Dr. Linda-Marie Lavenburg is an Assistant Professor of Medicine at the University of Pittsburgh Renal-Electrolyte Division. She is an internal-medicine and pediatric-trained physician, and a dual board-certified practicing adult nephrology and obesity medicine physician. Her research uses real-world clinical data to identify gaps in guideline-recommended kidney disease management. She also strives to raise awareness of kidney disease through community outreach and partnerships and to empower people living with kidney disease to maximize their health through lifestyle interventions.

Dr. Mariela Sierra Mendoza is an internal medicine resident physician training at UPMC Mercy. She is passionate about patient-centered care and improving her patients’ quality of life. She did her medical training at Universidad Nacional Autonoma de Honduras, and will be a primary care doctor after completion of her residency.

Cardiovascular disease remains the leading cause of death among individuals with chronic kidney disease (CKD). For many patients with CKD, the risk of dying from a cardiovascular event far exceeds the risk of progressing to kidney failure. Yet despite this disproportionate burden, patients with advanced kidney disease are frequently excluded from cardiovascular outcome trials evaluating new therapies.

Over the past decade, several landmark trials have reshaped the management of cardiometabolic disease. Sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial benefits across cardiovascular, metabolic, and kidney outcomes. Trials such as the LEADER, SUSTAIN‑6, and SOUL showed that GLP-1RAs reduce major adverse cardiovascular events in patients with type 2 diabetes at high cardiovascular risk. More recently, the SELECT trial extended these findings to individuals with overweight or obesity and established cardiovascular disease but without diabetes, demonstrating a significant reduction in cardiovascular events. Meanwhile, kidney-focused trials such as the FLOW trial have highlighted the potential for GLP-1RAs to slow kidney disease progression in patients with diabetic CKD (Table 1).

Despite this expanding body of evidence, an important population remains underrepresented: individuals with advanced CKD, dialysis-dependent kidney disease, and kidney transplant recipients. These patients face the highest cardiovascular risk but are commonly excluded from randomized clinical trials. Consequently, clinicians must rely on pharmacokinetic data, observational studies, and real-world evidence when considering these therapies in advanced kidney disease.

In this context, the study by Yau and colleagues provides important insights. Using population-based administrative health databases from Ontario, Canada, the investigators evaluated cardiovascular outcomes following initiation of GLP-1RAs in individuals with CKD. Unlike many cardiovascular outcome trials that exclude patients with estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m², this study included a broad spectrum of kidney disease severity, including patients with advanced CKD, dialysis dependence, and kidney transplantation.

In this retrospective cohort analysis, new users of GLP-1RAs were compared with new users of dipeptidyl peptidase-4 (DPP-4) inhibitors. The cohort included individuals with eGFR <90 mL/min/1.73 m², including 3,248 patients with eGFR <30 mL/min/1.73 m², those receiving maintenance dialysis, and kidney transplant recipients. The investigators observed that initiation of GLP-1RAs was associated with a significant reduction in cardiovascular risk, driven primarily by a 28% lower rate of cardiovascular death. Notably, reductions in major adverse cardiovascular events were consistent across CKD stages, levels of albuminuria, and concomitant use of SGLT2 inhibitors.

A key strength of this study lies in the investigators’ extensive sensitivity analyses. The authors evaluated multiple analytic scenarios, including different definitions of medication exposure, alternative follow-up strategies, and analytic approaches accounting for medication discontinuation or switching. They also compared intention-to-treat and as-treated analytic frameworks. Notably, the cardiovascular benefit of GLP-1 RAs remained consistent even when patients were censored at the time of medication switching or discontinuation. This consistency across analytic approaches strengthens confidence that the observed association is unlikely to be driven by exposure misclassification or analytic bias. Taken together, these real-world observations suggest that GLP-1RAs may provide cardiovascular protection across a wider spectrum of kidney disease than previously recognized.

The findings are particularly notable given the limited number of therapies with proven cardiovascular benefit in advanced CKD. Renin–angiotensin system (RAS) inhibitors—including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers—remain foundational therapies for patients with CKD, particularly those with diabetes and albuminuria.  These medications slow kidney disease progression, reduce proteinuria, and modestly lower cardiovascular risk. However, their use in advanced CKD can be complicated by hyperkalemia or worsening kidney function, which may limit their continued use in clinical practice. When hyperkalemia develops, clinicians often face difficult management decisions. One strategy is the addition of potassium binders to enable continuation of RAS inhibition, though this approach increases medication burden and polypharmacy. Alternatively, RAS inhibitors may be reduced or discontinued altogether, potentially forfeiting their kidney and cardiovascular benefits.

Other cardiometabolic therapies also have limitations in advanced CKD. SGLT2 inhibitors may be continued once initiated when eGFR declines below 20 mL/min/1.73 m², but current guidelines generally do not recommend initiating therapy at these lower levels of kidney function. GLP-1RAs offer another strategy for cardiovascular risk reduction, particularly in patients with diabetes. However, access remains limited for patients with CKD who do not have diabetes, as insurance coverage is typically restricted to approved indications.

Table 1. Summary of populations included in prior GLP-1RA cardiovascular outcome trials and the current evidence gap © Lavenburg and Mendoza.

Currently, GLP-1RAs are approved by the U.S. Food and Drug Administration for treatment of type 2 diabetes, chronic weight management, cardiovascular risk reduction in patients with cardiovascular disease, metabolic dysfunction-associated steatohepatitis, and chronic kidney disease in patients with diabetes. These indications exclude a large proportion of individuals living with CKD who do not have diabetes or a prior history of cardiovascular disease.

The findings from Yau and colleagues therefore raise an important clinical question: are we fully leveraging GLP-1RAs to reduce cardiovascular risk in CKD?

In the United States alone, an estimated 12 million adults have CKD without diabetes, representing approximately half of all individuals with CKD. As trials such as SELECT demonstrate cardiovascular benefit independent of diabetes, the possibility that GLP-1RAs may provide broader cardiometabolic protection warrants further investigation in non-diabetic CKD populations. Evaluation of the GLP-1RAs’ ability to reduce major adverse cardiovascular events in people with advanced kidney disease, dialysis dependence, and kidney transplantation, but without prior cardiovascular disease is particularly important considering the high prevalence of subclinical cardiovascular disease in this population.

As cardiometabolic therapies continue to evolve, the nephrology community faces a critical challenge: ensuring that patients with the most advanced kidney disease are not left behind as the therapeutic landscape advances.