Plasma proteomic comparisons change as coverage expands for SomaLogic and Olink.

The number of assays on highly-multiplexed proteomic platforms has grown ten-fold over the past 15 years from less than 1,000 to >11,000. The leading aptamer-based and antibody-based platforms have different strengths. For example, Eldjarn et al 1 demonstrated that the aptamer-based SomaScan 5k (4,907 assays, assessed in the Icelandic 36K) and the antibody-based Olink Explore 3072 (2,931 assays, assessed in the UK BioBank) had a similar number of cis -pQTLs among all targets (2,120 vs. 2,101) but Olink had a greater number of cis -pQTLs among the overlapping targets (1,164 vs. 1,467). Analysis of split plasma measures showed the SomaScan assays to be more precise: median coefficient of variation (CV) of 9.9% vs. 16.5% for Olink. 1 Precision of the newest versions of the platforms-SomaScan 11k (>11,000 assays, released in December 2023) and Olink Explore HT (>5,400 assays, released in July 2023)-has not yet been established. We assessed the reproducibility of the SomaScan 11k and Olink Explore HT using split plasma samples from 102 Atherosclerosis Risk in Communities (ARIC) Study participants. We found that the SomaScan 11k assays had a median CV of 6.8% (vs 6.6% for the subset of assays available on the SomaScan 5k) and the Olink Explore HT assays had a median CV of 35.7% (vs 19.8% for the subset of assays available on the Olink Explore 3072). Across Olink assays, the CVs were strongly negatively correlated with protein detectability, i.e., percent of samples above the limit of detection (LOD). For the 4,443 overlapping assays, the distribution of between-platform correlations was bimodal with a peak at r ∼0 and with another smaller peak at r ∼0.8. These findings on precision are consistent with the updated results by Eldjarn et al 1 but indicate that precision of these two leading platforms in human plasma has diverged as the number of included proteins has increased.

Plasma proteins associated with plant-based diets: Results from the Atherosclerosis Risk in Communities (ARIC) study and Framingham Heart Study (FHS).

BACKGROUND & AIMS: Plant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort. METHODS: ARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n = 7690) and replication (n = 2543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n = 1358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics. RESULTS: In ARIC discovery, a total of 837 diet-protein associations (PDI = 233; provegetarian = 182; hPDI = 406; uPDI = 16) were observed at false discovery rate (FDR) < 0.05. Of these, 453 diet-protein associations (PDI = 132; provegetarian = 104; hPDI = 208; uPDI = 9) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI = 1; provegetarian = 0; hPDI = 8; uPDI = 0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests). CONCLUSIONS: Using large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions.

Consistency of metabolite associations with measured glomerular filtration rate in children and adults.

Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < -0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.

Extreme Humid-Heat Exposure and Mortality Among Patients Receiving Dialysis.

RATIONALE & OBJECTIVE: Exposure to extreme heat events has been linked to increased morbidity and mortality in the general population. Patients receiving maintenance dialysis may be vulnerable to greater risks from these events, but this is not well understood. We characterized the association of extreme heat events and the risk of death among patients receiving dialysis in the United States. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Data from the US Renal Data System were used to identify adults living in US urban settlements prone to extreme heat who initiated maintenance dialysis between 1997 and 2016. EXPOSURE: An extreme heat event, defined as a time-updated heat index (a humid-heat metric) exceeding 40.6°C for≥2 days or 46.1°C for≥1day. OUTCOME: Death. ANALYTICAL APPROACH: Cox proportional hazards regression to estimate the elevation in risk of death during a humid-heat event adjusted for age, sex, year of dialysis initiation, dialysis modality, poverty level, and climate region. Interactions between humid-heat and these same factors were explored. RESULTS: Among 945,251 adults in 245 urban settlements, the mean age was 63 years, and 44% were female. During a median follow-up period of 3.6 years, 498,049 adults were exposed to at least 1 of 7,154 extreme humid-heat events, and 500,025 deaths occurred. In adjusted models, there was an increased risk of death (hazard ratio 1.18 [95% CI, 1.15-1.20]) during extreme humid-heat exposure. The relative mortality risk was higher among patients living in the Southeast (P<0.001) compared with the Southwest. LIMITATIONS: Possibility of exposure misclassification, did not account for land use and air pollution co-exposures. CONCLUSIONS: This study suggests that patients receiving dialysis face an increased risk of death during extreme humid-heat exposure. PLAIN-LANGUAGE SUMMARY: Patients who receive dialysis are vulnerable to extreme weather events, and rising global temperatures may bring more frequent extreme heat events. We sought to determine whether extreme heat exposure was associated with an increased risk of death in urban-dwelling patients receiving dialysis across the United States. We found that people receiving dialysis were more likely to die during extreme humid-heat events, defined by a heat index exceeding 40.6°C (105°F) for≥2 days or 46.1°C (115°F) for≥1day. These findings inform the nephrology community about the potential importance of protecting patients receiving maintenance dialysis from the risks associated with extreme heat.

Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis.

Physical frailty is a syndrome that typically manifests in later life, although the pathogenic process causing physical frailty likely begins decades earlier. To date, few studies have examined the biological signatures in mid-life associated with physical frailty later in life. Among 4,189 middle-aged participants (57.8 ± 5.0 years, 55.8% women) from the Atherosclerosis Risk in Community (ARIC) study, we evaluated the associations of 4,955 plasma proteins (log 2-transformed and standardized) measured using the SomaScan platform with their frailty status approximately 20 years later. Using multinomial logistic regression models adjusting for demographics, health behaviors, kidney function, total cholesterol, and comorbidities, 12 and 221 proteins were associated with prefrailty and frailty in later life, respectively (FDR p < 0.05). Top frailty-associated proteins included neurocan core protein (NCAN, OR = 0.66), fatty acid-binding protein heart (FABP3, OR = 1.62) and adipocyte (FABP4, OR = 1.65), as well proteins involved in the contactin-1 (CNTN1), toll-like receptor 5 (TLR5), and neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway relevant to skeletal muscle regeneration, myelination, and inflammation. Pathway analyses suggest midlife dysregulation of inflammation, metabolism, extracellular matrix, angiogenesis, and lysosomal autophagy among those at risk for late-life frailty. After further adjusting for midlife body mass index (BMI) - an established frailty risk factor - only CNTN1 (OR = 0.75) remained significantly associated with frailty. Post-hoc analyses demonstrated that the top 41 midlife frailty-associated proteins mediate 32% of the association between mid-life BMI and late-life frailty. Our findings provide new insights into frailty etiology earlier in the life course, enhancing the potential for prevention.

Pneumococcal vaccination effectiveness (PCV13 and PPSV23) in individuals with and without reduced kidney function: a test-negative design study.

Background: Streptococcus pneumoniae vaccination effectiveness (VE) in individuals with reduced kidney function is unknown. We estimated pneumococcal conjugate vaccine (PCV13), pneumococcal polysaccharide vaccine (PPSV23), and combined PCV13 and PPSV23 effectiveness against pneumococcal disease in individuals with and without reduced estimated glomerular filtration rate (eGFR). Methods: All eligible individuals (case and controls) were adults (aged ≥18 years) hospitalized within the Geisinger Health System and required to have S. pneumoniae urinary antigen testing (i.e. test-negative design). Vaccination records were obtained from the electronic health record and statewide vaccination registry. After controlling for the probability of receiving a pneumococcal vaccine, we used multivariable logistic regression models to estimate the odds ratios (ORs) of vaccination between those who did and did not meet the S. pneumoniae case definition. VE was calculated as (1 - OR) × 100%. Results: There were 180 cases and 3889 controls (mean age 69 years, female 48%, white 97%, mean eGFR 71 mL/min/1.73 m2). The adjusted population PCV13 VE was 39% (95% CI 13%-58%), and combination PCV13 and PPSV23 was 39% (95% CI 12%-58%). PPSV23 VE was -3.7% (95% CI -57% to 32%). Stratified by eGFR, adjusted PCV13 VE was consistent in eGFR ≥60 [VE 38% (95% CI 2.9%-61%)] and 30-59 [VE 61% (95% CI 24%-80%)] without significant interaction. VE was not calculable for eGFR <30 due to small sample size. Conclusion: PCV13 vaccination was associated with reduced risk of S. pneumoniae hospitalization in individuals with a reduced eGFR (30-59 mL/min/1.73 m2).

Associations of Urine and Plasma Metabolites with Kidney Failure and Death in a CKD Cohort.

RATIONALE & OBJECTIVE: Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. STUDY DESIGN: Prospective metabolome-wide association study. SETTING & PARTICIPANTS: Persons with CKD enrolled in the German CKD Study (GCKD) with metabolite measurements; with external validation within the Atherosclerosis Risk in Communities Study. EXPOSURES: 1,513 urine and 1,416 plasma metabolites (Metabolon, Inc.) measured at study entry using untargeted mass spectrometry. OUTCOMES: Main endpoints were kidney failure (KF), and a composite endpoint of KF, eGFR <15 mL/min/1.73m2, or 40% decline in eGFR (CKE). Death from any cause was a secondary endpoint. After a median of 6.5 years follow-up, 500 persons experienced KF, 1,083 experienced CKE and 680 died. ANALYTICAL APPROACH: Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design, with external validation. RESULTS: 5,088 GCKD participants were included in analyses of urine metabolites and 5,144 in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (hazard ratio: 1.95, 95% confidence interval: 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, CKE, and death. External validation of the identified associations of metabolites with KF or CKE revealed direction-consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LIMITATIONS: Use of observational data and semi-quantitative metabolite measurements at a single time point. CONCLUSIONS: The observed associations between metabolites and KF, CKE or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts.

Comparative CKD risk prediction using homocitrulline and carbamylated albumin: two circulating markers of protein carbamylation.

BACKGROUND: Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD. Biomarkers used to quantify carbamylation burden have mainly included carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine). In this study, we aimed to compare the prognostic utility of these two markers in order to facilitate comparisons of existing studies employing either marker alone, and to inform future carbamylation studies. METHODS: Both serum C-Alb and free HCit levels were assayed from the same timepoint in 1632 individuals with CKD stages 2-4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models were used to assess risks for the outcomes of death (primary) and end stage kidney disease (ESKD) using each marker. C-statistics, net reclassification improvement, and integrated discrimination improvement were used to compare the prognostic value of each marker. RESULTS: Participant demographics included mean (SD) age 59 (11) years; 702 (43%) females; 700 (43%) white. C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64). Higher C-Alb and HCit levels showed similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 (95% confidence interval [CI] 1.35-2.66) for C-Alb, and 1.89 [1.27-2.81] for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 [1.11 to 1.39] per standard deviation increase, and 1.27 [1.10-1.46] using HCit). Both biomarkers also had similar HRs for ESKD. The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 [0.707-0.743] with C-Alb and 0.725 [0.707-0.743] with HCit, both compared to a base model 0.723). Similarities were also observed for the net reclassification improvement and integrated discrimination improvement metrics. CONCLUSIONS: C-Alb and HCit had similar performance across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies.

Dihydropyridine Calcium Channel Blockers and Kidney Outcomes.

BACKGROUND: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. OBJECTIVE: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. DESIGN: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. PARTICIPANTS: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. MAIN MEASURES: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. KEY RESULTS: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005). CONCLUSIONS: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes.

Association of Sevelamer Initiation with Gastrointestinal Bleeding Hospitalization in Individuals Requiring Hemodialysis.

Introduction Case reports have suggested a causative role between sevelamer use and subsequent gastrointestinal bleeding (GIB), but no large observational studies have evaluated this association. Methods Using the United States Renal Data System database from 2015 to 2019, we examined the association between initiation of sevelamer (versus non-sevelamer containing phosphate binders) and GIB hospitalization as well as all-cause mortality among individuals on hemodialysis. We emulated a target trial using Cox regression models and inverse probability of treatment weights to estimate the adjusted hazard ratios (HR) across outcomes and subgroups. Results Among 21,354 new users of phosphate binders (11,276 sevelamer and 10,078 non-sevelamer) with baseline lab data (calcium, phosphorus, hemoglobin, and albumin), there were 2,811 GIB hospitalizations and 5,920 deaths after a median follow-up of 1.3 years. Compared with the initiation of non-sevelamer binders, sevelamer was not associated with an increased risk of GIB hospitalization (89 vs. 90 events per 1000 person-years; IPTW-HR 0.98, 95% CI 0.91 - 1.06) or all-cause mortality (220 vs. 224 events per 1000 person-years; IPTW-HR 0.98 95% CI 0.93 - 1.03). Subgroup analyses (such as diabetes and anti-coagulation use) were generally consistent, and there was no association between sevelamer dose and GIB hospitalization. Conclusion Among patients requiring hemodialysis, sevelamer (vs non-sevelamer) containing phosphate binders was not associated with increased risk of GIB hospitalization.

Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2 and JAK2. Mendelian randomization analyses supported a causal role for CHIP in promoting AKI. Non-DNMT3A-CHIP was also associated with a nonresolving pattern of injury in patients with AKI. To gain mechanistic insight, we evaluated the role of Tet2-CHIP and Jak2V617F-CHIP in two mouse models of AKI. In both models, CHIP was associated with more severe AKI, greater renal proinflammatory macrophage infiltration and greater post-AKI kidney fibrosis. In summary, this work establishes CHIP as a genetic mechanism conferring impaired kidney function recovery after AKI via an aberrant inflammatory response mediated by renal macrophages.

Serum Metabolomic Markers of Protein-Rich Foods and Incident CKD: Results From the Atherosclerosis Risk in Communities Study.

Rationale & Objective: While urine excretion of nitrogen estimates the total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of 6 protein-rich foods and to examine whether dietary protein-related metabolites are associated with incident chronic kidney disease (CKD). Study Design: Prospective cohort study. Setting & Participants: A total of 3,726 participants from the Atherosclerosis Risk in Communities study without CKD at baseline. Exposures: Dietary intake of 6 protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry), serum metabolites. Outcomes: Incident CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2 with ≥25% estimated glomerular filtration rate decline relative to visit 1, hospitalization or death related to CKD, or end-stage kidney disease). Analytical Approach: Multivariable linear regression models estimated cross-sectional associations between protein-rich foods and serum metabolites. C statistics assessed the ability of the metabolites to improve the discrimination of highest versus lower 3 quartiles of intake of protein-rich foods beyond covariates (demographics, clinical factors, health behaviors, and the intake of nonprotein food groups). Cox regression models identified prospective associations between protein-related metabolites and incident CKD. Results: Thirty significant associations were identified between protein-rich foods and serum metabolites (fish, n = 8; nuts, n = 5; legumes, n = 0; red and processed meat, n = 5; eggs, n = 3; and poultry, n = 9). Metabolites collectively and significantly improved the discrimination of high intake of protein-rich foods compared with covariates alone (difference in C statistics = 0.033, 0.051, 0.003, 0.024, and 0.025 for fish, nuts, red and processed meat, eggs, and poultry-related metabolites, respectively; P < 1.00 × 10-16 for all). Dietary intake of fish was positively associated with 1-docosahexaenoylglycerophosphocholine (22:6n3), which was inversely associated with incident CKD (HR, 0.82; 95% CI, 0.75-0.89; P = 7.81 × 10-6). Limitations: Residual confounding and sample-storage duration. Conclusions: We identified candidate biomarkers of fish, nuts, red and processed meat, eggs, and poultry. A fish-related metabolite, 1-docosahexaenoylglycerophosphocholine (22:6n3), was associated with a lower risk of CKD.

In this study, we aimed to identify associations between protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry) and serum metabolites, which are small biological molecules involved in metabolism. Metabolites significantly associated with a protein-rich food individually and collectively improved the discrimination of the respective protein-rich food, suggesting that these metabolites should be prioritized in future diet biomarker research. We also studied associations between significant diet-related metabolites and incident kidney disease. One fish-related metabolite was associated with a lower kidney disease risk. This finding supports the recent nutritional guidelines recommending a Mediterranean diet, which includes fish as the main dietary protein source.

Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C.

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: Stockholm, Sweden, 2010 to 2019. PARTICIPANTS: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. MEASUREMENTS: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. RESULTS: The associations between eGFRcr-cys and outcomes were monotonic, but most associations for eGFRcr were U-shaped. In addition, eGFRcr-cys was more strongly associated with outcomes than eGFRcr. For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFRcr-cys and 1.0 (CI, 0.9 to 1.0) for eGFRcr, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. LIMITATION: No GFR measurements. CONCLUSION: Compared with low eGFRcr in older patients, low eGFRcr-cys was more strongly associated with adverse outcomes and the associations were more uniform. PRIMARY FUNDING SOURCE: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. OBJECTIVE: To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. DESIGN: Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. PARTICIPANTS: Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. EXPOSURES: New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. MAIN MEASURES: The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. KEY RESULTS: In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). CONCLUSIONS: In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.