Vlado Perkovic is Dean and Scientia Professor of Medicine at UNSW Sydney. He is also a Professorial Fellow at The George Institute and a Staff Specialist in Nephrology at the Royal North Shore Hospital in Sydney.

Vlado Perkovic, MBBS, PhD

Interim Phase 3 VISIONARY Data Show Sibeprenlimab Preserved Kidney Function in IgA Nephropathy

Interim results from the phase 3 VISIONARY trial showed sibeprenlimab-szsi (VOYXACT), a selective APRIL inhibitor, was associated with preserved kidney function over 12 months in adults with primary 

at risk for disease progression, according to findings presented at the European Renal Association (ERA) Congress 2026 in Glasgow.¹

In a pre-specified interim analysis of 320 patients, with 152 receiving sibeprenlimab and 168 receiving placebo, the mean estimated glomerular filtration rate (eGFR) increased 0.7 mL/min/1.73 m² (95% Confidence Interval [CI], -0.9 to 2.3) from baseline with sibeprenlimab, compared with a decline of 4.8 mL/min/1.73 m² (95% CI, -6.3 to -3.3) with placebo, representing a treatment effect of 5.5 mL/min/1.73 m² (95% CI, 3.4 to 7.6).¹

"The magnitude of the benefits were a surprise to me. We saw such a profound protection of kidney function in the sibeprenlimab-treated patients compared with those on placebo that suggests we can completely transform the trajectory of kidney function in these patients moving forward," said Vlado Perkovic, MBBS, PhD, provost at the University of New South Wales, Australia, and a VISIONARY investigator, in an interview with 

What the Phase 3 VISIONARY Interim Data Showed

VISIONARY is an ongoing global phase 3 trial evaluating sibeprenlimab in adults with primary IgAN at risk for progression. The trial previously demonstrated a 51% reduction in proteinuria at 9 months with sibeprenlimab, supporting the potential role of APRIL inhibition as a disease-modifying approach in IgAN.

The current interim analysis evaluated kidney function outcomes over 12 months. A key secondary endpoint showed an annualized eGFR slope of -3.0 mL/min/1.73 m²/year (95% CI, -4.6 to -1.4) with sibeprenlimab compared with -7.6 mL/min/1.73 m²/year (95% CI, -9.1 to -6.1) with placebo, corresponding to a treatment effect of 4.6 mL/min/1.73 m²/year (95% CI, 2.5 to 6.8).¹

Perkovic noted that the placebo arm represented a high-risk population with rapidly progressive disease, while patients receiving sibeprenlimab experienced substantially slower kidney function decline. He said the magnitude of kidney protection observed exceeded expectations based on prior proteinuria findings.

According to Otsuka Pharmaceutical, the 12-month sibeprenlimab result meets the Kidney Disease: Improving Global Outcomes (KDIGO) benchmark for reducing annual eGFR decline to a normal physiologic rate of less than 1 mL/min/1.73 m² per year.¹

The trial will continue through the planned 24-month treatment period, with additional follow-up planned in an open-label extension study (NCT05248659).¹

Safety Findings Reported With Sibeprenlimab

Safety findings were generally comparable between treatment groups.¹ Infections occurred in 49% of patients receiving sibeprenlimab and 45% receiving placebo, while injection-site reactions occurred in 24% and 23%, respectively.¹

The most common infection was upper respiratory infection (15% vs 14%), and the most common injection-site reaction was erythema (13% vs 12%). Most adverse events were mild to moderate and resolved without treatment interruption.¹

Because sibeprenlimab reduces APRIL-mediated B-cell activity and immunoglobulin production, longer-term follow-up will be important to assess whether the safety profile remains consistent over 24 months.

Sibeprenlimab Mechanism and Regulatory History

Sibeprenlimab is a humanized monoclonal antibody that selectively binds APRIL, a cytokine involved in B-cell activation and production of pathogenic galactose-deficient IgA1 (Gd-IgA1), an upstream driver of IgAN.¹

Sibeprenlimab received FDA accelerated approval on November 25, 2025, for reducing proteinuria in adults with primary IgAN at risk for progression. Whether the therapy slows long-term kidney function decline has not yet been established.¹

The treatment is self-administered subcutaneously every 4 weeks. Otsuka has initiated a rolling supplemental Biologics License Application (sBLA) seeking traditional approval based on the VISIONARY trial's 24-month eGFR endpoint, which has not yet been reported.¹

Earlier phase 2 findings supporting selective APRIL inhibition were published in the 

IgAN is a chronic immune-mediated glomerular disease characterized by deposition of Gd-IgA1 immune complexes that drive progressive kidney injury.¹˒³ Although supportive care can slow progression, many patients continue to experience kidney function decline and may progress to kidney failure, highlighting the need for therapies targeting upstream disease mechanisms.

Perkovic emphasized that the ongoing 24-month analysis will be critical for confirming whether the observed kidney function benefit is sustained and for further evaluating long-term safety.

"The 24-month data is still going to be very important, and we're going to look to that to confirm these findings, and also to tell us more about the safety of these agents," Perkovic said.

Because VOYXACT's current indication is based on proteinuria reduction under accelerated approval, confirmation of clinical benefit through longer-term kidney outcomes will be necessary to support traditional approval.¹

Editor’s Note: Relevant disclosures for Perkovic include Boehringer Ingelheim, AbbVie, Inc., Bristol-Myers Squibb, Servier, Astellas Pharma US, Merck, Janssen Pharmaceuticals, GSK, and others.

V. Perkovic, H. Trimarchi, V. Tesar, R. Lafayette, M.G. Wong, J. Barratt, Y. Suzuki, A. Liew, H. Zhang, K. Carroll, V. Jha, A. Quevedo, S.H. Han, M. Praga, B. Chacko, M. Sahay, C.K. Cheung, L. Kooienga, M. Walsh, J. Xia, C. Fajardo, L. Shah, J. Hafkin, and D.V. Rizk. Sibeprenlimab in IgA Nephropathy — Interim Analysis of a Phase 3 Trial. The New England Journal of Medicine. 2025. Nejm.org. 

Otsuka Pharmaceutical Development & Commercialization, Inc. Otsuka presents positive interim phase 3 VISIONARY eGFR data showing VOYXACT preserved kidney function over 12 months in IgA nephropathy. Press release. June 2026. Accessed July 8, 2026.

Mathur M, Barratt J, Chacko B, et al. A phase 2 trial of sibeprenlimab in immunoglobulin A nephropathy. N Engl J Med. 2023;389(12):1111-1121. doi:10.1056/NEJMoa2305635.

Videos

Sibeprenlimab preserved kidney function over 12 months in adults with IgA nephropathy in interim phase 3 VISIONARY trial findings.

Kidney Compass: New 2-Year APPLAUSE-IgAN Data for Iptacopan at WCN 2026

The treatment landscape for IgA nephropathy (IgAN) continues to evolve at a rapid pace, and new data presented at the World Congress of Nephrology (WCN) in Yokohama, Japan, suggest a potential shift in how clinicians approach disease modification in high-risk patients. In this episode of 

, hosts Shikha Wadhwani, MD, MS, and Brendon Neuen, MBBS, PhD, spoke with Vlado Perkovic, MBBS, PhD, about newly presented 2-year eGFR slope data from the phase 3 APPLAUSE-IgAN trial evaluating iptacopan.

Perkovic explained that the trial built on previously published findings in the 

 showing a 38% reduction in proteinuria at 9 months, but emphasized that the key question remained whether this would translate into long-term kidney protection. As he noted during the discussion, the study enrolled a particularly high-risk population, with median proteinuria around 1.7 g/g and rapid progression in the placebo arm—where eGFR declined by more than 6 mL/min/1.73 m² per year. Both hosts highlighted how this rate of decline reinforced the urgency for new therapies.

According to Perkovic, treatment with iptacopan slowed that decline to just over 3 mL/min/1.73 m² annually, representing an approximately 50% reduction compared with placebo and a treatment effect that exceeded initial expectations. Wadhwani and Neuen both pointed to this magnitude of benefit as especially compelling, particularly given that the trial was powered for a much smaller difference. Perkovic further noted that the key secondary composite endpoint, 30% eGFR decline or kidney failure, was reduced by 43%, which the hosts emphasized as evidence that the slope findings are likely to translate into meaningful clinical outcomes.

Safety was another focal point of the conversation. Perkovic noted that adverse events, serious adverse events, and discontinuations were comparable between groups, with no deaths reported. While he acknowledged a numerical increase in infections with iptacopan, he emphasized that all cases were manageable and resolved with treatment, and there was no concerning signal for severe or encapsulated infections.

The discussion then shifted to how iptacopan might fit into an increasingly complex treatment paradigm. Wadhwani raised the question of where complement inhibition would sit alongside existing therapies and evolving guideline recommendations, prompting Perkovic to stress that foundational treatments such as renin-angiotensin system inhibitors and SGLT2 inhibitors remain essential. However, he noted that patients receiving SGLT2 inhibitors in the trial still derived clear additional benefit, supporting the idea of combination therapy.

Neuen also highlighted the importance of understanding eGFR slope dynamics, asking whether acute versus chronic effects might influence interpretation of treatment benefit. In response, Perkovic explained that, unlike some other therapies, iptacopan did not appear to have an acute hemodynamic effect on eGFR, resulting in a more linear and interpretable slope over time, a point both hosts noted could simplify comparisons across agents.

Looking ahead, all three speakers emphasized the likelihood that combination approaches will be necessary, particularly for patients with high baseline proteinuria. As Perkovic pointed out during the exchange, achieving guideline-recommended targets may require multiple therapies with complementary mechanisms. Wadhwani further stressed the importance of earlier diagnosis and intervention, while Perkovic suggested that evolving data may prompt clinicians to reconsider biopsy thresholds and treatment timing.

Editors’ Note: Relevant disclosures for 

 include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for

include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Relevant disclosures for

include Boehringer Ingelheim,AbbVie, Inc., Bristol-Myers Squibb, servier, Astellas Pharma US, Merck, Janssen Pharmaceuticals, GSK, and others.

Podcasts

Vlado Perkovic, MBBS, PhD, discusses APPLAUSE-IgAN data showing iptacopan reduced eGFR decline and lowered kidney event risk in IgA nephropathy.

Just 1 year ago, semaglutide (Ozempic) was approved by the 

This approval marked an important milestone as the first GLP-1 receptor agonist to reduce the risk of worsening kidney disease, kidney failure, and death due to cardiovascular disease in these patient populations.

Semaglutide, initially developed by Novo Nordisk, received its first approval from the FDA under the name Ozempic on December 5, 2017. Its first indication was as an injection of 0.5 mg or 1 mg once weekly for glycemic control in patients with type 2 diabetes (T2D) – as an adjunct to diet and exercise.

Since then, semaglutide has exploded into nearly every related field. Glucagon-like peptide-1(GLP-1) receptors were discovered everywhere from the pancreas and the gastrointestinal tract to the heart, kidney, and liver. GLP-1 receptor agonists were quickly introduced into nephrology and cardiology, expanding their indications over the years to meet need in a variety of organs. Semaglutide has been at the forefront of this expansion due to its comparatively superior reductions of A1c, glucose, and overall weight.

In 2020, semaglutide received approval for the reduction of cardiovascular risk in patients with T2D, marking its entry into the cardiology sphere. In January of 2025, semaglutide became the first GLP-1 receptor agonist approved for worsening kidney disease, kidney failure, and death due to cardiovascular disease in patients with T2D and chronic kidney disease (CKD). This approval marked semaglutide’s entry into the full cardio-kidney-metabolic (CKM) disease spectrum, addressing mortality and worsening outcomes for major contributing diseases.

Now, just over a year after semaglutide’s approval for CKD, the editorial team at 

 has gathered insights from key clinicians across the CKM spectrum to discuss how this revolutionary drug overhauled the treatment landscape for kidney disease from all sides.

Semaglutide’s revolutionary impact on the endocrinology field cannot be understated. Despite not being the first, for years, this GLP-1 RA was the best method of reducing 3 major contributing factors to mortality in T2D. A1c reduction, glucose management, and weight loss saw substantial improvements as a result of the drug’s approval. However, semaglutide’s efficacy now extends far beyond T2D.

“I think that, sometimes, there’s hesitancy around starting a new therapy because the clinicians don’t know if other specialties will be on board,” Diana Isaacs, PharmD,

the director of Education and Training in Diabetes Technology and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and a member of 

 in an interview. “Now, we’re seeing through notes that nephrology is saying, ‘Why don’t you consider using semaglutide?’ And when they come to me as part of endocrinology, I see that, and I’m encouraged to use it. I think semaglutide really has enhanced team-based care in that we’re all on board.”

Isaacs went on to describe how semaglutide’s CKD approval provided a major paradigm shift for the American Diabetes Association’s standards of care.

“By showing its positive outcomes, particularly in people with kidney disease, semaglutide was paradigm-changing for the ADA Standards of Care and for our guidelines in that, previously, SGLT2 inhibitors were preferred for people with T2D and CKD,” Isaacs said. “Now, it’s either SGLT2 inhibitors or GLP-1 therapy – in practice, we’re now utilizing both of them.”

The Cardio-Kidney-Metabolic Landscape of Semaglutide

On October 9, 2023, the American Heart Association (AHA) released a presidential advisory regarding CKM syndrome, highlighting the interplay between metabolic risk factors, the cardiovascular system, and CKD. This syndrome has a significant impact on morbidity and mortality – poor CKM health, which is prominent among the American population, is associated with increased incidence of cardiovascular disease events.

“CKM syndrome encompasses the entire spectrum of risk, starting from people who have no risk factors or cardiovascular disease, going all the way through 

, vascular risk factors, subclinical disease, and clinical cardiovascular disease,” Janani Rangaswami, MD, professor of medicine at George Washington University and co-chair of the Scientific Advisory Group of the AHA’s presidential advisory on CKM Health, told 

 in an exclusive interview. “In any healthcare setting, the interplay between cardiology, nephrology, and endocrinology is the bulk of practice. In my practice, when I see individuals with kidney disease, diabetes alone is responsible for close to 50% of the cause of that kidney disease. When you add in obesity, metabolic dysfunction, and hypertension, all of these come together very heavily.”

Semaglutide’s approval for CKD effectively provided a bridge between all 3 specialties. When coupled with its initial diabetes indications and its cardioprotective effect, the drug was approved to tackle CKM syndrome on all fronts. Additionally, semaglutide’s efficacy when combined with SGLT2 inhibitors and RAAS blockade in patients with both CKD and high cardiovascular risk made it an effective tool for bolstering the protective effects of existing therapies. In this collaborative space between cardiology and nephrology, semaglutide became something of a miracle drug.

“While GLPs like semaglutide are very effective for A1c management and weight management, the FLOW trial really showed that this therapy saved lives, hearts, and kidneys,” Rangaswami said. “So now these therapies do multiple things; they’re addressing everything from improving lifespan to improving health outcomes, heart and kidney, and even beyond.”

The Bilateral Relationship Of CKD and Obesity

CKD remains one of the most common and serious complications of T2D, with obesity increasingly shaping disease trajectory, transplant eligibility, and therapeutic decision-making.

As global rates of obesity and CKD continue to climb, clinicians are paying closer attention to how excess adiposity directly affects renal physiology, independent of diabetes and hypertension.

“In obesity, metabolic demands increase, so the kidneys have to increase glomerular filtration rate and renal plasma flow to meet those demands. If nephron number is already reduced, the remaining nephrons have to work even harder. That leads to increased pressure inside each nephron, which causes barotrauma, scarring, and increased urine protein excretion,” explained Holly Kramer, MD, a nephrologist at Loyola University Medical Center and editor in chief of 

. “Severe obesity can also directly contribute to nephron loss through inflammatory effects. Often, obesity is accompanied by diabetes and hypertension, which further accelerate kidney disease progression.”

At BMI levels >40, systemic inflammation rises, adipokine signaling alters renal hemodynamics, and insulin resistance further increases glomerular stress. These processes frequently coexist with hypertension and T2D, amplifying cumulative kidney injury.

Despite this convergence of risk factors, CKD is often managed reactively rather than proactively. By the time patients reach end-stage kidney disease (ESKD) and require maintenance dialysis, obesity can create additional barriers to transplantation because of higher perioperative and postoperative complication risks. Increasingly, clinicians are focused on intervening earlier in the disease course.

In this landscape, GLP-1 agonists have emerged as a treatment strategy for patients with CKD and T2D, especially as a anti-imflammatory marker.

Subsequent research has shown an association of persistent low‑grade inflammation with worsened clinical outcomes in CKD, including faster eGFR decline, higher cardiovascular risk, and increased all‑cause mortality. Additionally, inflammation is a driving factor in the development and progression of T2D and its complications.

The reduction of inflammatory markers, such as CRP, has been highlighted as a potential clinical strategy to protect kidney function. In turn, semaglutide has been associated with reductions in CRP and other inflammatory markers independent of glycemic effects.

“GLP-1 receptor agonists have become another pillar we can use for people with chronic kidney disease. I see them being used as an adjunct to other medications, such as SGLT2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists. Especially when used in conjunction with those therapies, I think they have kidney benefits,” said Kramer. “They reduce urine albumin-to-creatinine ratios. If patients lose weight, we improve blood pressure control. If they have type 2 diabetes, glucose control improves. All of those factors help slow kidney disease progression, so I think GLP-1 receptor agonists are a great addition to our existing armamentarium.”

Where Obesity, CKD, and T2D Intersect with Semaglutide: The FLOW Trial

The approval for semaglutide for patients with T2D and CKD was based on data from FLOW, a phase 3b, multinational, parallel-group, double-blind, randomized, placebo-controlled trial investigating the effects of 1.0 mg once weekly semaglutide, a once-weekly GLP-1RA, on kidney outcomes in participants with CKD and T2D.

“I think it has largely removed the uncertainty that once existed around the effects of GLP-1 receptor agonists on kidney function and has clearly demonstrated that these agents are kidney-protective,” FLOW study investigator, Vlado Perkovic, MBBS, PhD, and provost at the University of New South Wales, told 

 “That, in turn, has informed guideline updates and helped the clinical community accept GLP-1 receptor agonists as a fourth pillar of care for people with diabetic kidney disease. That is a major advance.”

FLOW included 3533 participants with T2D and CKD, with the composite primary endpoint being time to first kidney failure, defined as persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy, persistent ≥50% reduction in eGFR, or death from kidney or cardiovascular causes.

Over a median follow-up of 3.4 years, semaglutide reduced the risk of a primary outcome event by 24% compared with placebo (331 vs 410 first events; HR, 0.76; 95% CI, 0.66-0.88; P = .0003). Similar reductions were observed for the kidney-specific composite (HR, 0.79; 95% CI, 0.66-0.94) and cardiovascular death (HR, 0.71; 95% CI, 0.56-0.89).

All confirmatory secondary outcomes favored semaglutide, including a slower annual decline in eGFR (difference, 1.16 mL/min/1.73 m²; P <.001), an 18% reduction in major cardiovascular events (HR, 0.82; 95% CI, 0.68-0.98; P = .029), and a 20% lower risk of all-cause mortality (HR, 0.80; 95% CI, 0.67-0.95; P = .01). Serious adverse events occurred in 49.6% of the semaglutide group versus 53.8% with placebo.

Beyond Weight Loss: Inflammation and Future Directions of Semaglutide

Perkovic emphasized that FLOW was not intended to be a weight-loss trial, with a broad range of BMIs among participants, including 25% with BMI <27. While GLP-1 receptor agonists, especially semaglutide and emerging combination therapies, present efficacy regarding weight loss, FLOW indicated semaglutide’s specific kidney benefits not simply attributable to obesity treatment.

However, Perkovic also remarked on patterns from the FLOW trial’s participant population, where the mean BMI was 32. Additionally, in the CREDENCE trial, which also evaluated patients with T2D and CKD, the mean BMI was 31. This highlights obesity as a prevalent, rather than incidental, comorbidity in contemporary CKD populations. Taken together, these findings underscore the importance of considering body weight as a core component of CKD risk assessment, rather than a secondary concern.

“What that tells us is that people with diabetes and kidney disease are, on average, significantly overweight and often fall into the obese category. Many of these patients are therefore likely to benefit from weight loss as well,” explained Perkovic. “These therapies address multiple, parallel pathologies that commonly coexist in our patients, which makes them particularly exciting. It also raises the question of whether more potent agents that induce greater weight loss might confer additional kidney benefits, something that still needs to be tested.”

As obesity, T2D, and CKD increasingly converge in clinical practice, therapies capable of targeting overlapping metabolic, hemodynamic, and inflammatory pathways may redefine standard care. For clinicians managing complex kidney disease populations, GLP-1 receptor agonists now represent not simply a metabolic adjunct, but a foundational component of comprehensive CKD risk reduction.

Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others.

Rangaswami reports relevant disclosures with the Veterans Health Administration, Boehringer Ingelheim, Bayer, Procyrion, and the American Heart Association.

Kramer reports relevant disclosures with Bayer, Alexion, American Journal of Kidney Disease, National Kidney Foundation, and others.

Perkovic reports relevant disclosures with AstraZeneca, Bayer, Boehringer Ingelheim, and others.

Novo Nordisk. Novo Nordisk Receives FDA Approval of OZEMPIC (semaglutide) Injection For the Treatment of Adults with Type 2 Diabetes. 

. December 5, 2017. Accessed February 19, 2026. 

https://www.prnewswire.com/news-releases/novo-nordisk-receives-fda-approval-of-ozempic-semaglutide-injection-for-the-treatment-of-adults-with-type-2-diabetes-300567052.html

Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. 

Novo Nordisk. FDA approves Ozempic for cardiovascular risk reduction in adults with type 2 diabetes and known heart disease, updates Rybelsus label. 

. January 16, 2020. Accessed February 19, 2026. 

https://www.prnewswire.com/news-releases/fda-approves-ozempic-for-cardiovascular-risk-reduction-in-adults-with-type-2-diabetes-and-known-heart-disease-updates-rybelsus-label-300988672.html

Anderer S. FDA approves semaglutide to reduce risk of kidney disease progression. 

Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-kidney-metabolic health: A presidential advisory from the American Heart Association. 

Furth SL, Colhoun HM, Kanbay M, et al. The relationship between obesity and chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 

. Published online September 2025:S0085-2538(25)007744. doi:

https://doi.org/10.1016/j.kint.2025.09.019

Good PI, Li L, Hurst HA, et al. Low nephron endowment increases susceptibility to renal stress and chronic kidney disease. 

https://doi.org/10.1172/jci.insight.161316

Wang H, Fan K, Ning Y, et al. Hypertension and BMI as Mediators of Type 2 Diabetes-Induced CKD: Insights from an Integrative Multi-Database Study. 

Perkovic V. Inflammation Emerges as Promising CKD Treatment Target, With Vlado Perkovic, MBBS, PhD. HCPLive. Published February 9, 2026. Accessed February 20, 2026. 

https://www.hcplive.com/view/inflammation-emerges-as-promising-ckd-treatment-target

Rossing P, Baeres FMM, Bakris G, et al. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. 

Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. 

Pruijm M, Belmar N, Bjornstad P, et al. REMODELing mechanistic trials for kidney disease: a multimodal, tissue-centered approach to understand the renal mechanism of action of semaglutide. 

https://doi.org/10.1016/j.kint.2025.10.005

Articles

Semaglutide has expanded from a T2D glycemic agent to a cardio-kidney-metabolic therapy, culminating in FDA approval for reducing CKD progression, kidney failure, and CV death in T2D with CKD. Cross-specialty adoption is accelerating, reshaping guideline positioning alongside SGLT2 inhibitors and enabling combination strategies with RAAS blockade and nsMRAs. Obesity is increasingly recognized as a direct mediator of renal injury via hyperfiltration, inflammation, and nephron stress, influencing progression and transplant candidacy. FLOW established kidney and survival benefits beyond weight loss.

1 year into real-world use, 4 clinicians discuss how semaglutide is transforming the endocrinology, nephrology, and cardiology landscape.


1 Year After CKD Approval, Semaglutide Transforms Diabetes, Kidney, and Heart Care

Inflammation Emerges as Promising CKD Treatment Target, With Vlado Perkovic, MBBS, PhD

Recent trials, including FLOW and SELECT, have reinforced the suggested link between inflammation and chronic kidney disease (CKD) progression.1

Although FLOW was not designed to isolate an inflammatory mechanism, the parallel improvements in C‑reactive protein (CRP), kidney outcomes, and cardiovascular events reinforce inflammation as a plausible, and potentially targetable, facet of CKD management.

“We now know that GLP‑1 receptors are expressed in the kidney, often on immune cells, and in FLOW we saw a roughly 40% reduction in CRP,” explained Vlado Perkovic, MBBS, PhD, provost at the University of New South Wales, in an interview with 

. Taken together, these findings suggest that GLP‑1 receptor agonists have an important anti‑inflammatory effect that may be at least partly independent of their impact on weight loss, which itself would be expected to reduce inflammation. Inflammation clearly appears to be an important part of the story, and newer studies such as the REMODEL trial will help us understand this axis in more detail.”

Since the 1990s, investigators have recognized the central role inflammation plays in the pathogenesis and progression of CKD. Early work focused on monocyte‑derived interleukin‑1 (IL‑1), with investigators proposing IL‑1 release as a key initiating event underlying major complications and increased mortality in patients undergoing dialysis.

Subsequent research has shown an association of persistent low‑grade inflammation with worsened clinical outcomes in CKD, including faster eGFR decline, higher cardiovascular risk, and increased all‑cause mortality. Multiple factors contribute to the inflammatory burden in CKD, including pro‑inflammatory cytokines, oxidative stress and metabolic acidosis, chronic or recurrent infections, altered adipose tissue metabolism, and gut microbiota dysbiosis.

Collectively, these findings, together with the historical burden of inflammation in patients with CKD, have highlighted the reduction of inflammatory markers, such as CRP, as a potential clinical strategy to protect kidney function.

Semaglutide, a GLP-1 receptor agonist, has been associated with reductions in CRP and other inflammatory markers independent of glycemic effects. Potentially supporting this concept, the FLOW study, which evaluated patients with type 2 diabetes and CKD, demonstrated that semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes. Over a median follow‑up of 3.4 years, investigators randomized 3533 participants to receive either semaglutide (n = 1767) or placebo (n = 1766).

Upon analysis, investigators observed a 24% reduction in the risk of the primary outcome in the semaglutide group compared with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; 

= .0003). Similar benefits were seen for a composite of the kidney‑specific components of the primary outcome (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (HR, 0.71; 95% CI, 0.56 to 0.89).

The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decline) by 1.16 ml per minute per 1.73 m² in the semaglutide group (

< .001); the risk of major cardiovascular events was 18% lower (HR, 0.82; 95% CI, 0.68 to 0.98; 

 = .029); and the risk of death from any cause was 20% lower (HR, 0.80; 95% CI, 0.67 to 0.95; 

 = 0.01). Serious adverse events occurred in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs 53.8%).

“Ongoing trials of other anti‑inflammatory agents, such as interleukin‑6 (IL‑6) receptor antagonists, may also help clarify whether inflammation reduction alone can protect kidney function,” said Perkovic. “Those data could shed light on how much the CRP reductions seen in FLOW contributed to the observed kidney benefits. For now, what we can say is that the mechanism is likely multifactorial and still not fully understood.”

Perkovic also highlighted the SELECT trial, which evaluated semaglutide in patients with obesity but without diabetes. Investigators in SELECT reported improvements in several kidney parameters, including reductions in albuminuria and slower kidney function decline, findings that were broadly consistent with the renal effects observed in FLOW. However, SELECT was not designed to formally test kidney outcomes, he noted.

“This is an important and exciting area for future research. With SGLT2 inhibitors, we saw kidney benefits that were just as robust in people without diabetes as in those with diabetes, suggesting glucose‑independent mechanisms. I suspect we will see something similar with GLP‑1 receptor agonists,” said Perkovic. “Ideally, future trials will demonstrate kidney protection in non‑diabetic chronic kidney disease as well, allowing us to expand the therapeutic toolbox for those patients.”

Editor’s Note: Perkovic reports relevant disclosures with AbbVie, AstraZeneca, Bayer. 

Perkovic V. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. 

New England journal of medicine/The New England journal of medicine

Stenvinkel P, Chertow GM, Devarajan P, et al. Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2. 

https://doi.org/10.1016/j.ekir.2021.04.023

Mihai S, Codrici E, Popescu ID, et al. Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome. 

Habib Yaribeygi, Maleki M, Tannaz Jamialahmadi, Amirhossein Sahebkar. Anti-inflammatory benefits of semaglutide: State of the art. 

Journal of clinical & translational endocrinology

https://doi.org/10.1016/j.jcte.2024.100340

FLOW/SELECT suggest. GLP-1 receptor agonists may protect kidneys beyond glucose control