Impact of remission from type 2 diabetes on long-term health outcomes: findings from the Look AHEAD study.

AIMS/HYPOTHESIS: We examined the association of attainment of diabetes remission in the context of a 12 year intensive lifestyle intervention with subsequent incidence of chronic kidney disease (CKD) and CVD. METHODS: The Look AHEAD study was a multi-centre RCT comparing the effect of a 12 year intensive lifestyle intervention with that of diabetes support and education on CVD and other long-term health conditions. We compared the incidence of CVD and CKD among 4402 and 4132 participants, respectively, based on achievement and duration of diabetes remission. Participants were 58% female, and had a mean age of 59 years, a duration of diabetes of 6 year and BMI of 35.8 kg/m2. We applied an epidemiological definition of remission: taking no diabetes medications and having HbA1c <48 mmol/mol (6.5%) at a single point in time. We defined high-risk or very high-risk CKD based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria, and CVD incidence as any occurrence of non-fatal acute myocardial infarction, stroke, admission for angina or CVD death. RESULTS: Participants with evidence of any remission during follow-up had a 33% lower rate of CKD (HR 0.67; 95% CI 0.52, 0.87) and a 40% lower rate of the composite CVD measure (HR 0.60; 95% CI 0.47, 0.79) in multivariate analyses adjusting for HbA1c, BP, lipid levels, CVD history, diabetes duration and intervention arm, compared with participants without remission. The magnitude of risk reduction was greatest for participants with evidence of longer-term remission. CONCLUSIONS/INTERPRETATION: Participants with type 2 diabetes with evidence of remission had a substantially lower incidence of CKD and CVD, respectively, compared with participants who did not achieve remission. This association may be affected by post-baseline improvements in weight, fitness, HbA1c and LDL-cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov NCT00017953 DATA AVAILABILITY: https://repository.niddk.nih.gov/studies/look-ahead/.

Social and Psychosocial Determinants of Racial and Ethnic Differences in Cardiovascular Health in the United States Population.

BACKGROUND: Social and psychosocial factors are associated with cardiovascular health (CVH). Our objective was to examine the contributions of individual-level social and psychosocial factors to racial and ethnic differences in population CVH in the NHANES (National Health and Nutrition Examination Surveys) 2011 to 2018, to inform strategies to mitigate CVH inequities. METHODS: In NHANES participants ages ≥20 years, Kitagawa-Blinder-Oaxaca decomposition estimated the statistical contribution of individual-level factors (education, income, food security, marital status, health insurance, place of birth, depression) to racial and ethnic differences in population mean CVH score (range, 0-14, accounting for diet, smoking, physical activity, body mass index, blood pressure, cholesterol, blood glucose) among Hispanic, non-Hispanic Asian, or non-Hispanic Black adults compared with non-Hispanic White adults. RESULTS: Among 16 172 participants (representing 255 million US adults), 24% were Hispanic, 12% non-Hispanic Asian, 23% non-Hispanic Black, and 41% non-Hispanic White. Among men, mean (SE) CVH score was 7.45 (2.3) in Hispanic, 8.71 (2.2) in non-Hispanic Asian, 7.48 (2.4) in non-Hispanic Black, and 7.58 (2.3) in non-Hispanic White adults. In Kitagawa-Blinder-Oaxaca decomposition, education explained the largest component of CVH differences among men (if distribution of education were similar to non-Hispanic White participants, CVH score would be 0.36 [0.04] points higher in Hispanic, 0.24 [0.04] points lower in non-Hispanic Asian, and 0.23 [0.03] points higher in non-Hispanic Black participants; P<0.05). Among women, mean (SE) CVH score was 8.03 (2.4) in Hispanic, 9.34 (2.1) in non-Hispanic Asian, 7.43 (2.3) in non-Hispanic Black, and 8.00 (2.5) in non-Hispanic White adults. Education explained the largest component of CVH difference in non-Hispanic Black women (if distribution of education were similar to non-Hispanic White participants, CVH score would be 0.17 [0.03] points higher in non-Hispanic Black participants; P<0.05). Place of birth (born in the United States versus born outside the United States) explained the largest component of CVH difference in Hispanic and non-Hispanic Asian women (if distribution of place of birth were similar to non-Hispanic White participants, CVH score would be 0.36 [0.07] points lower and 0.49 [0.16] points lower, respectively; P<0.05). CONCLUSIONS: Education and place of birth confer the largest statistical contributions to the racial and ethnic differences in mean CVH score among US adults.

Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study.

BACKGROUND: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) participants with the haptoglobin (Hp) 2-2 phenotype only. It remains unknown whether Hp phenotype modifies the effect of an intensive lifestyle intervention (ILI) on CAD in type 2 diabetes. METHODS: Haptoglobin phenotype was measured in 4542 samples from the Action for Health in Diabetes (Look AHEAD) study. Cox regression models assessed the effect of ILI (focused on weight loss from caloric restriction and physical activity) versus diabetes support and education (DSE) on CAD events in each phenotype group, and within pre-specified subgroups including race/ethnicity, sex, history of cardiovascular disease, diabetes medication use, and diabetes duration. RESULTS: 1590 (35%) participants had the Hp2-2 phenotype. The ILI did not lower glycated hemoglobin (%HbA1c) to < 6.5% in either phenotype, with a peak significant difference between treatment arms of 0.5% [non-Hp2-2] and 0.6% [Hp2-2]. The cumulative CAD incidence was 13.4% and 13.8% in the DSE arm and 12.2% and 13.6% in the ILI arm for non-Hp2-2 and Hp2-2 groups, respectively. Compared to DSE, the ILI was not associated with CAD among participants without (HR = 0.95, 95% CI 0.78-1.17) or with (0.89, 0.68-1.19) the Hp2-2 phenotype (p-interaction between Hp phenotype and ILI = 0.58). After Bonferroni correction, there were no significant results among any subgroups. CONCLUSIONS: Hp phenotype did not modify the effect of the weight loss ILI on risk of CAD in Look AHEAD, potentially because it did not substantially impact glycemic control among participants with or without the Hp2-2 phenotype. Further research is needed to determine if these results are conclusive.

Efficacy of Aspirin for primary prevention among adults with high-risk type 2 diabetes in the ACCORD trial.

AIM: To assess the  of aspirin use for primary prevention of cardiovascular disease (CVD) with incident atherosclerotic CVD and mortality in high-risk type 2 diabetes. METHODS: In this post hoc analysis, we included participants in the ACCORD trial without CVD at baseline. The association between aspirin use and the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular [CV] death) and all-cause mortality was evaluated using Cox proportional hazard analysis adjusting for demographics, CV risk factors and comorbidities. RESULTS: Eligible participants (n = 6330) were aged 62.8 ± 5.9 years at baseline, 43.8% of the participants were female, and 3026 (47.8%) used aspirin. Over a median (interquartile range) follow-up of 4.9 (4.1-5.7) years, the number (%) of primary outcome and all-cause mortality events in those who used aspirin (vs. those who did not), was 196 (6.5) versus 229 (6.9) and 146 (4.8) versus 147 (4.5), respectively. The adjusted hazard ratios (95% confidence interval) associated with aspirin use for the primary outcome and all-cause mortality were 0.94 (0.77-1.14) and 1.08 (0.85-1.36), respectively. CONCLUSION: In high-risk individuals with type 2 diabetes, the use of aspirin for primary prevention was not associated with a decreased risk of incident CVD or all-cause mortality.

Racial difference in the association between non-alcoholic fatty liver disease and incident type 2 diabetes: findings from the CARDIA study.

AIMS/HYPOTHESIS: Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) are prevalent diseases of metabolic origin. We examined the association between NAFLD and the development of type 2 diabetes among non-Asian adults, and whether the association differs by race. METHODS: We analysed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based prospective cohort study. Participants underwent non-contrast abdominal computed tomography (CT) at baseline (2010-2011) and assessment of glucose measures at the follow-up exam (2015-2016). NAFLD was defined as liver attenuation ≤51 Hounsfield units on CT images after exclusion for other liver fat causes. Race was self-reported. We used targeted maximum likelihood estimation (TMLE) with machine-learning algorithms to estimate difference in type 2 diabetes risk between the NAFLD and non-NAFLD groups. RESULTS: Of the 1995 participants without type 2 diabetes at baseline (mean age±SD, 50.0±3.6 years; 59% women; 55.0% White and 45.0% Black), 21.7% of White and 16.8% of Black participants had NAFLD at baseline, and 3.7% of White and 8.0% of Black participants developed type 2 diabetes at follow up. After multivariable adjustment, risk difference for type 2 diabetes associated with NAFLD vs no NAFLD was 4.1% (95% CI 0.3%, 7.9%) among White participants and -1.9% (95% CI -5.7%, 2.0%) in Black participants. CONCLUSIONS/INTERPRETATION: NAFLD was associated with a higher risk of type 2 diabetes among White participants but not among Black participants. This finding suggests that the effect of liver fat on impaired glucose metabolism may be smaller in Black than in White individuals.

Associations of Clinical and Social Risk Factors With Racial Differences in Premature Cardiovascular Disease.

BACKGROUND: Racial differences in cardiovascular disease (CVD) are likely related to differences in clinical and social factors. The relative contributions of these factors to Black-White differences in premature CVD have not been investigated. METHODS: In Black and White adults aged 18 to 30 years at baseline in the CARDIA study (Coronary Artery Risk Development in Young Adults), the associations of clinical, lifestyle, depression, socioeconomic, and neighborhood factors across young adulthood with racial differences in incident premature CVD were evaluated in sex-stratified, multivariable-adjusted Cox proportional hazards models using multiply imputed data assuming missing at random. Percent reduction in the ß estimate (log-hazard ratio [HR]) for race quantified the contribution of each factor group to racial differences in incident CVD. RESULTS: Among 2785 Black and 2327 White participants followed for a median 33.9 years (25th-75th percentile, 33.7-34.0), Black (versus White) adults had a higher risk of incident premature CVD (Black women: HR, 2.44 [95% CI, 1.71-3.49], Black men: HR, 1.59 [1.20-2.10] adjusted for age and center). Racial differences were not statistically significant after full adjustment (Black women: HR, 0.91 [0.55-1.52], Black men: HR 1.02 [0.70-1.49]). In women, the largest magnitude percent reduction in the ß estimate for race occurred with adjustment for clinical (87%), neighborhood (32%), and socioeconomic (23%) factors. In men, the largest magnitude percent reduction in the ß estimate for race occurred with an adjustment for clinical (64%), socioeconomic (50%), and lifestyle (34%) factors. CONCLUSIONS: In CARDIA, the significantly higher risk for premature CVD in Black versus White adults was statistically explained by adjustment for antecedent multilevel factors. The largest contributions to racial differences were from clinical and neighborhood factors in women, and clinical and socioeconomic factors in men.

Methods for estimating insulin resistance from untargeted metabolomics data.

CONTEXT: Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming. OBJECTIVE: Develop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data. DESIGN: Insulin Resistance Atherosclerosis Family Study (IRASFS). SETTING: Community based. PARTICIPANTS: Mexican Americans (MA) and African Americans (AA). MAIN OUTCOME: Estimation models for measures of insulin resistance, i.e. SI and HOMA-IR. RESULTS: Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build insulin resistance estimation models from 1274 metabolites combined with clinical data, e.g. age, sex, body mass index (BMI). Metabolite data were transformed using three approaches, i.e. inverse normal transformation, standardization, and Box Cox transformation. The analysis was performed in one MA recruitment site (San Luis Valley, Colorado (SLV); N = 450) and tested in another MA recruitment site (San Antonio, Texas (SA); N = 473). In addition, the two MA recruitment sites were combined and estimation models tested in the AA recruitment sample (Los Angeles, California; N = 495). Estimated and empiric SI were correlated in the SA (r2 = 0.77) and AA (r2 = 0.74) testing datasets. Further, estimated and empiric SI were consistently associated with BMI, low-density lipoprotein cholesterol (LDL), and triglycerides. We applied similar approaches to estimate HOMA-IR with similar results. CONCLUSIONS: We have developed a method for estimating insulin resistance with metabolomics data that has the potential for application to a wide range of biomedical studies and conditions.

A National Survey of Physicians' Views on the Importance and Implementation of Deintensifying Diabetes Medications.

BACKGROUND: Guidelines recommend deintensifying hypoglycemia-causing medications for older adults with diabetes whose hemoglobin A1c is below their individualized target, but this rarely occurs in practice. OBJECTIVE: To understand physicians' decision-making around deintensifying diabetes treatment. DESIGN: National physician survey. PARTICIPANTS: US physicians in general medicine, geriatrics, or endocrinology providing outpatient diabetes care. MAIN MEASURES: Physicians rated the importance of deintensifying diabetes medications for older adults with type 2 diabetes, and of switching medication classes, on 5-point Likert scales. They reported the frequency of these actions for their patients, and listed important barriers and facilitators. We evaluated the independent association between physicians' professional and practice characteristics and the importance of deintensifying and switching diabetes medications using multivariable ordered logistic regression models. KEY RESULTS: There were 445 eligible respondents (response rate 37.5%). The majority of physicians viewed deintensifying (80%) and switching (92%) diabetes medications as important or very important to the care of older adults. Despite this, one-third of physicians reported deintensifying diabetes medications rarely or never. While most physicians recognized multiple reasons to deintensify, two-thirds of physicians reported barriers of short-term hyperglycemia and patient reluctance to change medications or allow higher glucose levels. In multivariable models, geriatricians rated deintensification as more important compared to other specialties (p=0.027), and endocrinologists rated switching as more important compared to other specialties (p<0.006). Physicians with fewer years in practice rated higher importance of deintensification (p<0.001) and switching (p=0.003). CONCLUSIONS: While most US physicians viewed deintensifying and switching diabetes medications as important for the care of older adults, they deintensified infrequently. Physicians had ambivalence about the relative benefits and harms of deintensification and viewed it as a potential source of conflict with their patients. These factors likely contribute to clinical inertia, and studies focused on improving shared decision-making around deintensifying diabetes medications are needed.

Self-reported experiences of discrimination and incident dementia.

INTRODUCTION: Discrimination negatively impacts health and may contribute to racial/ethnic disparities in dementia risk. METHODS: Experiences of lifetime and everyday discrimination were assessed among 6509 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We assessed the association of discrimination with incidence of dementia including adjustment for important risk factors, cohort attrition, and we assessed for effect modification by race/ethnicity. RESULTS: Prevalence of any lifetime discrimination in MESA was 42%, highest among Black adults (72%). Over a median 15.7 years of follow-up, there were 466 incident cases of dementia. Lifetime discrimination, but not everyday discrimination, was associated with incident dementia (Wald p = 0.03). Individuals reporting lifetime discrimination in ≥2 domains (compared to none) had greater risk for dementia (hazard ratio: 1.40; 95%: 1.08, 1.82) after adjustment for sociodemographic, clinical, and behavioral risk factors. Associations did not differ by race/ethnicity. CONCLUSIONS: These findings demonstrate an association of greater experiences of lifetime discrimination with incident dementia.

Impact of the COVID-19 Pandemic on Diabetes Care Among a North Carolina Patient Population.

In this study, researchers reviewed electronic health record data to assess whether the coronavirus disease 2019 pandemic was associated with disruptions in diabetes care processes of A1C testing, retinal screening, and nephropathy evaluation among patients receiving care with Wake Forest Baptist Health in North Carolina. Compared with the pre-pandemic period, they found an increase of 13-21 percentage points in the proportion of patients delaying diabetes care for each measure during the pandemic. Alarmingly, delays in A1C testing were greatest for individuals with the most severe disease and may portend an increase in diabetes complications.

Racial Differences in Urinary Incontinence Prevalence, Overactive Bladder and Associated Bother among Men: The Multi-Ethnic Study of Atherosclerosis.

PURPOSE: We examined the association of race/ethnicity with urinary incontinence subtypes and overactive bladder, and associated bother in older men. MATERIALS AND METHODS: This cross-sectional analysis used data from the Multi-Ethnic Study of Atherosclerosis, an observational cohort of 4 racial/ethnic groups. At the sixth followup examination (age 60 to 98 years, 2015 to 2016) urinary symptoms were ascertained with the International Consultation on Incontinence Questionnaire. Prevalence ratios of urinary incontinence subtypes and overactive bladder without incontinence by race/ethnicity were calculated while adjusting for demographics, comorbidities and medications. Degree of bother was based on scale of 0 (none) to 10 (most) with bother presence defined as a score of 3 or greater. RESULTS: Among 1,536 men 94% completed the questionnaire. Among completers, race/ethnicity was 40.7% nonHispanic White, 14.3% Chinese, 23.0% nonHispanic Black and 22.1% Hispanic. Urinary incontinence was reported by 11.1% and urgency urinary incontinence accounted for 78.0% of all urinary incontinence. The highest prevalence of urgency urinary incontinence was noted among nonHispanic Black men (13.0%) followed by Hispanic (11.3%), nonHispanic White (6.8%) and Chinese (2.9%) men. NonHispanic Black men showed a higher prevalence of any urinary incontinence (PR 1.62, 95% CI 1.06-2.47) and urgency urinary incontinence (1.63, 95% CI 1.01-2.61) compared to nonHispanic White men after adjustments for covariates. No significant association was noted with other urinary incontinence subtypes by race/ethnicity after adjustment for covariates. More than 70% of urinary incontinence was associated with bother for all racial/ethnic groups. CONCLUSIONS: Urinary incontinence prevalence differs by race/ethnicity but most urinary incontinence is associated with bother regardless of race/ethnicity.

Association of fasting glucose with lifetime risk of incident heart failure: the Lifetime Risk Pooling Project.

BACKGROUND: Given the rising prevalence of dysglycemia and disparities in heart failure (HF) burden, we determined race- and sex-specific lifetime risk of HF across the spectrum of fasting plasma glucose (FPG). METHODS: Individual-level data from adults without baseline HF was pooled from 6 population-based cohorts. Modified Kaplan-Meier analysis, Cox models adjusted for the competing risk of death, and Irwin's restricted mean were used to estimate the lifetime risk, adjusted hazard ratio (aHR), and years lived free from HF in middle-aged (40-59 years) and older (60-79 years) adults with FPG < 100 mg/dL, prediabetes (FPG 100-125 mg/dL) and diabetes (FPG ≥ 126 mg/dL or on antihyperglycemic agents) across race-sex groups. RESULTS: In 40,117 participants with 638,910 person-years of follow-up, 4846 cases of incident HF occurred. The lifetime risk of HF was significantly higher among middle-aged White adults and Black women with prediabetes (range: 6.1% [95% CI 4.8%, 7.4%] to 10.8% [95% CI 8.3%, 13.4%]) compared with normoglycemic adults (range: 3.5% [95% CI 3.0%, 4.1%] to 6.5% [95% CI 4.9%, 8.1%]). Middle-aged Black women with diabetes had the highest lifetime risk (32.4% [95% CI 26.0%, 38.7%]) and aHR (4.0 [95% CI 3.0, 5.4]) for HF across race-sex groups. Middle-aged adults with prediabetes and diabetes lived on average 0.9-1.6 and 4.1-6.0 fewer years free from HF, respectively. Findings were similar in older adults except older Black women with prediabetes did not have a higher lifetime risk of HF. CONCLUSIONS: Prediabetes was associated with higher lifetime risk of HF in middle-aged White adults and Black women, with the association attenuating in older Black women. Black women with diabetes had the highest lifetime risk of HF compared with other race-sex groups.

Racial differences in urinary incontinence prevalence and associated bother: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Urinary incontinence is influenced by multiple factors, and the prevalence of urinary incontinence subtypes may differ by race and ethnicity. OBJECTIVE: This study aimed to determine the prevalence of urinary incontinence subtypes and associated bother among women by race and ethnicity. STUDY DESIGN: This cross-sectional analysis used data from the Multi-Ethnic Study of Atherosclerosis, an observational cohort study of 4 racial and ethnic groups recruited from 6 communities from the United States. At the sixth follow-up examination, urinary symptoms were ascertained with the International Consultation on Incontinence Questionnaire. The prevalence rate ratios of stress urinary incontinence, urgency urinary incontinence, and mixed urinary incontinence by race and ethnicity were calculated using generalized linear models for the binomial family while adjusting for covariates. The degree of bother was based on a scale of 0 (none) to 10 (greatest bother), and presence of any bother was defined as a score of ≥3. RESULTS: Among the 1749 female participants in the Multi-Ethnic Study of Atherosclerosis who completed the sixth follow-up examination, 1628 (93%) completed the questionnaire. Women who did not complete the questionnaire were older than those who completed the questionnaire (average age, 82.2 [standard deviation, 9.5] vs 73.7 [standard deviation, 8.4] years; P<.01) and more likely to use diuretics (29.8% vs 18.9%; P<.01). Among those who completed the questionnaire (n=1628), 39.4% were white, 12.5% were Chinese, 27.2% were black, and 20.9% were Hispanic. After adjusting for covariates, stress urinary incontinence (prevalence rate ratio, 0.47; 95% confidence interval, 0.25-0.86) and mixed urinary incontinence (prevalence rate ratio, 0.58; 95% confidence interval, 0.38-0.89) regardless of bother scores were significantly less prevalent among black vs white women, although no significant racial and ethnic differences in stress or mixed urinary incontinence prevalence were noted for Chinese or Hispanic women vs white women. No racial and ethnic differences in the prevalence of urgency urinary incontinence were noted after the adjustment for covariates. Most women with urinary incontinence reported bother scores of ≥3 regardless of race and ethnicity and urinary incontinence subtype, and bother scores did not differ significantly by race and ethnicity. CONCLUSION: Frequency of urinary incontinence subtypes may differ by race and ethnicity, but older women who report urinary incontinence are likely to have associated bother regardless of race and ethnicity.

Trends in Prevalence of Diabetes and Control of Risk Factors in Diabetes Among US Adults, 1999-2018.

IMPORTANCE: Understanding population-wide trends in prevalence and control of diabetes is critical to planning public health approaches for prevention and management of the disease. OBJECTIVE: To determine trends in prevalence of diabetes and control of risk factors in diabetes among US adults between 1999-2000 and 2017-2018. DESIGN, SETTING, AND PARTICIPANTS: Ten cycles of cross-sectional National Health and Nutrition Examination Survey (NHANES) data between 1999-2000 and 2017-2018 were included. The study samples were weighted to be representative of the noninstitutionalized civilian resident US population. Adults aged 18 years or older were included, except pregnant women. EXPOSURES: Survey cycle. MAIN OUTCOMES AND MEASURES: Diabetes was defined by self-report of diabetes diagnosis, fasting plasma glucose level of 126 mg/dL or more, or hemoglobin A1c (HbA1c) level of 6.5% or more. Three risk factor control goals were individualized HbA1c targets, blood pressure less than 130/80 mm Hg, and low-density lipoprotein cholesterol level less than 100 mg/dL. Prevalence of diabetes and proportion of adults with diagnosed diabetes who achieved risk factor control goals, overall and by sociodemographic variables, were estimated. RESULTS: Among the 28 143 participants included (weighted mean age, 48.2 years; 49.3% men), the estimated age-standardized prevalence of diabetes increased significantly from 9.8% (95% CI, 8.6%-11.1%) in 1999-2000 to 14.3% (95% CI, 12.9%-15.8%) in 2017-2018 (P for trend < .001). From 1999-2002 to 2015-2018, the estimated age-standardized proportion of adults with diagnosed diabetes who achieved blood pressure less than 130/80 mm Hg (P for trend = .007) and low-density lipoprotein cholesterol level less than 100 mg/dL (P for trend < .001) increased significantly, but not individualized HbA1c targets (P for trend = .51). In 2015-2018, 66.8% (95% CI, 63.2%-70.4%), 48.2% (95% CI, 44.6%-51.8%), and 59.7% (95% CI, 54.2%-65.2%) of adults with diagnosed diabetes achieved individualized HbA1c targets, blood pressure less than 130/80 mm Hg, and low-density lipoprotein cholesterol level less than 100 mg/dL, respectively. Only 21.2% of these adults (95% CI, 15.5%-26.8%) achieved all 3. During the entire study period, these 3 goals were significantly less likely to be achieved among young adults aged 18 to 44 years (vs older adults ≥65 years: estimated proportion, 7.4% vs 21.7%; adjusted odds ratio, 0.32 [95% CI, 0.16-0.63]), non-Hispanic Black adults (vs non-Hispanic White adults: estimated age-standardized proportion, 12.5% vs 20.6%; adjusted odds ratio, 0.60 [95% CI, 0.40-0.90]), and Mexican American adults (vs non-Hispanic White adults: estimated age-standardized proportion, 10.9% vs 20.6%; adjusted odds ratio, 0.48 [95% CI, 0.31-0.77]). CONCLUSIONS AND RELEVANCE: Based on NHANES data from US adults, the estimated prevalence of diabetes increased significantly between 1999-2000 and 2017-2018. Only an estimated 21% of adults with diagnosed diabetes achieved all 3 risk factor control goals in 2015-2018.

Fasting glucose variability in young adulthood and incident diabetes, cardiovascular disease and all-cause mortality.

AIMS/HYPOTHESIS: The aim of this study was to determine whether long-term intra-individual variability in fasting glucose (FG) during young adulthood is associated with incident diabetes, cardiovascular disease (CVD) and mortality. METHODS: We included participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18-30 years at baseline (1985-1986) and followed with eight examinations for up to 30 years. Long-term glucose variability was assessed using the CV (CV-FG) and the absolute difference between successive FG measurements (average real variability; ARV-FG). For participants who developed any event (diabetes, CVD or mortality), FG variability measurement was censored at the examination prior to event ascertainment. We estimated HRs for incident diabetes, CVD and mortality with adjustment for demographics, baseline FG, change in FG (censor - baseline) and time-varying education, smoking, alcohol consumption, BMI, physical activity, systolic BP, BP medications, LDL-cholesterol and cholesterol medications (and incident diabetes and diabetes medications for CVD and mortality outcomes). RESULTS: Among 3769 black and white participants, there were 317 incident diabetes cases (102,677 person-years), 159 incident CVD events (110,314 person-years) and 174 deaths (111,390 person-years). After adjustment, HRs per 1 SD higher ARV-FG were 1.64 (95% CI 1.52, 1.78) for diabetes, 1.15 (95% CI 1.01, 1.31) for CVD and 1.25 (95% CI 1.11, 1.40) for mortality. The HRs per 1 SD higher CV-FG were 1.39 (95% CI 1.21, 1.58) for diabetes, 1.32 (95% CI 1.13, 1.54) for CVD and 1.08 (95% CI 0.92, 1.27) for mortality, after adjustment. The cause-specific HRs per 1 SD higher ARV-FG were 1.29 (95% CI 1.14, 1.47) for non-CVD death and 1.05 (95% CI 0.76, 1.45) for CVD death. We did not observe evidence for effect modification of any association by sex or race. CONCLUSIONS/INTERPRETATION: Our results suggest that higher intra-individual FG variability during young adulthood before the onset of diabetes is associated with incident diabetes, CVD and mortality.

Quantifying the extent to which index event biases influence large genetic association studies.

As genetic association studies increase in size to 100 000s of individuals, subtle biases may influence conclusions. One possible bias is 'index event bias' (IEB) that appears due to the stratification by, or enrichment for, disease status when testing associations between genetic variants and a disease-associated trait. We aimed to test the extent to which IEB influences some known trait associations in a range of study designs and provide a statistical framework for assessing future associations. Analyzing data from 113 203 non-diabetic UK Biobank participants, we observed three (near TCF7L2, CDKN2AB and CDKAL1) overestimated (body mass index (BMI) decreasing) and one (near MTNR1B) underestimated (BMI increasing) associations among 11 type 2 diabetes risk alleles (at P < 0.05). IEB became even stronger when we tested a type 2 diabetes genetic risk score composed of these 11 variants (-0.010 standard deviations BMI per allele, P = 5 × 10- 4), which was confirmed in four additional independent studies. Similar results emerged when examining the effect of blood pressure increasing alleles on BMI in normotensive UK Biobank samples. Furthermore, we demonstrated that, under realistic scenarios, common disease alleles would become associated at P < 5 × 10- 8 with disease-related traits through IEB alone, if disease prevalence in the sample differs appreciably from the background population prevalence. For example, some hypertension and type 2 diabetes alleles will be associated with BMI in sample sizes of >500 000 if the prevalence of those diseases differs by >10% from the background population. In conclusion, IEB may result in false positive or negative genetic associations in very large studies stratified or strongly enriched for/against disease cases.

Twenty-five-year trajectories of insulin resistance and pancreatic ß-cell response and diabetes risk in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Insulin resistance is a risk marker for non-alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and ß-cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non-alcoholic fatty liver disease. METHODS: Three thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi-racial cohort of adults age 18-30 years at baseline (1985-1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010-2011), non-alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25-year trajectories in homeostatic model assessment insulin resistance and ß-cell response homeostatic model assessment-ß. RESULTS: Three distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low-stable [47%]; moderate-increasing [42%]; and high-increasing [12%]) and homeostatic model assessment-ß (low-decreasing [16%]; moderate-decreasing [63%]; and high-decreasing [21%]). Y25 non-alcoholic fatty liver disease prevalence was 24.5%. Among non-alcoholic fatty liver disease, high-increasing homeostatic model assessment insulin resistance (referent: low-stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0-31.9) and incident (OR = 10.5, 2.6-32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non-alcoholic fatty liver disease participants with low-decreasing homeostatic model assessment-ß (referent: high-decreasing) had the highest odds of prevalent (OR = 14.1, 3.9-50.9) and incident (OR = 10.3, 2.7-39.3) diabetes. CONCLUSION: Trajectories of insulin resistance and ß-cell response during young and middle adulthood are robustly associated with diabetes risk in non-alcoholic fatty liver disease. Thus, how persons with non-alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non-alcoholic fatty liver disease assessment.

Cumulative Lifetime Marijuana Use and Incident Cardiovascular Disease in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

OBJECTIVES: To investigate the effects of marijuana in the development of incident cardiovascular and cerebrovascular outcomes. METHODS: Participants were 5113 adults aged 18 to 30 years at baseline (1985-1986) from the Coronary Artery Risk Development in Young Adults study, who were followed for more than 25 years. We estimated cumulative lifetime exposure to marijuana using repeated assessments collected at examinations every 2 to 5 years. The primary outcome was incident cardiovascular disease (CVD) through 2013. RESULTS: A total of 84% (n = 4286) reported a history of marijuana use. During a median 26.9 years (131 990 person-years), we identified 215 CVD events, including 62 strokes or transient ischemic attacks, 104 cases of coronary heart disease, and 50 CVD deaths. Compared with no marijuana use, cumulative lifetime and recent marijuana use showed no association with incident CVD, stroke or transient ischemic attacks, coronary heart disease, or CVD mortality. Marijuana use was not associated with CVD when stratified by age, gender, race, or family history of CVD. CONCLUSIONS: Neither cumulative lifetime nor recent use of marijuana is associated with the incidence of CVD in middle age.

Association of Modifiable Risk Factors in Young Adulthood With Racial Disparity in Incident Type 2 Diabetes During Middle Adulthood.

Importance: In the United States, black individuals are twice as likely to develop type 2 diabetes compared with white individuals, and these disparities are particularly pronounced in young and middle age. Prior studies have identified differences in traditional risk factors that may be associated with racial disparities in diabetes incidence but have not simultaneously adjusted for risk factors measured across multiple domains (eg, the individual and the environment) and updated over time. Objective: To determine the relative associations of modifiable biological, neighborhood, psychosocial, socioeconomic, and behavioral factors in young adulthood with the observed racial disparity in diabetes incidence between middle-aged black and white individuals. Design, Setting, and Participants: Black and white men and women from the observational Coronary Artery Risk Development in Young Adults study, aged 18 to 30 years, without diabetes at baseline (1985-1986; N = 4251) were observed through 2015-2016. Sex-stratified multivariable-adjusted Cox proportional hazards modeling, with adjustment for time-updated covariates, was used to estimate risk for incident diabetes. Percent reduction in the ß coefficient (the logarithm used to calculate the hazard ratio [HR]) was calculated to compare black to white participants. Exposures: Self-identified race and factors including biological (eg, fasting glucose, body mass index), neighborhood (racial segregation and tract-level poverty), psychosocial (depressive symptoms), socioeconomic (eg, personal and parental educational attainment, current employment), and behavioral (eg, regular alcohol consumption, smoking) domains. Main Outcomes and Measures: Incident type 2 diabetes mellitus. Results: The mean (SD) age at baseline was 25 (3.6) years, 49% (n = 2066) of the sample was black, and 54% (n = 2304) were women. Over a mean follow-up of 24.5 years, 504 cases of incident diabetes were identified. Using sex-stratified multivariable-adjusted Cox proportional hazards models, black women and men were more likely to develop diabetes than white men and women (black women: HR, 2.86 [95% CI, 2.19-3.72] and risk difference [RD], 89 cases/1000 people [95% CI, 61-117]; black men: HR, 1.67 [95% CI, 1.28-2.17] and RD, 47 cases/1000 people [95% CI, 15-78]) after adjustment for age and center. Biological factors were most strongly associated with the disparity in diabetes risk between black and white individuals for women (percent reduction in ß, 112%) and men (percent reduction in ß, 86%). There was no longer disparity in diabetes risk between black and white middle-aged adults after adjustment for biological, neighborhood, psychosocial, socioeconomic, and behavioral factors measured over time (HR for women, 0.79 [95% CI, 0.55-1.14]; HR for men, 0.92 [95% CI, 0.62-1.38]). Conclusions and Relevance: In this cohort study comparing black and white participants, there was a statistically significant increased risk of incident type 2 diabetes among black women and men. However, after adjustment for modifiable risk factors during young adulthood, the disparity was no longer statistically significant.