GLP-1 Receptor Agonists Reshape CKD Treatment Sequencing, With Pranav Garimella, MD

As chronic kidney disease (CKD) management continues to evolve beyond glucose control alone, GLP-1 receptor agonists are increasingly being incorporated into treatment strategies aimed at reducing both kidney and cardiovascular risk.

According to Pranav Garimella, MD, of the American Kidney Fund, the drug class is no longer viewed solely as a diabetes therapy but as an important component of comprehensive CKD management alongside renin-angiotensin system (RAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptor antagonists (MRAs).

"GLP-1 [receptor agonists] no longer belong just in the treatment of diabetes, but they are integral to preventing heart failure and kidney disease progression," Garimella said.

GLP-1 Receptor Agonists and the Cardiovascular-Kidney-Metabolic Model

Garimella described a shift away from treating the heart, kidneys, and metabolic system as separate entities, instead emphasizing their overlapping risk factors and interconnected disease pathways.

"We're no longer thinking about these as isolated organ systems," Garimella said. "They're all connected."

This perspective aligns with the growing emphasis on cardiovascular-kidney-metabolic (CKM) syndrome in contemporary cardiovascular and kidney care.

Supporting this evolving treatment paradigm, the FLOW trial demonstrated semaglutide reduced the composite risk of major kidney outcomes, cardiovascular events, and death from any cause by 24% compared with placebo among patients with type 2 diabetes and CKD. Secondary analyses also showed an 18% reduction in major adverse cardiovascular events and a 20% reduction in all-cause mortality, reinforcing the cardiorenal benefits of GLP-1 receptor agonists beyond glycemic control alone.¹

Identifying Patients Most Likely to Benefit

According to Garimella, patients with type 2 diabetes, obesity, albuminuria, and elevated cardiovascular risk are among those most likely to benefit from GLP-1 receptor agonist therapy because of the class’s established cardiovascular and kidney protective effects.

However, he emphasized that careful patient selection remains essential.

"If you have patients who have a history of diabetic gastroparesis and maybe cannot stay hydrated, GLP-1 receptor agonists may not be the best drugs as first-line therapy," Garimella said.

He noted that gastrointestinal adverse effects, including appetite suppression, nausea, vomiting, and dehydration, may increase the risk of acute kidney injury in susceptible patients. While these individuals may still benefit from treatment, he said clinicians should weigh the potential benefits against tolerability and safety on a case-by-case basis.

Sequencing GLP-1 Therapy in Contemporary CKD Care

Asked where GLP-1 receptor agonists fit within current CKD management, Garimella described an approach that begins with RAS inhibition for patients with diabetes, hypertension, and albuminuria, followed by SGLT2 inhibitors as foundational kidney-protective therapy. For patients with persistent proteinuria despite optimized treatment, nonsteroidal MRAs may then be added.

Garimella described GLP-1 receptor agonists as complementary to these therapies and, in selected patients, a potential alternative to nonsteroidal MRAs—particularly among individuals with obesity, obstructive sleep apnea, or elevated heart failure risk who do not have substantial proteinuria.

His approach generally aligns with the 2024 KDIGO Clinical Practice Guideline for CKD, which recommends RAS inhibition and SGLT2 inhibitor therapy for appropriate patients with CKD while incorporating emerging evidence supporting nonsteroidal MRAs and GLP-1 receptor agonists for kidney protection.²

References

1. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121. doi:10.1056/NEJMoa2403347.

2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S).