regard to factors related to nonadherence, poor access to care such as difficulty paying for medications was associated with prescription refill nonadherence (odds ratio [OR], 4.12; 95% CI, 1.88-9.03). Pill-taking nonadherence was not associated with poor access to care; however, it was associated with factors related to treatment ambivalence including lower hypertension knowledge (OR, 2.97; 95% CI, 1.39-6.32), side effects (OR, 3.44; 95% CI, 1.47-8.03), forgetfulness (OR, 3.62; 95% CI, 1.78-7.34), and feeling that the medications do not help (OR, 2.78; 95% CI, 1.09-7.09). These data suggest that greater access to care is a necessary but insufficient remedy to the disparities experienced by urban African Americans with hypertension. To achieve its full promise, health reform must also address treatment ambivalence.

Perceptions of division directors in general internal medicine about the importance of and support for scholarly work done by clinician-educators.

PURPOSE: To determine perceptions of general internal medicine (GIM) division directors of the importance of and support for clinician-educators' (CEs') scholarship. METHOD: In 2010, the authors identified 127 accredited U.S. MD-granting medical schools with a GIM division, identified 144 GIM directors, and were able to survey 129 of them. Directors were asked to rate the importance of specific CE scholarly accomplishments for promotion from assistant to associate professor, to describe current research support for CEs, and to state how they would support the scholarly work of CEs if they had funding. RESULTS: Fifty-five directors (42.6%) from 52 institutions responded; there were no significant differences between responding and nonresponding schools. Curriculum development, presentations at national meetings and other institutions, review articles, and book chapters were rated as "most/very important" or "important/somewhat important" by over 90%. Approximately half rated published original peer-reviewed articles as "most/very important"; slightly less than half rated these "not important," a difference associated with having a specific CE track. If $100,000 per year were available to enhance the scholarly productivity of CEs, directors suggested spending it on faculty development, project coordination, protected time for CEs, and methodological and statistical support. CONCLUSIONS: This nationwide survey of GIM division directors confirms that academic CEs in GIM are judged on a wide variety of scholarly activities, many of which are consistent across institutions. However, academic GIM CEs need to understand their institutions' specific criteria, especially regarding the value placed on original, peer-reviewed publications.

Potassium and glucose measures in older adults: the Cardiovascular Health Study.

BACKGROUND: We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults. METHODS: Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk. RESULTS: Among 4,754 participants aged ≥65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium ≥4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of -0.18 (-0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of -0.61 (-0.94, -0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk. CONCLUSIONS: Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.

The use of clinical guidelines highlights ongoing educational gaps in physicians' knowledge and decision making related to diabetes.

BACKGROUND: Clinical guidelines for type 2 diabetes are a resource for providers to manage their patients and may help highlight specific areas in need of further education and training. We sought to determine how often guidelines are used and the relationship to physicians' diabetes-related knowledge and decision making. METHODS: Existing users of electronic clinical support tools were invited to complete an online questionnaire. A knowledge score was calculated for five questions related to prevention of diabetes and treatment of its complications. We explored the association of clinical guideline use with diabetes-related knowledge and self-reported decision making using logistic regression models, adjusted for key covariates. RESULTS: Of 383 physicians completing the questionnaire, 53% reported using diabetes guidelines routinely. Mean diabetes knowledge score for guideline users (GU) was significantly higher than non-guideline users (NGU) (3.37 ± 0.072 vs. 2.76 ± 0.084; p < 0.001). GU were significantly more likely to report a good understanding of type 2 diabetes medications (OR = 2.99, 95% CI 1.95-4.61; p < 0.001). GU were less likely to report their unfamiliarity with insulin as an important barrier to early insulin use (OR = 0.41, 0.21-0.80; p = 0.007) and with pharmacologic options as a barrier to prescribing intensive multifactorial interventions (OR = 0.32, 0.17-0.58; p < 0.001). Associations remained significant after adjusting for physician specialty, practice volume and frequency diagnosing or treating diabetes patients. CONCLUSIONS: Significant gaps exist in diabetes-related knowledge and decision making among practicing physicians, as highlighted by clinical guideline use. The development of educational and training strategies to address these needs may ultimately improve outcomes for patients with diabetes and should be investigated in the future.

Impact of an intensive lifestyle intervention on use and cost of medical services among overweight and obese adults with type 2 diabetes: the action for health in diabetes.

OBJECTIVE: To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. RESEARCH DESIGN AND METHODS: A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. RESULTS: ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385-7,175); however, these were not evident among individuals with a history of cardiovascular disease. CONCLUSIONS: Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs.

Impact of intensive lifestyle intervention on depression and health-related quality of life in type 2 diabetes: the Look AHEAD Trial.

OBJECTIVE: We examined the effects of an intensive lifestyle intervention (ILI), compared with a diabetes support and education (DSE) control intervention, on long-term changes in depression symptoms, antidepressant medication (ADM) use, and health-related quality of life (HRQoL) in overweight/obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Look AHEAD was a multisite randomized controlled trial of 5,145 overweight/obese participants assigned to ILI (designed to produce weight loss) or DSE and followed for a median of 9.6 years. The Beck Depression Inventory (BDI) was administered at baseline, annually at years 1-4, and again at year 8. Mean BDI scores and incidence of BDI scores ≥10, indicative of likely mild or greater depression, were examined. Annually through year 10, participants reported their ADM use and completed the Medical Outcomes Study Short Form 36 (SF-36) questionnaire, which yields physical component summary (PCS) and mental component summary (MCS) scores. RESULTS: ILI significantly reduced the incidence of mild or greater depression symptoms (BDI scores ≥10) compared with DSE (hazard ratio [HR] = 0.85; 95% CI 0.75-0.97; P = 0.0145). Although SF-36 PCS scores worsened over time in both groups, ILI participants reported better physical function than DSE throughout the first 8 years (all P values <0.01). There were no significant differences between treatment arms in the proportion of participants who used ADMs or in SF-36 MCS scores. CONCLUSIONS: ILI for overweight/obese patients with type 2 diabetes may reduce the risk of developing clinically significant symptoms of depression and preserve physical HRQoL. These findings should be considered when evaluating the potential benefits of ILIs.

Effect of improved fitness beyond weight loss on cardiovascular risk factors in individuals with type 2 diabetes in the Look AHEAD study.

BACKGROUND: Because lifestyle-induced improvements in cardiovascular risk factors vary substantially across individuals with type 2 diabetes, we investigated the extent to which increases in fitness explain cardiovascular risk factor improvements independent of weight loss in a lifestyle intervention. METHODS: We studied 1-year changes in Look AHEAD, a randomized trial comparing an intensive lifestyle intervention (ILI) to a diabetes support and education (DSE) control group in adults with type 2 diabetes. Assessments included weight, fitness, blood pressure (BP), glucose, HbA1c, and lipids. We evaluated the effects of changes in weight and fitness on changes in cardiovascular risk factors by study arm, using R (2) from multiple linear regression. RESULTS: Analyses included participants with fitness data at baseline and 1-year (n = 4408; 41% male, 36% non-white; mean age 58.7 ± 6.8 years). Weight change alone improved R (2) for explaining changes in risk factors up to 8.2% in ILI and 1.7% in DSE. Fitness change alone improved R (2) up to 3.9% in ILI and 0.8% in DSE. After adjusting for weight change, fitness was independently associated (p < 0.05) with improvements in R (2) for glucose (+0.7%), HbA1c (+1.1%), high-density lipoprotein (HDL) cholesterol (+0.4%), and triglycerides (+0.2%) in ILI and diastolic BP (+0.3%), glucose (+0.3%), HbA1c (+0.4%), and triglycerides (+0.1%) in DSE. Taken together, weight and fitness changes explained from 0.1-9.3% of the variability in cardiovascular risk factor changes. CONCLUSION: Increased fitness explained statistically significant but small improvements in several cardiovascular risk factors beyond weight loss. Further research identifying other factors that explain cardiovascular risk factor change is needed.

Non-traditional risk factors are important contributors to the racial disparity in diabetes risk: the atherosclerosis risk in communities study.

BACKGROUND: Traditional risk factors, particularly obesity, do not completely explain the excess risk of diabetes among African Americans compared to whites. OBJECTIVE: We sought to quantify the impact of recently identified, non-traditional risk factors on the racial disparity in diabetes risk. DESIGN: Prospective cohort study. PARTICIPANTS: We analyzed data from 2,322 African-American and 8,840 white participants without diabetes at baseline from the Atherosclerosis Risk in Communities (ARIC) Study. MAIN MEASURES: We used Cox regression to quantify the association of incident diabetes by race over 9 years of in-person and 17 years of telephone follow-up, adjusting for traditional and non-traditional risk factors based on literature search. We calculated the mediation effect of a covariate as the percent change in the coefficient of race in multivariate models without and with the covariate of interest; 95 % confidence intervals (95 % CI) were calculated using boot-strapping. KEY RESULTS: African American race was independently associated with incident diabetes. Body mass index (BMI), forced vital capacity (FVC), systolic blood pressure, and serum potassium had the greatest explanatory effects for the difference in diabetes risk between races, with mediation effects (95 % CI) of 22.0 % (11.7 %, 42.2 %), 21.7 %(9.5 %, 43.1 %), 17.9 % (10.2 %, 37.4 %) and 17.7 % (8.2 %, 39.4 %), respectively, during 9 years of in-person follow-up, with continued effect over 17 years of telephone follow-up. CONCLUSIONS: Non-traditional risk factors, particularly FVC and serum potassium, are potential mediators of the association between race and diabetes risk. They should be studied further to verify their importance and to determine if they mark causal relationships that can be addressed to reduce the racial disparity in diabetes risk.

Body-Mass Index and All-Cause Mortality in US Adults With and Without Diabetes.

BACKGROUND: Previous studies found normal weight compared to overweight/obese adults with type 2 diabetes had a higher mortality risk, and body-mass index (BMI)-mortality studies do not typically account for baseline diabetes status. OBJECTIVE: To determine if diabetes influences the BMI-mortality relationship. DESIGN: Using a prospective study design, we analyzed data from a nationally representative sample of US adults participating in the National Health Interview Survey from 1997 to 2002, and followed for mortality through 2006. PARTICIPANTS: Excluding those with heart disease or cancer, our final analytic sample included 74,710 (34,805 never smoker) adults. MAIN MEASURES: BMI was calculated from self-reported height and weight. Diabetes status was based on self-reported diagnosis from a health professional. We used direct age standardization to calculate all-cause mortality rates and adjusted Cox models for all-cause mortality hazard ratios by BMI quintile; this was done separately for adults with diabetes and without diabetes. KEY RESULTS: Among never smokers, mean age was 50.1 years and 43 % were men. Mean BMI was 27.4 kg/m(2), 26 % were obese, and 2,035 (5 %) reported diagnosed diabetes. After 9 years, there were 4,355 deaths (754 of 4,740 with diabetes; 3,601 of 69,970 without) among 74,710 participants, and 1,238 (247 of 2,035 with diabetes; 991 of 32,770 without) among 34,805 never smokers. We observed a qualitative interaction with diabetes on the BMI-mortality relationship (p = 0.002). Death rates were substantially higher among participants with diabetes compared to those without diabetes across all BMI quintiles. However, death rates in participants with diabetes fell with increasing BMI quintile, while rates followed a J-shaped curve among those without diabetes. In adjusted Cox models, BMI was positively associated with mortality in adults without diabetes, but inversely associated with mortality among participants with diabetes. CONCLUSIONS: Mortality increased with increasing BMI in adults without diabetes, but decreased with increasing BMI among their counterparts with diabetes. Future studies need to be better designed to answer the question of whether normal weight adults with diabetes have a higher risk of mortality, by minimizing the possibility of reverse causation. Future studies should also account for prevalent diabetes in all investigations of the BMI-mortality relationship.

Body-mass index and mortality risk in U.S. blacks compared to whites.

OBJECTIVE: To compare body-mass index (BMI)-related mortality risk in U.S. Blacks vs. Whites as the relationship appears to differ across race/ethnicity groups. METHODS: Cross-sectional surveys of nationally representative samples of 11,934 Blacks and 59,741 Whites aged 35-75 in the National Health Interview Survey from 1997 to 2002 with no history of cardiovascular disease (CVD) or cancer were pooled. Mortality follow-up was available through 2006. BMI was calculated from self-reported height and weight. We used adjusted Cox regression analysis to adjust for potential confounders. RESULTS: Over 9 years of follow-up, there were 4303 deaths (1205 among never smokers). Age-adjusted mortality rates were higher in Blacks compared to Whites at BMI < 25 kg/m2 and showed no increase at higher levels of BMI. In men, adjusted hazard ratios for all-cause death rose in a similar fashion across upper BMI quintiles in Blacks and Whites; in women, however, BMI was positively associated with mortality risk in Whites, but inversely associated in Blacks (P interaction = 0.01). Racial disparities were amplified in subsidiary analyses that introduced a 12-month lag for mortality or focused on CVD mortality. CONCLUSIONS: The relationship of elevated BMI to mortality appeared weaker in US Blacks than in Whites, especially among women.

Baseline predictors of missed visits in the Look AHEAD study.

OBJECTIVE: To identify baseline attributes associated with consecutively missed data collection visits during the first 48 months of Look AHEAD­a randomized, controlled trial in 5,145 overweight/obese adults with type 2 diabetes designed to determine the long-term health benefits of weight loss achieved by lifestyle change. DESIGN AND METHODS: The analyzed sample consisted of 5,016 participants who were alive at month 48 and enrolled at Look AHEAD sites. Demographic, baseline behavior, psychosocial factors, and treatment randomization were included as predictors of missed consecutive visits in proportional hazard models. RESULTS: In multivariate Cox proportional hazard models, baseline attributes of participants who missed consecutive visits (n 5 222) included: younger age (hazard ratio [HR] 1.18 per 5 years younger; 95% confidence Interval 1.05, 1.30), higher depression score (HR 1.04; 1.01, 1.06), non-married status (HR 1.37; 1.04, 1.82), never self-weighing prior to enrollment (HR 2.01; 1.25, 3.23), and randomization to minimal vs. intensive lifestyle intervention (HR 1.46; 1.11, 1.91). CONCLUSIONS: Younger age, symptoms of depression, non-married status, never self-weighing, and randomization to minimal intervention were associated with a higher likelihood of missing consecutive data collection visits, even in a high-retention trial like Look AHEAD. Whether modifications to screening or retention efforts targeted to these attributes might enhance long-term retention in behavioral trials requires further investigation.

Plasma lactate and diabetes risk in 8045 participants of the atherosclerosis risk in communities study.

PURPOSE: Determinants of oxidative capacity, such as fitness and level of adiposity, are strongly associated with type 2 diabetes. Whether decreased oxidative capacity itself is a cause or consequence of insulin resistance and diabetes is unknown. METHODS: We examined the association of plasma lactate, a marker of oxidative capacity, with incident diabetes in 8045 participants from the Atherosclerosis Risk in Communities (ARIC) Study with no history of subclinical or diagnosed diabetes at baseline (1996-1998). Incident diabetes was self-reported during annual telephone calls. RESULTS: During a median follow-up of 12 years, there were 1513 new cases of diabetes. In Cox proportional hazards models, baseline plasma lactate (per 10 mg/dL) was significantly associated with diabetes (hazard ratio, 1.20; 95% confidence interval, 1.01-1.43), even after adjustment for diabetes risk factors, fasting glucose, and insulin. The upper quartile of baseline lactate (≥ 8.1 mg/dL) was also significantly associated with diabetes risk (hazard ratio, 1.20; 95% confidence interval, 1.02-1.41) compared with the lowest quartile (≤ 5.1 mg/dL). Significant associations persisted among persons without insulin resistance (homeostatic model assessment insulin resistance index < 2.6 U) (P-trend < .01). CONCLUSIONS: These findings suggest that low oxidative capacity may precede diabetes. Future studies should evaluate the physiological origins of elevated lactate to better understand its possible role in the pathogenesis of diabetes.

Creating a transdisciplinary research center to reduce cardiovascular health disparities in Baltimore, Maryland: lessons learned.

Cardiovascular disease (CVD) disparities continue to have a negative impact on African Americans in the United States, largely because of uncontrolled hypertension. Despite the availability of evidence-based interventions, their use has not been translated into clinical and public health practice. The Johns Hopkins Center to Eliminate Cardiovascular Health Disparities is a new transdisciplinary research program with a stated goal to lower the impact of CVD disparities on vulnerable populations in Baltimore, Maryland. By targeting multiple levels of influence on the core problem of disparities in Baltimore, the center leverages academic, community, and national partnerships and a novel structure to support 3 research studies and to train the next generation of CVD researchers. We also share the early lessons learned in the center's design.

Early response to preventive strategies in the Diabetes Prevention Program.

BACKGROUND: Recommendations for diabetes prevention in patients with prediabetes include lifestyle modification and metformin. However, the significance of early weight loss and glucose measurements when monitoring response to these proven interventions is unknown. OBJECTIVE: To quantify the relationship between early measures of weight and glucose and subsequent diabetes in patients undergoing diabetes prevention interventions. DESIGN: Analysis of results from a randomized controlled trial in 27 academic medical centers in the United States. PARTICIPANTS/INTERVENTIONS: 3,041 adults with hyperglycemia randomized to lifestyle (n = 1,018), metformin (n = 1,036), or placebo (n = 987) with complete follow-up in The Diabetes Prevention Program. MAIN MEASURES: Independent variables were weight loss at 6 and 12 months; fasting glucose (FG) at 6 months; hemoglobin A1c (HbA1c) at 6 months; and post-load glucose at 12 months. The main outcome was time to diabetes diagnosis. KEY RESULTS: After 6 months, 604 participants developed diabetes in the lifestyle (n = 140), metformin (n = 206), and placebo (n = 258) arms over 2.7 years. In the lifestyle arm, 6-month weight loss predicted decreased diabetes risk in a graded fashion: adjusted HR (95 % CI) 0.65 (0.35-1.22), 0.62 (0.33-1.18), 0.46 (0.24-0.87), 0.34 (0.18-0.64), and 0.15 (0.07-0.30) for 0-<3 %, 3-<5 %, 5-<7 %, 7-<10 %, and ≥10 % weight loss, respectively (reference: weight gain). Attainment of optimal 6-month FG and HbA1c and 12-month post-load glucose predicted >60 % lower diabetes risk across arms. We found a significant interaction between 6-month weight loss and FG in the lifestyle arm (P = 0.038). CONCLUSION: Weight and glucose at 6 and 12 months strongly predict lower subsequent diabetes risk with a lifestyle intervention; lower FG predicts lower risk even with substantial weight loss. Early reduction in glycemia is a stronger predictor of future diabetes risk than weight loss for metformin. We offer the first evidence to guide clinicians in making interval management decisions for high-risk patients undertaking measures to prevent diabetes.

The association of plasma lactate with incident cardiovascular outcomes: the ARIC Study.

We examined the association of plasma lactate at rest, a marker of oxidative capacity, with incident cardiovascular outcomes in 10,006 participants in the Atherosclerosis Risk in Communities (ARIC) Study visit 4 (1996-1998). We used Cox proportional-hazards models to estimate hazard ratios of incident coronary heart disease, stroke, heart failure, and all-cause mortality by quartiles of plasma lactate (Q1, ≤5.3 mg/dL; Q2, 5.4-6.6; Q3, 6.7-8.6; and Q4 ≥8.7). During a median follow-up time of 10.7 years, there were 1,105 coronary heart disease cases, 379 stroke cases, 820 heart failure cases, and 1,408 deaths. A significant graded relation between lactate level and cardiovascular events was observed in the demographically adjusted model (all P for trend < 0.001). After further adjustment for traditional and other potential confounders, the association remained significant for heart failure (Q4 vs. Q1: hazard ratio (HR) = 1.35, 95% confidence interval (CI): 1.07, 1.71) and all-cause mortality (HR = 1.27, 95% CI: 1.07, 1.51) (P for trend < 0.02 for these outcomes) but not for coronary heart disease (HR = 1.02, 95% CI: 0.84, 1.24) and stroke (HR = 1.26, 95% CI: 0.91, 1.75). The results for heart failure were robust across multiple subgroups, after further adjustment for N-terminal pro-B-type natriuretic peptide and after exclusion of participants with incident heart failure within 3 years. The independent associations of plasma lactate with heart failure and all-cause mortality suggest an important role for low resting oxidative capacity.

No racial differences in the association of glycated hemoglobin with kidney disease and cardiovascular outcomes.

OBJECTIVE: There is debate regarding the clinical significance of well-established racial differences in HbA1c. We compared the associations of diabetes diagnostic categories for HbA1c and fasting glucose with clinical outcomes in black and white persons in the community. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort analysis of participants without diabetes or cardiovascular disease from the Atherosclerosis Risk in Communities study. We examined the associations of clinical categories of HbA1c (<5.7%, 5.7-6.4%, ≥6.5%) and fasting glucose (<100, 100-125, ≥126 mg/dL) with outcomes separately among 2,484 black and 8,593 white participants and tested for race interactions. RESULTS: Baseline characteristics differed significantly in blacks compared with whites, including HbA1c (5.8 vs. 5.4%; P<0.001). During 18 years of follow-up, there were trends of increased risk of kidney disease, fatal and nonfatal coronary heart disease, and stroke across categories of HbA1c in both blacks and whites. The adjusted hazard ratios for each outcome across categories of HbA1c were similar in blacks and whites (P for interaction>0.05) except for all-cause mortality. Patterns of association were similar, but weaker, for fasting glucose. HbA1c and fasting glucose both were more strongly associated with all-cause mortality in whites compared with blacks, largely explained by racial differences in the rate of cardiovascular deaths. CONCLUSIONS: HbA1c is a risk factor for vascular outcomes and mortality in both black and white adults. Patterns of association for HbA1c were similar to or stronger than those for fasting glucose. With respect to long-term outcomes, our findings support a similar interpretation of HbA1c in blacks and whites for diagnosis and treatment of diabetes mellitus.

NH2-terminal pro-brain natriuretic peptide and risk of diabetes.

Brain natriuretic peptide (BNP) has an established role in cardiovascular disease (CVD). However, recent animal studies suggest direct metabolic effects of BNP. To determine the association of BNP with the risk of diabetes, we conducted a prospective analysis of participants from the Atherosclerosis Risk in Communities (ARIC) study. We included 7,822 men and women without history of diabetes, CVD, or reduced kidney function at baseline. At baseline, NH2-terminal (NT)-proBNP, a cleavage product of BNP, was inversely associated with adiposity, fasting glucose, insulin, and cholesterol but positively associated with blood pressure and C-reactive protein levels. During a median follow-up of 12 years, 1,740 participants reported a new diagnosis of diabetes or medication use for diabetes. Baseline quartiles of NT-proBNP were inversely associated with diabetes risk, even after multivariable adjustment including fasting glucose. The adjusted HRs for diabetes were 1.0 (reference), 0.84 (95% CI 0.74-0.96), 0.79 (95% CI 0.68-0.90), and 0.75 (95% CI 0.64-0.87) for the 1st, 2nd, 3rd, and 4th quartiles of baseline NT-proBNP, respectively (P for trend <0.001). This inverse association was robust across sex, race, and obesity subgroups. Our results extend animal studies and support a direct and important metabolic role of BNP in humans.