Sunil V. Badve

Chronic kidney disease (CKD) and cardiovascular disease (CVD) are major causes of morbidity and mortality in people with type 2 diabetes (T2D). Contemporary CKD guidelines increasingly support incorporation of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) as an additional pillar of cardiorenal therapy alongside renin–angiotensin–aldosterone system (RAAS) blockade, sodium–glucose co‐transporter 2 inhibitors (SGLT2i) and finerenone. Semaglutide is the first GLP‐1RA with kidney‐outcome data from a dedicated trial in T2D‐CKD: the Evaluate Renal Function with Semaglutide Once Weekly (FLOW) study. In FLOW, once‐weekly subcutaneous semaglutide 1 mg reduced major kidney disease events by 24%, major adverse cardiovascular events by 18% and all‐cause mortality by 20% versus placebo on a background of guideline‐directed therapy. Here a multidisciplinary expert panel summarises Australian Therapeutic Goods Administration indications and Pharmaceutical Benefits Scheme restrictions, highlights common access barriers and outlines approaches to shared care between primary and tertiary services for use of GLP‐1RAs. Guidance is also provided on treatment sequencing of GLP‐1RA alongside RAAS blockade, SGLT2i and finerenone. Evidence from key GLP‐1RA trials, in addition to FLOW, is reviewed and translated into practical, implementable prescribing strategies for Australian clinicians. The panel also identified priority patient groups for GLP‐1RA therapy, including those with residual albuminuria, heart failure with preserved ejection fraction, established CVD, obesity and Aboriginal and Torres Strait Islander peoples at high cardiorenal risk. Remaining evidence gaps, particularly for non‐diabetic CKD, advanced CKD, dialysis and transplant populations and equity of access, are identified as priorities for future research and policy.

Introduction: Patients with advanced stages of chronic kidney disease (CKD) and dialysis-dependent kidney failure are at a greater risk of cardiovascular events and mortality than those with early stages of CKD. There are no completed definitive randomized trials on the safety and efficacy of anticoagulant therapy in this patient population. Methods: Treatment of cardiovascular disease with low-dose Rivaroxaban in Advanced Chronic Kidney disease (TRACK) is a multicenter, randomized, placebo-controlled trial (NCT03969953), designed to enroll 1,886 adult participants with CKD stage 4 or 5 (estimated glomerular filtration rate ≤29 mL/min/1.73 m2) or dialysis-dependent kidney failure and high cardiovascular risk (defined as at least one of the following risk factors; coronary artery disease, nonhemorrhagic non-lacunar stroke, peripheral artery disease [PAD], diabetes mellitus, or age ≥65 years). Participants are randomized to rivaroxaban 2.5 mg twice daily or matching placebo. The primary efficacy outcome is a composite of cardiovascular death, myocardial infarction, stroke, or PAD event. The primary safety outcome is major bleeding, defined as a composite of fatal bleeding, bleeding leading to hospitalization, or symptomatic bleeding in a critical area or organ. From January 2021 to July 2025, 1,458 eligible participants (mean age 63.2 years, 700 [48%] age ≥65 years, 432 [29.6%] women, 715 [49%] dialysis-dependent kidney failure and 743 [51%] CKD stage 4 or 5, 1,125 [77.2%] diabetes mellitus, 674 [46.2%] treated with aspirin at baseline) underwent randomization. Conclusion: TRACK will evaluate the effect of low dose rivaroxaban on major adverse cardiovascular events in participants with CKD stages 4 and 5 and dialysis-dependent kidney failure, and elevated cardiovascular risk.

The ASPIRED trial aims to determine whether a daily low-dose of aspirin is effective in preventing major cardiovascular events when compared to placebo in patients receiving dialysis. It is designed as a pragmatic trial two-arm double-blind randomised trial conducted within an established Dialysis Registry consisting of at least 80 centres and 30,000 participants. This statistical analysis plan pre-specifies the method of analysis for every outcome and key variables collected in the trial. The primary outcome is time from randomisation to first occurrence of major cardiovascular event including myocardial infarction, ischemic stroke or death from cardiovascular cause. The primary analysis will consist in a Cox proportional hazard model adjusted for stratification variables. The analysis plan also includes planned sensitivity analyses including covariate adjustments and subgroup analyses.

Key Points: Increased eGFR variability over 3 years independently predicts a higher risk of kidney outcomes and all-cause mortality. This association remained consistent across subgroups and sensitivity analyses. Routine eGFR variability assessment may enable identification of high-risk patients and provide an opportunity for the initiation of interventions. Background: eGFR variability may predict adverse outcomes, such as cardiovascular events and mortality, yet its influence on kidney impairment progression in routine clinical practice is not well described. Methods: This retrospective cohort study used longitudinal eGFR data from MedicineInsight, a comprehensive primary care database. We included adults (18 years or older) with at least three eGFR measurements over 3 years between January 1, 2011, and December 31, 2018. eGFR variability between visits was assessed using the coefficient of variation and categorized into groups by quintiles. A kidney composite end point, comprising a sustained 40% decline in eGFR from baseline, a sustained eGFR of 2 , and all-cause mortality, was tracked over a 3-year follow-up. Cox proportional hazards models quantified the association between eGFR variability and outcomes. Results: Among 754,306 patients, with a mean age of 59.1 years and 58.0% female, higher eGFR variability was associated with an increased risk of the kidney composite end point (hazard ratio, 2.17;95% confidence interval, 2.03 to 2.32) for the highest versus lowest fifth after adjusting for mean eGFR and eGFR slope, as well as other cardiovascular disease risk factors and medication use. Similar trends were observed for components of the primary outcome and across all subgroups including age, sex, hypertension, diabetes, and baseline eGFR. Conclusions: Increased eGFR variability independently predicts adverse kidney outcomes, underscoring its potential as a clinical biomarker for identifying high-risk patients. Including eGFR variability in routine kidney assessments may improve risk stratification, enabling timely interventions and potentially enhancing patient outcomes in primary care.

Key Points: Acute effects impact the clinical endpoint independently of treatment effects on the chronic slope. Our findings support the 3-year total slope as the primary slope-based outcome in randomized trials. Background: Slope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs). Methods: We estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes. Results: Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R² (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m² greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%–15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years. Conclusions: Treatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.

Key Points: This real-world study involved a large cohort of 38,598 adults with atrial fibrillation from five jurisdictions across Australia and Canada. This study supports the use of apixaban as a safe and effective alternative to warfarin for atrial fibrillation across differing levels of kidney function. This study also adds important safety data on the use of apixaban in patients with reduced kidney function. Background: Evidence to guide the use of apixaban in people with atrial fibrillation (AF) and CKD in routine clinical practice has been limited. We assessed comparative safety (major bleeding) and effectiveness (ischemic stroke and death) of apixaban versus warfarin in patients with AF across the spectrum of non–dialysis-dependent CKD using large, routinely collected data. Methods: We combined findings from five retrospective cohorts (2013–2018) across Australia and Canada. Adults with AF, new dispensation of apixaban or warfarin, and a recorded eGFR grouped as ≥60, 45–59, 30–44, and 2 were included. Patients on dialysis or kidney transplant recipients were excluded. We assessed outcomes within 1 year of initiating either therapy: (1) composite of all-cause death, ischemic stroke, or transient ischemic attack and (2) first hospitalization for major bleeding (intracranial, gastrointestinal, or other). Cox models estimated hazard ratios (HRs; 95% confidence intervals) for outcomes across eGFR categories, after 1:1 matching using propensity scores. We summarized center-level data using random effects meta-analysis. Results: Among 38,598 matched apixaban and warfarin users, there were 4130 (10.7%) ischemic and 697 (1.8%) bleeding events within 1 year. Apixaban was associated with lower or similar risk for the ischemic outcome compared with warfarin in all eGFR categories (pooled HRs [95% confidence interval]: 0.78 [0.64 to 0.94], 0.77 [0.62 to 0.97], 0.82 [0.68 to 0.98], and 0.99 [0.68 to 1.45] for eGFR ≥60, 45–59, 30–44, and 2, respectively). Apixaban was associated with lower or similar risk of bleeding across the range of kidney function (pooled HRs: 0.55 [0.43 to 0.69], 0.73 [0.52 to 1.02], 0.55 [0.31 to 0.97], and 0.68 [0.47 to 0.99], respectively). There was no significant heterogeneity across jurisdictions or eGFR categories. Conclusions: In adults with AF and non–dialysis-dependent CKD, apixaban compared with warfarin was associated with lower or similar risk of ischemic and bleeding outcomes. Our results suggest that apixaban offers a favorable risk-benefit ratio in patients with AF independent of kidney function.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP-1RA) reduce the incidence of major adverse cardiovascular events (MACE) in type 2 diabetes (T2D), although whether benefits extend to both subcutaneous and oral formulations remains unclear. PURPOSE: In these meta-analyses, including new data from the Semaglutide cardiOvascular oUtcomes triaL (SOUL) (oral semaglutide) and Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial, we examined cardiovascular (CV) and kidney benefits and risks of long-acting (defined as having pharmacokinetics sufficient to provide 24-h activity) GLP-1RA in T2D. DATA SOURCES: A systematic review of PubMed was conducted (to 7 February 2025). STUDY SELECTION: Randomized placebo-controlled CV and kidney outcomes trials of GLP-1RA with ≥500 individuals with T2D were included. DATA EXTRACTION: A random-effects model was used to estimate hazard ratios (HRs) for MACE, its components, all-cause mortality, hospitalization for heart failure (HHF), a composite kidney outcome (kidney failure [kidney replacement therapy or persistent estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2], sustained ≥50% eGFR decline or nearest equivalent, or kidney-related death), worsening kidney function, and safety outcomes. DATA SYNTHESIS: Across 10 trials (n = 71,351), long-acting GLP-1RA reduced incidence rate of MACE by 14% (HR 0.86 [95% CI 0.81, 0.90]; I2 = 27.6%), HHF by 14% (0.86 [0.79, 0.93]; I2 = 2.1%), and the composite kidney outcome by 17% (0.83 [0.75, 0.92]; I2 = 20.4%) and all-cause mortality by 12% (0.88 [0.82, 0.93]; I2 = 17.5%). A consistent 14% reduction was seen for all MACE components. There was no significant heterogeneity by GLP-1RA administration route (subcutaneous vs. oral). There were no increased risks of severe hypoglycemia, retinopathy, or pancreatic events. LIMITATIONS: Trial-level meta-analyses preclude detailed subgroup analyses and may introduce ecological bias. CONCLUSIONS: As a group, long-acting GLP-1RA, including both injectable and oral formulations, reduce incidence of MACE, HHF, and kidney events and all-cause mortality in T2D.

BACKGROUND: GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter 2) inhibitors both improve cardiovascular and kidney outcomes in people with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. METHODS: We searched MEDLINE and Embase databases from inception until July 12, 2024, for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance-weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50% reduction in estimated glomerular filtration rate, kidney failure or death caused by kidney failure, and annualized rate of decline in estimated glomerular filtration rate (estimated glomerular filtration rate slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024565765). RESULTS: We identified 3 trials with 1743 of 17 072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of major adverse cardiovascular events by 21% (hazard ratio [HR], 0.79 [95% CI, 0.71–0.87]), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR, 0.77 [95% CI, 0.54–1.09] and HR, 0.79 [95% CI, 0.71–0.87], respectively; P -heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR, 0.58 [95% CI, 0.36–0.93] and HR, 0.73 [95% CI, 0.63–0.85]; P -heterogeneity=0.26). Effects on the composite kidney outcome (risk ratio, 0.79 [95% CI, 0.66–0.95]) and estimated glomerular filtration rate slope (0.78 mL/min/1.73 m ² /y [95% CI, 0.57–0.98]) also did not vary according to SGLT2 inhibitor use ( P -heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use ( P -heterogeneity=0.29 and 0.50, respectively). CONCLUSIONS: In people with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.

Key Points: Is performing a large definitive trial to establish the optimal anticoagulation strategy in dialysis recipients with atrial fibrillation feasible? One hundred fifty-one patients at 28 dialysis centers were enrolled and randomized to apixaban ( n =51), warfarin ( n =52), or no oral anticoagulation ( n =48). Despite coronavirus disease–related pauses, recruitment was completed in 30 months, with 83% of participants completing follow-up in their assigned treatment arm. Background: Atrial fibrillation is common in individuals receiving dialysis. The role of oral anticoagulation in this population is uncertain given its exclusion from previous seminal clinical trials. Our objective was to determine the feasibility of performing a large definitive trial to establish the optimal anticoagulation strategy in individuals with atrial fibrillation receiving dialysis. Methods: The Strategies for the Management of Atrial Fibrillation in Patients Receiving Dialysis trial was a parallel-group, open-label, allocation-concealed, pilot randomized control trial that took place at 28 centers in Canada and Australia. The trial included adults (18 years or older) undergoing dialysis with a history of nonvalvular atrial fibrillation who met the CHADS-65 criteria. Participants were randomized 1:1:1 to receive dose-adjusted warfarin, apixaban 5 mg twice daily, or no oral anticoagulation and followed for 26 weeks. The primary outcomes evaluated the following measures of feasibility: ( 1 ) recruitment of the target population within 2 years from the start of the trial and ( 2 ) adherence of >80% of randomized patients to the allocated treatment strategy at the conclusion of follow-up. Secondary outcomes included stroke and bleeding. Results: From December 2019 to June 2022, 151 patients were enrolled and randomized to apixaban ( n =51), warfarin ( n =52), or no oral anticoagulation ( n =48). Allowing for pauses related to the coronavirus disease pandemic, recruitment was completed in 30 months, and 123 (83%) of participants completed follow-up in their allocated treatment arm. There was one adjudicated stroke event. Eight participants had a major bleeding event (four warfarin, two apixaban, two no oral anticoagulation). Death occurred in 15 participants (nine warfarin, two apixaban, four no oral anticoagulation). Time in the therapeutic range for warfarin recipients was 58% (interquartile range, 47%–70%). Conclusions: We have demonstrated the feasibility of recruitment and adherence in a trial that compared different anticoagulation strategies in patients with atrial fibrillation receiving dialysis. Clinical Trial registry name and registration number: Strategies for the Management of Atrial Fibrillation in Patients Receiving Dialysis (SAFE-D), NCT03987711. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2025_04_09_ASN0000000000000495.mp3