Add-On, Not Replacement: Semaglutide’s Role in Chronic Kidney Disease Management

More than a year after U.S. Food and Drug Administration approval of semaglutide (Ozempic®) to reduce the risk of kidney disease progression, kidney failure, and cardiovascular death in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD), its impact on clinical practice is becoming increasingly evident.

According to Rute Paixao, MD, a board-certified nephrologist with Cleveland Clinic in Florida, the therapy has already begun to reshape referral patterns and treatment strategies.

“Patients are increasingly requesting Ozempic by name, often prompted by media exposure or counseling from primary care providers about a medication that may help protect kidney function,” she says.

Clinical utility

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exert multiple effects relevant to CKD progression, including reductions in blood pressure, systemic inflammation, and albuminuria, as well as clinically meaningful weight loss.

Dr. Paixao describes semaglutide as an important addition to the nephrology armamentarium that complements, rather than replaces, established therapies. Reflecting its growing role, GLP-1–based therapies have been incorporated into the nephrology fellowship curriculum at Cleveland Clinic in Florida.

Evolving referral patterns

The availability of semaglutide has coincided with a broader shift in CKD care, driven by an expanding number of therapies capable of delaying disease progression and reducing the likelihood of dialysis or kidney transplantation.

Compared with two decades ago, nephrologists now have multiple pharmacologic options with demonstrated renal and cardiovascular benefit, reports Dr. Paixao. She completed her internal medicine residency and a nephrology fellowship at Cleveland Clinic Weston Hospital prior to joining the Department of Nephrology and Hypertension as a staff physician in 2003.

This therapeutic expansion has contributed to increased referrals from primary care, internal medicine, endocrinology, and cardiology, as well as from obesity and lifestyle medicine programs, like the one established at Weston Hospital.

At the same time, practice patterns are evolving. Whereas GLP-1 RAs were previously initiated primarily by endocrinologists, nephrologists are now increasingly prescribing these agents directly. Clinicians are also encountering more patients who are already receiving GLP-1 therapy for indications such as diabetes, obesity or sleep apnea.

As nephrologists assume a more active role in prescribing these medications, questions regarding their optimal integration into CKD treatment algorithms have become increasingly relevant.

Positioning within CKD treatment algorithms

Semaglutide should be incorporated within a stepwise, guideline-aligned treatment strategy for patients with diabetes-related CKD. Pharmacotherapies include:

• Renin-angiotensin system (RAS) inhibitors (ACE inhibitors or ARBs) to control blood pressure and reduce albuminuria.
• Sodium-glucose cotransporter-2 (SGLT2) inhibitors to reduce intraglomerular pressure and hyperfiltration.
• Nonsteroidal mineralocorticoid receptor antagonists (e.g., finerenone) to address inflammation and fibrosis.

These agents act through complementary mechanisms to preserve renal function. Within this framework, semaglutide is best considered an add-on therapy rather than a replacement for established treatments.

Dr. Paixao also notes potential implications for kidney transplant eligibility. Because many transplant programs require a body mass index (BMI) below 30 to 35, weight loss associated with GLP-1 therapy may help more patients qualify for transplantation while simultaneously delaying disease progression.

Patient selection and safety

Appropriate patient selection remains critical. Semaglutide is not suitable for all individuals, and clinicians must carefully weigh risks and benefits.

Common adverse effects include gastrointestinal symptoms such as nausea, vomiting, diarrhea, constipation, and abdominal pain. Gradual dose titration can improve tolerability.

Patients should be monitored closely for volume status and electrolyte balance, glycemic control, albuminuria, and estimated glomerular filtration rate (eGFR). “I typically reassess patients one month after initiation and then every three months once a stable dose is achieved,” Dr. Paixao explains.

Volume depletion is a key concern, as it may precipitate acute kidney injury. Monitoring should also include assessment of nutritional status, muscle strength, and bone health.

Contraindications include a history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2 (MEN 2), pancreatitis, significant gastroparesis, or gallbladder disease.

Supporting clinical evidence

Current indications for semaglutide are limited to patients with both CKD and T2D, although this may evolve with future research.

In the FLOW trial, semaglutide reduced the risk of kidney disease progression and major adverse cardiovascular events when added to standard care in patients with T2D and CKD.

Mechanistic insights from the REMODEL trial further support its role, identifying improvements in renal microvascular function through reduction of kidney fat, improved glomerular hemodynamics, attenuation of endothelial injury via metabolic reprogramming, and decreased inflammation and fibrosis.

Together, these findings suggest that semaglutide provides both renal and systemic benefits by addressing metabolic and inflammatory pathways underlying CKD progression.

Comparison with other GLP-1 therapies

Although semaglutide is currently the only GLP-1 RA with a specific indication for CKD progression, other agents in the class – such as liraglutide and dulaglutide – remain clinically relevant in the management of T2D and may offer renal benefits.

Clinical decision-making is often individualized. In patients already receiving a GLP-1 RA, continuation of the current therapy may be appropriate, particularly in the setting of formulary restrictions or adequate glycemic control.

Liraglutide, for example, is administered as a once-daily subcutaneous injection, which may affect adherence compared with once-weekly agents.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, is approved for T2D, weight management and obstructive sleep apnea. Findings from the TREASURE-CKD study suggest an association with reductions in albuminuria, as well, though its role in CKD management continues to be defined.

“For patients with diabetes and CKD, I generally prefer semaglutide given the strength of evidence from the FLOW trial,” Dr. Paixao notes, while acknowledging that continuation of alternative agents may be reasonable in selected cases.

Primary care’s role in early detection

Primary care providers remain central to early CKD detection and prevention of disease progression. High-risk populations include patients with hypertension, diabetes or prediabetes, coronary artery disease, and dyslipidemia.

Routine evaluation should extend beyond serum creatinine to include longitudinal assessment of eGFR and albuminuria. A doubling of the urine albumin-creatinine ratio (uACR), particularly above 30 mg/g and accompanied by declining eGFR, should prompt nephrology referral. “Any unexplained abnormal kidney function warrants specialist evaluation,” Dr. Paixao emphasizes.

Looking ahead

The introduction of semaglutide represents a meaningful advancement in the management of CKD in patients with T2D. When integrated into a comprehensive, guideline-directed treatment strategy, it offers both renal and cardiovascular benefit.

As clinical experience expands and evidence continues to evolve – including in populations without diabetes – GLP-1 receptor agonists are likely to play an increasingly central role in modifying CKD progression and improving long-term outcomes.