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 HCPLive. 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.2,3

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.2,3

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).1,4

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; P = .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).1

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 (P < .001); the risk of major cardiovascular events was 18% lower (HR, 0.82; 95% CI, 0.68 to 0.98; P = .029); and the risk of death from any cause was 20% lower (HR, 0.80; 95% CI, 0.67 to 0.95; P = 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%).1

“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.”

Reference

1. 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. 2024;391(2). doi:https://doi.org/10.1056/nejmoa2403347

2. Stenvinkel P, Chertow GM, Devarajan P, et al. Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2. Kidney International Reports. 2021;6(7). doi:https://doi.org/10.1016/j.ekir.2021.04.023

3. Mihai S, Codrici E, Popescu ID, et al. Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome. Journal of Immunology Research. 2018;2018:1-16. doi:https://doi.org/10.1155/2018/2180373

4. Habib Yaribeygi, Maleki M, Tannaz Jamialahmadi, Amirhossein Sahebkar. Anti-inflammatory benefits of semaglutide: State of the art. Journal of clinical & translational endocrinology. 2024;36:100340-100340. doi:https://doi.org/10.1016/j.jcte.2024.100340

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