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Background: Regular physical activity (PA) has been associated with reduced risk of coronary heart disease, but conflicting results have been reported regarding its association with coronary artery calcification (CAC), one of the strongest predictors of cardiovascular disease. Moreover, different domains of PA (e.g., sports vs. work) and extra coronary calcification (ECC) have not been extensively studied in this context. Methods: We investigated 2,025 ARIC participants (age 73-95 years) who had no coronary heart disease and underwent a non-contrast cardiac-gated computed tomography scan at visit 7 (2018-19). PA was based on a modified Baecke questionnaire, which provides total and domain-specific (sport, non-sport leisure, and work) PA scores. We modeled the cumulative PA scores in middle-age at visit 1 (1987-89) and visit 3 (1993-95). We explored continuous CAC and ECC (log-transformed [Agatston score+1]) or any CAC and ECC (Agatston score >0 vs. 0) as dependent variables using linear regression and multivariable logistic models, as appropriate. Results: Higher total and domain-specific PA scores showed no association with lower CAC. Among ECC, descending aorta calcification demonstrated the strongest association with total PA scores (coefficient -0.10 [95% CI -0.21, 0.01], p=0.075) ( Figure ). When specific domains were explored, higher sport and work PA scores were significantly associated with lower descending aorta calcification. When we analyzed any CAC and ECC as the outcome variable, the results were generally consistent. Conclusions: Higher PA in midlife was associated with lower calcification of descending aorta in late life. Our results further support the health benefits of PA and unique pathological process across different vascular beds.

Background: High dietary calcium and phosphorus intakes may accelerate vascular calcification. A few studies have explored the association of dietary calcium and phosphorus intakes with vascular calcification but reported inconsistent results. Most studies relied on dietary assessment at one time point and evaluated only coronary artery calcification. Aim: To assess the associations of dietary calcium and phosphorus intakes over two time points during middle age with coronary artery and extra-coronary calcification at older age. Methods: We studied 1,940 ARIC participants who underwent chest CT scans at ≥75 years of age in 2018-19 and completed a 66-item food frequency questionnaire at two earlier visits (1987-89 and 1993-95). We calculated the average of dietary calcium and phosphorus intakes across these two visits. Calcification was quantified as Agatston score in coronary arteries, ascending aorta, descending aorta, aortic valve ring, aortic valve, and mitral valve. We ran multivariable linear (for continuous Agatston score) and logistic regression models (for Agatston score >75 th percentile). Results: The mean dietary calcium and phosphorus intake was 659 mg/day and 1,074 mg/day, respectively. Overall, we did not observe any positive associations of dietary calcium intake with vascular/valvular calcification. Rather, we saw its inverse association with ascending aorta calcification (Figure). In contrast, dietary phosphorus was not associated with the calcification of any vascular beds. The results were largely similar in linear regression models and after excluding 332 participants (17%) taking calcium supplements. Conclusion: Dietary calcium intake at middle age was largely neutral in its association with vascular calcification while showing a mild inverse association with ascending aorta calcification at older age. No evident associations were seen for dietary phosphorus. Our findings do not support a concern that a calcium or phosphorus-rich diet may accelerate vascular calcification.

Introduction: Renal dose adjustment is imperative to appropriate direct oral anticoagulant (DOAC) prescribing among patients with atrial fibrillation (AF). Serum creatinine is routinely used to estimate GFR (eGFRcr) in clinical practice, but eGFRcr may be less accurate in certain settings. It is unknown whether other kidney function biomarkers, like cystatin C, is helpful to guide DOAC dosing. Hypothesis: Appropriate DOAC dosing by eGFRcr but supratherapeutic dosing by cystatin C-based eGFR (eGFRcys) is associated with bleeding, compared to appropriate dosing by both eGFRcr and eGFRcys. Methods: We conducted observational study from the SCREAM project, a healthcare utilization cohort of Stockholm, Sweden, during 2006-2018. We identified patients with AF on DOACs who had creatinine and cystatin C measured on the same day. We calculated eGFRcr with the 2021 Chronic Kidney Disease (CKD)-EPI and eGFRcys with 2012 CKD-EPI cystatin C equations. We estimated defined daily dose consumed per day and considered Results: Among 5427 AF patients on DOACs, mean age (SD) was 76 (9) years and 43% were women. Compared to eGFRcr, eGFRcys identified more patients with CKD (61% for eGFRcys 2 vs. 35% for eGFRcr 2 ), as well as more patients with supratherapeutic dosing (7.9 vs. 2.4%). Among 3064 patients who were classified as appropriate dosing by eGFRcr, 312 (10.2%) were reclassified as supratherapeutic dosing by eGFRcys and had a higher risk of bleeding (hazard ratio=1.58, 95% CI: 1.03-2.42), compared with those who were classified as appropriate dosing by both eGFRcr and eGFRcys ( Table ). Conclusions: Appropriate DOAC dosing by eGFRcr but supratherapeutic dosing by eGFRcys was associated with a higher risk of bleeding. The findings suggest that eGFRcys may inform decisions on DOAC dosing.

Background: Landmark trials of direct oral anticoagulants (DOACs) versus warfarin for non-valvular atrial fibrillation (NVAF) excluded patients with severe chronic kidney disease (CKD). Real-world data on safety and effectiveness of DOACs in severe CKD is limited. Methods: New users of DOACs (apixaban, rivaroxaban, and dabigatran) or warfarin with NVAF and severe CKD between 2010 and 2020 were identified using the de-identified electronic health records form the Optum Labs Data Warehouse. We estimated the risks of bleeding, ischemic stroke, and death for apixaban and rivaroxaban separately (vs. warfarin) using Cox regression models. Incidence rate (IR) and hazard ratio (HR) were adjusted for baseline characteristics by inverse probability of treatment weighting (IPTW). Dabigatran users were not included for the analysis due to small sample size (n=318). Results: Compared with warfarin users (n=7548), apixaban users (n=3719) were older (mean age 77 vs. 76 years) and had more hypertension (94% vs. 90%). In IPTW analysis, apixaban was associated with a lower risk of any bleeding (HR [95% CI], 0.71 [0.56, 0.89]), as well as major bleeding (HR [95% CI], 0.61 [0.46, 0.81]). There were no significant differences in ischemic stroke and death between apixaban and warfarin users ( Figure A ). Rivaroxaban users (n=920) were older (mean age 76 vs. 75 years) and had higher estimated glomerular filtration rate than warfarin users (mean: 25 vs. 23 ml/min/1.73 m 2 ). In IPTW analysis, risks of bleeding were higher among rivaroxaban users than warfarin users (any bleeding: HR [95% CI], 1.43 [1.05, 1.95]; major bleeding: HR [95% CI], 1.54 [1.09, 2.17]), with no significant differences in ischemic stroke and death ( Figure B ). Conclusion: Apixaban was associated with a lower risk of bleeding, but rivaroxaban was associated with a higher risk of bleeding, compared with warfarin in patients with NVAF and severe CKD. Risks of ischemic stroke and death were similar between agents. Apixaban may be a preferable oral anticoagulant in this population.

Background: Arterial stiffness was cross-sectionally associated with the prevalence of chronic kidney disease (CKD). Whether arterial stiffness was prospectively associated with incident CKD is not well characterized. Methods: Among 3,777 participants (mean age 75 years old, 42.7% female, 21.3% Blacks) without prevalent CKD in ARIC study at visit 5 (2011 to 2013), we examined the association of six measures for arterial stiffness measurements, carotid-femoral pulse wave velocity (cfPWV), heart-ankle PWV (haPWV), brachial-ankle PWV (baPWV), heart-femoral PWV (hfPWV), femoral-ankle PWV (faPWV), heart-carotid PWV (hcPWV) with the risk of incident CKD (defined by >25% decline to estimated glomerular filtration rate 2 or hospitalization with CKD diagnosis) using Cox regression models to estimate hazard ratios (HRs). Each arterial stiffness parameter was stratified by quartiles. Results: During follow-up (median 6.6 years) through 2019, 590 had incident CKD (incidence rate 23.2 per 1000 person-years). In the demographically adjusted model, the highest quartile (Q4) of cfPWV, haPWV, baPWV, and hfPWV were significantly associated with an increased risk of incident CKD compared to the lowest (Q1) (HR, 1.70 [95%CI 1.31 to 2.22], 1.29 [95% CI 1.01 to 1.64], 1.51 [95% CI 1.16 to 1.97], and 1.36 [95% CI 1.05 to 1.76], respectively). Once the model was further adjusted for major clinical risk factors for CKD, the associations were modestly attenuated but remained significant for cfPWV and haPWV (HR in Q4 vs. Q1, 1.34 [95% CI 1.02 to 1.76] and 1.38 [95% CI 1.04 to 1.82]), but not for baPWV and hfPWV. Subgroup analyses showed the associations were consistent in subgroups by gender, race, age, hypertension, and diabetes. Conclusion: Arterial stiffness as measured by PWV was associated with a higher risk of incident CKD in older adults, especially cfPWV and haPWV. Our findings support the temporal relationship of subclinical arterial stiffness predating incident CKD in older adults.

Introduction: Femur fracture can have devastating consequences in older patients. Lower extremity peripheral artery disease (PAD) reduces physical function, which can in turn increase the risk of falls. However, less is known regarding the association of PAD with incident femur fracture in older adults. Hypothesis: PAD is associated with a higher risk of incident femur fracture independent of potential confounders. Methods: We included 5,276 participants from ARIC Visit 5 (2011-2013) (mean age 76 [standard deviation: 5] years, 57% women and 22% self-identified Black race). Femur fractures were defined as an outpatient encounter or hospitalization with ICD-9 codes: 820-821 or ICD-10 codes: S72. We quantified the association of PAD status at baseline, based on ankle-brachial index (ABI) ≤0.9 or clinical history of PAD, with incident femur fracture using multivariable Cox regression and follow-up until 2019. Results: There were 224 incident femur fractures over a median follow-up of 7.2 [IQI 5.6-7.8] years. The incidence rate of femur fracture was almost 2-times higher in participants with PAD compared to those without a history of PAD and ABI 1.11-1.20 (reference group) (10.5 [7.5-14.8] vs. 5.5 [4.3-6.9] per 1,000 person-years). This association persisted after accounting for demographic (hazards ratio [HR]: 1.86 [95% CI 1.23-2.84] in Model 1) and other confounders (HR 1.59 [1.04-2.46] in Model 2) (Table). When we excluded participants with a clinical history of PAD, low ABI (≤0.9) remained significantly associated with incident femur fracture compared to the reference group (HR 1.94 [1.18-3.19]). Our findings were consistent in demographic and clinical subgroups (e.g., by sex and diabetes status). Conclusions: In community-dwelling older adults, PAD, even when not clinically diagnosed, was associated with an increased risk of femur fracture. Clinicians and patients should be aware of this complication of PAD and consider preventive measures to avoid falls (e.g., exercise counseling, and making home safer).

Introduction: Medication non-adherence increases the risk of hospitalization and mortality in older adults. Evidence from previous studies was not conclusive due to small sample size or lack of adjustment for potential confounders. This study aims to investigate the prevalence and predictors of medication non-adherence in older adults, considering both individual-level and neighborhood-level factors. Methods: We studied participants (aged 66-90 years) who were on at least one medication at visit 5 (2011-2013) of the ARIC Study. Potential predictors included demographic factors, individual-level and neighborhood-level socioeconomic factors, behavioral factors, depressive symptoms, and cognitive function. We estimated the prevalence of self-reported medication adherence using the Morisky Green Levine medication adherence questionnaire and considered intermediate and low as medication non-adherence. We used multivariable logistic regression to identify independent predictors of medication non-adherence, further adjusting for race-center, insurance types, comorbidities, and number of medications. Results: Among 5304 participants (mean age of 75.5 [SD 5.1] years, 21.6% Black, and 58.2% female), 2.3% and 37.1% reported low and intermediate medication adherence, respectively. After adjustment, age 66-74 (odds ratio [OR]= 1.23 [95% CI, 1.10-1.38]), current drinker (1.31 [1.10-1.55]), lack of physical activity (PA) (1.18 [1.01-1.37] for intermediate PA; 1.38 [1.21-1.58] for low PA), and depressive symptoms (2.30 [1.82-2.91]) were significant predictors of medication non-adherence ( Table ). Education and ADI were not associated with medication non-adherence. Conclusions: We found that almost 40% of older adults have medication non-adherence. Unhealthy lifestyle factors and depressive symptoms were associated with medication non-adherence. Education and neighborhood-level SES were not. Depression is an important modifiable factor to improve medication adherence in older adults.

Potentially inappropriate medication (PIM) use is an important public health problem, particularly among older adults who may need multiple pharmacologic therapies for various chronic conditions. As socioeconomic status (SES) affects the quality of healthcare that individuals receive, SES may be associated with the use of PIM in older adults. This study aimed to determine whether low SES is associated with increased use of PIM.We studied 4927 participants (aged 66-90 years) who were on at least one medication at visit five (2011-2013) of the Atherosclerosis Risk in Communities Study. We created a cumulative SES score categorized as high (7-9), middle (3-6), and low (0-2) based on education, income, and area deprivation index. We use multivariable logistic regression to examine the associations between SES and use of two or more PIM for older adults, defined by the 2019 Beers Criteria.A total of 31.0% and 6.9% of the participants used one or more PIM and two or more PIM, respectively. After adjusting for demographic characteristics and insurance type, low cumulative SES score was associated with significantly greater use of two or more PIM (odds ratio [OR] = 1.83 [95% confidence interval (CI) 1.18-2.86]), as was middle cumulative SES score (OR = 1.40 [95% CI 1.06-1.83]), compared to high cumulative SES score. The results remained significant after further adjusting for comorbidities and medication burden for low cumulative SES score (OR = 1.66 [95%CI 1.02-2.71]).We found that lower SES was associated with greater use of PIM among older adults independent of their medication burden and comorbidities, suggesting socioeconomic disparities in quality of medication management. Focused efforts targeting older adults with low SES to reduce PIM use may be needed to prevent adverse drug events.

The benefits of routine engagement in physical activity (PA) on vascular health are well established; lesser known is whether vascular health associates with accelerometry-based daily patterns of PA in mid-to-late life. Using linear regression models adjusted for demographics and comorbidities, we modeled the cross-sectional associations between ankle brachial index (ABI) and PA patterns (diurnal activity and activity fragmentation) in 7,848 HCHS/SOL participants (45.5% men, 56.4±0.2 years). Compared to those with normal ABI (1.0-1.4), those with low ABI (≤0.9) had more fragmented daily activity (B=1.0%, SE=0.4, p=.04); primarily between 12 and 8 PM (B=1.66%, SE=0.55, p

Introduction: The use of potentially inappropriate medications (PIM), defined as medications for which the risk of adverse events outweighs the expected benefits, increases the risk of hospitalization, adverse drug events, and mortality in older adults. As socioeconomic status (SES) influences health care quality, the purpose of this study is to investigate whether PIM use differs by SES in older adults. Hypothesis: We hypothesized that low SES was independently associated with increased use of PIM. Methods: We studied participants (aged 66-90 years) who were on at least one medication at visit 5 (2011-2013) of the Atherosclerosis Risk in Communities (ARIC) Study. We created a cumulative SES score, based on neighborhood SES (area deprivation index [ADI]) as well as individual SES (education and income). Because PIM for older adults defined by the 2019 Beers Criteria was extremely common (31% of the population), we focused on the use of two or more PIM. We used multivariable logistic regression to examine the associations between SES and PIM use ≥2. Results: Among 4927 participants (mean age of 75.6 (SD 5.1) years, 19.6% Black, and 57.8% female), 6.9% were on two or more PIMs. Overall, compared with individuals with high cumulative SES, those with lower SES had higher odds of PIM use in a dose-dependent manner (odds ratio [OR]: 1.40 [95% confidence interval (CI), 1.06-1.83] for middle cumulative SES; 1.83 [1.18-2.86] for low cumulative SES, Table ), adjusting for demographics and insurance type. For each SES component, low neighborhood SES (i.e., high ADI) and low education was significantly associated with higher odds of PIM use, but not income. Conclusions: We found that lower SES was associated with greater use of PIM among older adults, suggesting that there exist disparities in quality of care by SES. Focused efforts targeting older adults with low SES to reduce PIM use may be needed to prevent adverse outcomes.

Introduction: Our understanding of traditional atherosclerotic risk factors is largely based on their contributions to adverse atherosclerotic events. However, the relative contributions of mid-life and late-life risk factor exposures to persistent zero coronary artery calcium (CAC=0) in older adulthood, a representative healthy vascular aging phenotype, have not been fully examined. Hypothesis: Both mid-life and late-life risk factors are associated with CAC=0, with stronger results for the former. Methods: Using data from 2,035 community-dwelling participants free of coronary heart disease in the ARIC study, we evaluated traditional modifiable risk factors (i.e., lipids, systolic blood pressure, obesity, smoking, and diabetes) at mid-life (median age 49, visit 1 from 1987-1989) and late-life (median age 73, visit 5 from 2011-2013) and their associations with CAC=0 at visit 7 (median age 80, from 2018-2019), using multivariable logistic regression models adjusted for within-visit factors. Results: There were 204 participants (10.0%) with CAC=0. Compared with participants with any CAC, those with CAC=0 had more favorable values for most traditional risk factors (lower cholesterol, BMI, and systolic blood pressure, higher HDL-C, and not smoking) in both mid-life and late-life, with the exception of fasting glucose ( Table ). The results were similar when we modeled diabetes instead of fasting glucose. Lower total cholesterol in mid-life, but not late-life, was associated with CAC=0. Conclusions: Having favorable modifiable risk factors both at mid-life and late-life were independently associated with CAC=0 in older adults free of clinical coronary heart disease. These results highlight the importance of maintaining a healthy risk factor profile from mid-life, with implications on public health promotion and strategy.

Introduction: Peripheral artery disease (PAD) increases the risk of various adverse outcomes such as other cardiovascular diseases, lower-extremity amputation, and infection. However, its impact on kidney outcomes is yet to be characterized. Hypothesis: Both symptomatic and asymptomatic PAD will be associated with kidney outcomes. Methods: Using data from the ARIC study (1987-1989), we categorized 13,864 participants with estimated glomerular filtration rate (eGFR) >15 mL/min (mean age 54 [SD 6 years]) into symptomatic PAD (clinical history or intermittent claudication); asymptomatic PAD (ankle-brachial index [ABI] ≤0.90 but not symptomatic PAD); and ABI categories of 0.91-1.00, 1.01-1.10, 1.11-1.20 (reference), 1.21-1.30, and >1.30. Incident end-stage kidney disease (ESKD) was defined by the need for renal replacement therapy or death due to chronic kidney disease (CKD), and incident CKD was defined by ≥25% decline in eGFR to Results: There were 580 ESKD cases and 4,602 CKD cases over ~30 years of follow-up. Both symptomatic PAD and asymptomatic PAD were significantly associated with incident ESKD with hazard ratios (HR) of 2.21 (95%CI 1.16-4.22) and 1.59 (1.07-2.36), respectively, after adjusting for potential confounders such as other cardiovascular diseases and diabetes (Table). The corresponding HRs for incident CKD were 1.43 (1.05-1.95) and 1.60 (1.35-1.90). Borderline low ABI 0.91-1.00 showed an elevated risk of kidney outcomes in demographically- adjusted Model 1. Conclusions: Symptomatic PAD and asymptomatic PAD were independently associated with a higher long-term risk of ESKD and CKD. These results further support the close link between atherosclerosis and kidney prognosis and highlight the need for kidney monitoring in persons with PAD regardless of leg symptoms.

Background: Kidney function is a crucial determinant of bone-mineral metabolism (BMM); however, the contribution of kidney dysfunction, especially at mild to moderate stages, to vascular calcification remains controversial. Moreover, little is known about whether BMM markers are associated with coronary artery calcification (CAC) and extra-coronary calcification (ECC) beyond kidney function. Methods: In 1935 ARIC participants (age 73-95 years) with no coronary heart disease and data on CAC and ECC at visit 7 (2018-2019), we evaluated estimated glomerular filtration (eGFR) (based on creatinine, cystatin C, and both) and serum BMM markers (calcium, fibroblast growth factor 23, magnesium, parathyroid hormone, and phosphorus) as exposures. The exposures were modeled as weighted averages over ~15 years (visit 1 [1987-89] to visit 5 [2011-13] to allow a lag time for vascular calcification), and the outcome variables were high CAC and ECC (sex-race specific ≥75 th vs. th percentile Agatston score) or any CAC and ECC (Agatston score >0 vs. 0) using multivariable logistic regression. Results: Low eGFR (overall range 30-149 mL/min/1.73m 2 ), regardless of equations, was not robustly associated with high CAC and ECC. Among BMM markers, only higher phosphorus levels, even within the normal range, showed significant associations with high CAC and ECC, independent of kidney function ( Figure ). Considering presence of any calcification, results were generally consistent, although cystatin C-based eGFR 2 was associated with mitral valve calcification (present in 47%) (odds ratio 1.70 [95% CI 1.13, 2.58]). Conclusion: Cumulative exposure to lower eGFR showed weak associations with vascular calcification in community-dwelling older adults. Among BMM markers, phosphorus was most robustly associated with CAC and ECC beyond kidney function. Our results suggest a potential key role of phosphorus in the pathophysiology of vascular calcification.

IMPORTANCE Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.OBJECTIVE To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).DESIGN, SETTING, AND PARTICIPANTS Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).EXPOSURES Demographic and clinical factors.MAIN OUTCOMES AND MEASURES Incident eGFR of less than 60 mL/min/1.73 m(2).RESULTS Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A(1c), and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.CONCLUSIONS AND RELEVANCE Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.

Introduction: Hemoglobin A1c (HbA1c) is a risk marker for incident peripheral artery disease (PAD). However, its relationship to critical limb ischemia (CLI), the most severe form of PAD, has not been fully characterized. Also, the prognostic value of non-traditional glycemic markers, glycated albumin, fructosamine, and 1,5-anhydroglucitol (1,5-AG) for PAD/CLI risk is unknown. Hypotheses: These glycemic markers will be particularly strongly associated with incident CLI, and non-traditional markers may provide additional information on PAD risk beyond HbA1c. Methods: We quantified the associations of four glycemic markers with PAD (hospitalizations with PAD diagnosis [ICD-9: 440.2-440.4] or leg revascularization [eg, 38.18]) in 11,797 ARIC participants free of a history of PAD at baseline (1990-92) using Cox models. Within these PAD cases, CLI was defined with an ICD code of ulcer, gangrene, or leg amputation. All markers were categorized into five groups according to diagnosed diabetes status and percentiles for clinical cut-points of HbA1c as in Table. Results: Over a median follow-up of 20.7 years, there were 397 cases of PAD (137 were CLI). Compared with the non-diabetic reference group, elevated glycemic marker levels (or reduced levels for 1-5AG) significantly contributed to increased risk of PAD (Table). The glycemic contribution was particularly strong for CLI events, with hazard ratios ranging 14-18 (vs. 6-8 for PAD, p for difference Conclusions: Glycemic markers were significantly associated with PAD, particularly with its severe form, CLI, supporting the importance of glucose metabolism in the progression of PAD. Non-traditional glycemic markers provide similar (but not much additional) predictive value as HbA1c for classifying PAD risk.

Introduction: The risk of dementia increases with increasing levels of hemoglobin A1c (HbA1c), a measure of average blood glucose. However the association between glucose peaks and dementia in persons with diabetes is unclear. 1,5-anhydroglucitol (1,5-AG) is a novel biomarker of glucose peaks, with low levels reflecting blood glucose concentrations that exceed the renal filtration threshold (~180 mg/dl) over the prior 7-10 days. Hypothesis: Glucose peaks, indicated by low levels of 1,5-AG, will be associated with higher risk of dementia, independent of HbA1c and other dementia risk factors. Methods: We conducted a prospective analysis of 1568 participants with diabetes from visit 2 (1990-1992) of the ARIC Study. Diabetes was defined based on self-reported physician diagnosis, diabetes medication use, or HbA1c ≥ 6.5%. Community surveillance of hospitalizations was used to identify incident dementia. Cases were defined as the first occurrence of a hospitalization with an ICD-9 code for dementia appearing in any position in the hospital discharge record. We used Cox regression to examine the association between 1,5-AG (modeled linearly) and incident dementia, adjusted for demographic and clinical risk factors, including HbA1c. Results: At baseline, the mean age was 58 years, 58% were female, 54% were white, and mean HbA1c was 8.1%. Over a median follow-up of 18 years, 158 participants had a hospitalization with an ICD-9 code of dementia. Each unit decrease in 1,5-AG increased the risk of dementia by 4% (HR=1.04, p-value=0.03, Figure). Associations were similar when 1,5-AG was modeled using linear splines. Conclusions: Short-term glucose peaks were associated with higher risk of dementia among adults with diabetes, independent of HbA1c and other dementia risk factors. More studies are needed to determine if targeting glucose peaks, in addition to average glucose, among persons with diabetes can reduce the risk of dementia.

Introduction: Abdominal aortic aneurysm (AAA) is considered a subtype of atherosclerotic disease, but its risk factor profile is somewhat different than other atherosclerotic disease subtypes. For example, prior studies have demonstrated a null or even inverse association between diabetes and AAA. Chronic kidney disease (CKD) is a known risk factor for cardiovascular outcomes, but its association with AAA has not been explicitly investigated. Methods: We studied 10,722 participants (aged 53-75 years) without clinical history of AAA who attended the ARIC Study fourth visit (1996-98). Cox regression models were used to quantify the association of two key CKD measures—estimated glomerular filtration rate [eGFR] based on serum creatinine and cystatin C and urine albumin-to-creatinine ratio [ACR]—with incidence of AAA-related hospitalizations or deaths (ICD-9 codes: 38.44, 39.71, 441.3, 441.4, or 441.02). Results: During a median follow-up of 14 years, there were 350 cases of AAA (incidence rate 2.5 per 1000 person-years). Both low eGFR and high ACR were associated with increased risk of clinical AAA independently of each other and potential confounders, with a slightly sharper risk gradient for ACR compared to eGFR (Table). We also confirmed an inverse association between diabetes and AAA in our study, although ACR was a significant positive risk factor for AAA risk in both those with and without diabetes. By contrast, low eGFR was associated with AAA risk only in those without diabetes. Conclusion: Both eGFR and ACR were independently associated with increased risk of clinical AAA in the community, suggesting potential usefulness of CKD to identify persons at high risk of AAA beyond traditional atherosclerotic risk factors.

Evaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a person's probable long-term risk of ESRD if that person does not donate a kidney.We used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics. We then compared 15-year projections with the observed risk among 52,998 living kidney donors in the United States.A total of 4,933,314 participants from seven cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics that were similar to those of age-matched kidney donors, the 15-year projections of the risk of ESRD in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of a lower estimated glomerular filtration rate, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. In the model-based lifetime projections, the risk of ESRD was highest among persons in the youngest age group, particularly among young blacks. The 15-year observed risks after donation among kidney donors in the United States were 3.5 to 5.3 times as high as the projected risks in the absence of donation.Multiple demographic and health characteristics may be used together to estimate the projected long-term risk of ESRD among living kidney-donor candidates and to inform acceptance criteria for kidney donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Background: Several studies indicate that lower extremity peripheral artery disease (PAD), commonly defined by an ankle-brachial index (ABI) Methods: We studied 15,160 ARIC participants (age 45-64 years in 1987-1989) whose ABI was measured in a randomly selected leg at baseline. Hip or lower extremity fracture-related diagnostic codes were identified through active surveillance of hospitalizations. We used Cox proportional hazards to estimate the independent association between ABI including high ABI (≥1.4), a condition shown in PAD with vascular stiffness, and incident fracture hospitalization, adjusting for potential confounders. Results: There were 668 hip or lower extremity fracture hospitalizations during a median follow-up of 22 years. In the crude model, there was a dose-response relationship between low ABI and fracture risk (Table). However, only ABI 0.9-1.1 remained statistically significant after demographic adjustment compared to normal ABI (1.1-1.4) and inclusion of other covariates rendered this association non-significant. The results were largely consistent among most demographic and clinical subgroups, but we observed increased risk of fracture in low ABI ( Conclusion: An independent association of ABI with increased risk of hip or lower extremity fracture hospitalization was not that evident overall in our biracial population of middle-aged adults. However, ABI may contribute to increased risk of fracture in subgroups, warranting further investigation.

Background: Lower extremity peripheral artery disease (PAD), commonly defined by an ankle-brachial index (ABI) Methods: We studied 5,351 ARIC participants (age 71-90 years during 2011-2013) who underwent the assessment of ABI and the Short Physical Performance Battery (SPPB, 0-12 scale), a summary measure of physical function based on three domains (4-meter walk velocity, timed chair stands, and standing balance). Logistic regression models examined the association of ABI with poor physical function (SPPB score Results: There were 463 participants (8.2%) with ABI Conclusion: In our population of community-dwelling older adults, ~25% had low, borderline low, or high ABI suggestive of PAD and demonstrated poorer physical function compared to those with normal ABI. Since physical function is a key element for independent living in older adults and several therapeutic options for PAD exist, our findings may have broad and important implications.