Shoshana H. Ballew, PhD

OBJECTIVE Previous studies suggested that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may initially worsen and possibly increase the risk of diabetic retinopathy. However, data on this possible association remain limited. Thus, this population-based study aimed to determine whether use of GLP-1 RAs is associated with an increased risk of incident diabetic retinopathy. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink (CPRD), we conducted a cohort study among 77,115 patients with type 2 diabetes initiating antidiabetic drugs between January 2007 and September 2015. Adjusted hazard ratios (HRs) and 95% CIs of incident diabetic retinopathy were estimated using time-dependent Cox proportional hazards models, comparing use of GLP-1 RAs with current use of two or more oral antidiabetic drugs. In an ancillary analysis …

Background The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFRcr), which may be less accurate in older adults. Objective To evaluate associations in older adults between eGFRcr versus eGFR based on creatinine and cystatin C levels (eGFRcr-cys) and 8 outcomes. Design Population-based cohort study. Setting …

BACKGROUND Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were …

Background and aimsReduced kidney function is a risk factor for lower-extremity peripheral artery disease (PAD). However, the associations of novel filtration markers with PAD are yet to be quantified. Moreover, little is known on whether bone-mineral metabolism (BMM) markers are related to incident PAD beyond kidney function.MethodsUsing data from 12,472 participants at baseline (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) study, we comprehensively quantified the associations of kidney related markers with incident PAD (defined as hospitalizations with diagnosis of lower-extremity atherosclerosis, revascularization, or amputation). Kidney related markers of interest included estimated glomerular filtration rate (eGFR) (based on creatinine, cystatin C, and both), cystatin C, beta-2 microglobulin (B2M), and BMM markers (serum fibroblast growth factor 23, parathyroid hormone, calcium, and …

PurposeThere are well-known socioeconomic status (SES) gradients in children and adolescents' health which may be associated with time use. Our aim was to evaluate the association between Australian children's 24-hour time use and SES using four separate surveys from 2005 to 2021.MethodsTime use was assessed in 4526 8-19-year-olds from the 2005 Health of Young Victorians, 2007 National Children's Nutrition and Physical Activity, 2015 Child Health CheckPoint, and 2019-21 Life on Holidays study. Each survey used the same reliable, valid, 24-hour recall instrument. SES was quantified using tertiles of household income, education, and postcode-level measures. Compositional data analysis was used to compare 24-hour time use between SES categories, adjusting for age, sex, and puberty.ResultsTime-use compositions differed significantly by SES in each survey. Relative to the lowest SES, children …

Introduction: Intermittent claudication is manifestation of lower extremity peripheral artery disease (PAD). However, most patients with PAD either have atypical leg symptoms or no symptoms. To what extent leg symptoms are associated with the presence of PAD in the community is unknown. Methods: We studied 8,402 HCHS/SOL participants aged 45 and older (mean age 56.2 years, 54% female) without a clinical diagnosis of PAD. We categorized leg symptoms with walking into: (a) typical calf pain (calf pain on exertion relieved within 10 min after stopping); (b) atypical calf pain (same as (a) except no quick relief after 10 min); (c) non-calf pain (exertional leg pain but not in calf); and (d) leg pain at rest (ever pain during standing or sitting) based on a questionnaire. PAD was defined as an ankle-brachial index (ABI) ≤0.9. We first quantified the associations of leg symptoms with the presence of PAD using …

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 …

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 …

BackgroundThe kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict kidney failure risk in people with GFR< 60 ml/min per 1.73 m 2.MethodsUsing 59 cohorts with 312,424 patients with CKD, we tested several modifications to the KFRE for their potential to improve the KFRE: using the CKD-EPI 2021 creatinine equation for eGFR, substituting 1-year average ACR for single-measure ACR and 1-year average eGFR in participants with high eGFR variability, and adding 2-year prior eGFR slope and cardiovascular comorbidities. We also assessed calibration of the KFRE in subgroups of eGFR and age before and after accounting for the competing risk of death.ResultsThe KFRE remained accurate and well calibrated overall using the CKD-EPI 2021 eGFR equation. The other modifications did not improve KFRE performance. In subgroups of eGFR 45–59 ml/min …

BACKGROUND Current clinical guidelines recommend a coronary artery calcium (CAC) score of 100 Agatston Units or demographic-specific 75th percentile as high-risk thresholds for guiding atherosclerotic cardiovascular disease preventive therapy. Meanwhile, low CAC can help derisk individuals who may safely defer statin therapy. However, limited data from the early 2000s, including just 208 older Black individuals, inform CAC percentiles for adults aged 75 to 85 years, and none have been established in adults aged ≥85 years. This study aims to characterize the distribution of CAC and establish demographic-specific CAC percentiles in the population aged ≥75 years. METHODS We assessed 2886 participants aged ≥75 years without clinical coronary heart disease from the ARIC study (Atherosclerosis Risk in Communities) visit 7 (2018–2019; n=2217) and the MESA (Multi-Ethnic Study of …

METHODSWe performed a cross-sectional analysis in the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study of cardiovascular risk factors in midlife conducted in four US communities (Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland). 1 We included 5164 participants (≥ 65 years) at visit 5 (2011–2013) who were taking at least one prescribed medication and had covariate data (see Table 1).

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 …

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 …

BackgroundGlucagon-like peptide-1 receptor agonists (GLP1RA) have proven cardiovascular benefits among patients with type 2 diabetes. However, a safety signal from a meta-analysis of clinical trials suggested higher risk of atrial fibrillation with albiglutide vs. comparator (placebo or other diabetes medication (s)). There has been little post-marketing surveillance to assess real-world risk.AimWe sought to examine the real-world risk of atrial fibrillation comparing GLP1RA with other oral diabetes medications.MethodUsing deidentified electronic health record data from the Optum Labs Data Warehouse, we included patients with type 2 diabetes initiating non-insulin diabetes medications (excluding metformin which is considered first-line therapy) between 2005 and 2020. Because of a previous report of lower risk of atrial fibrillation with sodium-glucose cotransporter 2 inhibitors (SGLT2i), we separately compared …

Rationale & ObjectiveCystatin C is recommended for measuring estimated glomerular filtration rate (eGFR) when estimates based on creatinine (eGFRcr) are not thought to be accurate enough for clinical decision making. While global adoption is slow, routine cystatin C testing in Sweden has been available for over a decade, providing real-world evidence about the magnitude of differences between eGFRcys and eGFRcr and their association with clinical outcomes.Study DesignObservational study.Setting & Participants158,601 adults (48% women; mean age 62 years, eGFRcr 80, and eGFRcys 73 mL/min/1.73/m2) undergoing testing for creatinine and cystatin C on the same day in connection with a health care encounter during 2010-2018 in Stockholm, Sweden.ExposurePercentage difference of eGFRcys minus eGFRcr (eGFRdiff).OutcomeKidney failure with replacement therapy (KFRT), acute kidney injury …

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 …

Rationale & ObjectiveAnemia is common in chronic kidney disease (CKD); although anemia is associated with adverse outcomes, the available treatments are not ideal. We characterized the burden, risk factors for, and risks associated with anemia by estimated glomerular filtration rate (eGFR) and hemoglobin level.Study DesignCross-sectional and prospective cohort study.Setting & ParticipantsOutpatient data from 5,004,957 individuals across 57 health care centers in the United States from 2016 to 2019, extracted from the Optum Labs Data Warehouse.ExposureSeverity of anemia, presence of low iron test results, eGFR.OutcomeIncident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, death.Analytical ApproachThe prevalences of anemia, low iron test results, vitamin B12 deficiency, and erythropoiesis-stimulating agent (ESA) use, stratified by sex and …

Aims The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an ‘Add-on’ to incorporate CKD measures into these algorithms, using a validated approach. Methods In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net …

Importance Chronic kidney disease (low eGFR or albuminuria) affects approximately 14% of people in the United States. Objective To evaluate associations of lower eGFR using creatinine alone (eGRFcr), lower eGFR using creatinine combined with cystatin C (eGFRcr-cys), and higher albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, setting, participants: Retrospective individual-level data analysis of 27,503,140 participants from 114 global cohorts (eGFRcr) and 720,736 participants from 20 cohorts (eGFRcr-cys) and 9,067,753 participants from 114 cohorts (albuminuria) from 1980 to 2021. Exposures CKD-EPI 2021 equations for eGFRcr and eGFRcr-cys; albuminuria estimated as urine albumin-to-creatinine ratio (ACR). Main outcomes and measures The risk of kidney failure with replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. Analyses were performed within each cohort and summarized with random-effect meta-analyses. Results Within the eGFRcr population (mean age: 54 years, 51% women), mean eGFRcr was 90 ml/min/1.73 m2 (SD, 22) and median ACR was 11 mg/g (interquartile range 8-16 mg/g). Within the eGFRcr-cys population (mean age: 59 years, 53% women), mean eGFRcr-cys was 88 ml/min/1.73 m2 (SD, 22) and median ACR was 9 mg/g (interquartile range 6-18 mg/g). Lower eGFR (whether based on eGFRcr or eGFRcr-cys) and higher ACR were each associated with higher risk of all ten adverse outcomes, including in …

Background: Neighborhood-level social determinants of health (SDOH) impact cardiovascular disease (CVD) risk. However, limited data are available from large, multi-ethnic, national samples with CVD risk factors on how place-based SDOH independently relates to CVD risk, and on whether accounting for place-based SDOH attenuates race/ethnicity differences in CVD risk. Methods: We studied 2,538,811 patients free of prior CVD in the Optum Labs Data Warehouse (OLDW). Billing addresses were geocoded to derive social deprivation index (SDI, deciles 0 to 10 as a composite measure of poverty, education, employment, home rental & crowding, single-parent households and no car ownership) at the zip code level. SDI was compared by race/ethnicity, as coded in the electronic health record. Multivariable Cox models quantified the adjusted relative hazard of incident CVD (using hospitalization discharge …