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GLP-1 RAs for CKD in T2D
Expanding Our Therapeutic Horizons: The Role of GLP-1 Receptor Agonists in Managing CKD in Type 2 Diabetes

Released: October 31, 2024

Expiration: October 30, 2025

David Charytan
David Charytan, MD, MSc
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Key Takeaways
  • Glucagon-like peptide-1 (GLP-1) receptor agonists show promise in slowing chronic kidney disease (CKD) progression and reducing cardiovascular events in patients with diabetes and CKD.
  • Evidence suggests that combining sodium-glucose cotransporter-2  inhibitors with GLP-1 receptor agonists may provide additive renal benefits.
  • Class effects and differences among GLP-1 agents require further study, but semaglutide shows strong efficacy for renal protection in diabetic CKD.

Introduction
The landscape of chronic kidney disease (CKD) management, particularly within the context of type 2 diabetes (T2D), has shifted dramatically over the past few decades. From a time when angiotensin receptor blockers (ARBs) alone were the main therapeutic option, we have now moved into an era where multiple classes of medications—sodium-glucose cotransporter-2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid receptor antagonists (MRAs), and most recently, glucagon-like peptide-1 (GLP-1) receptor agonists—demonstrate substantial benefits. The FLOW trial, released in 2024, marks a pivotal moment for nephrologists, reinforcing GLP-1 receptor agonists as a standard part of the therapeutic arsenal for CKD in patients with T2D. Here, I’ll discuss the FLOW trial results and the evolving role of GLP-1 receptor agonists in addressing CKD progression alongside related cardiovascular risks.

The Evolution of CKD Therapy in T2D
When I began my practice, our treatment options for diabetic kidney disease (DKD) were limited. The RENAAL and IDNT trials brought ARBs to the forefront, becoming the standard of care. Yet, for nearly 2 decades, there was minimal advancement. That changed with the emergence of SGLT2 inhibitors, starting with the CREDENCE trial in 2019, followed by EMPA-REG and the DAPA-CKD trials, which firmly established these agents for DKD.

Following these advancements, we saw promising results with nonsteroidal MRAs, especially finerenone, highlighted by FIDELIO-DKD, FIGARO-DKD, albeit with somewhat discordant results in FINEARTS-HF. These trials redefined nephrology, equipping us to better combat CKD progression in patients with diabetes. Adding to this paradigm shift is the arrival of GLP-1 receptor agonists, particularly semaglutide, which has shown renal benefits in patients with diabetes and obesity. However, the FLOW trial took this further by focusing specifically on a CKD patient population, finally demonstrating robust data on GLP-1s for hard renal and cardiovascular endpoints.

FLOW Trial: Expanding Our Therapeutic Toolkit
The FLOW trial examined the use of semaglutide in a high-risk population with T2D and CKD, either with a low estimated glomerular filtration rate (eGFR) and moderate albuminuria or a higher eGFR with significant albuminuria. These inclusion criteria were essential as they focused the trials on patients at risk of CKD progression and also with heightened risk of cardiovascular disease and related mortality. By addressing both renal and cardiovascular endpoints, FLOW speaks directly to the dual threats facing our patients, making it a landmark study in understanding how GLP-1 receptor agonists fit into our therapeutic toolkit.

FLOW’s results are clear: semaglutide significantly reduces the progression of kidney disease and cardiovascular events in high-risk populations. This evidence, along with existing data on other GLP-1 agents, positions GLP-1 receptor agonists as part of the emerging standard care approach for patients with diabetes and CKD.

Addressing Clinical Questions: Where Do GLP-1 Agonists Fit?
Despite these advancements, several clinical questions remain. As nephrologists, we now have 4 distinct classes of medications for managing CKD in T2D. Beyond ACE inhibitors and ARBs, we can use SGLT2 inhibitors, MRAs, and GLP-1 receptor agonists. However, these options raise questions regarding how to best combine these agents for our patients’ benefit. Below are some critical considerations:

1. Combining Agents: Are the Benefits Additive?
A primary question is whether combining these medications provides cumulative benefits. Evidence thus far suggests that combining SGLT2 inhibitors with GLP-1 receptor agonists does not significantly diminish their independent efficacy. In the FLOW trial, no strong attenuation of effect was seen when GLP-1 receptor agonists were combined with SGLT2 inhibitors, indicating potential additive benefits. However, it remains to be seen if all high-risk patients should be on all 4 agents. Even if efficacy is additive, tolerance and patient-specific factors may limit using all 4. While maximizing therapy to include all classes may be ideal for some, individual side effect profiles and patient preferences will guide our decision-making.

2. Class Effects: Do All GLP-1 Agonists Offer Equal Benefits?
 Unlike SGLT2 inhibitors, where class effects are fairly consistent across agents like canagliflozin, empagliflozin, and dapagliflozin, the nephroprotective effects of GLP-1 agonists may vary. Semaglutide has the strongest evidence for renal benefits thus far, yet we lack large, head-to-head trials comparing it with other GLP-1 receptor agonists for CKD outcomes and most agents have not been tested in trials powered specifically for kidney outcomes. This variability complicates our decisions, particularly when a patient is well-controlled on another GLP-1 agent like dulaglutide.

This nuance extends to tolerability: different agents in the GLP-1 class can have varied side effects and weight loss effects, which may influence their renal benefits indirectly. For example, we know that tirzepatide, a GIP/GLP-1 coagonist, is a potent agent for weight loss, but do not yet have strong data regarding its renal and cardiovascular benefits. Without conclusive data, it remains reasonable to prioritize semaglutide when renal protection is a primary goal, with the flexibility to switch agents as needed based on patient response.

3. GLP-1 Agonists and Obesity: Do Benefits Extend to Patients Without Obesity?
The role of GLP-1 receptor agonists in patients with CKD and without obesity raises further questions. Although weight loss can offer metabolic benefits in CKD, it is not required for renal benefit. The FLOW trial, which did not require obesity as an inclusion criterion, suggests that these agents may benefit patients regardless of weight status. Clinically, we may encounter challenges in convincing some patients to take injectable medications, particularly given potential side effects, but the renal protection alone makes GLP-1 receptor agonists worth considering in appropriate patients.

Conversely, we should be cautious with patients with underweight or those at risk of excessive weight loss. This is a population for whom close monitoring is essential, as we balance the risk of CKD progression against the potential adverse effects of weight loss in this group.

4. GLP-1 Agonists in CKD Without T2D: What’s the Potential?
Although most evidence supports GLP-1 receptor agonists for DKD, trials from the obesity literature suggest there could be benefits for patients with CKD without diabetes. Although unproven, this possibility remains intriguing and warrants further study. As nephrologists, we may see future opportunities to extend these therapies to other patients with CKD, broadening their utility in the population at large.

Addressing Interdisciplinary Concerns: A New Paradigm in CKD Care
There can be hesitation around prescribing these agents in nephrology, partly because of their long association with diabetes management. Yet, similar hesitation existed when SGLT2 inhibitors first came to market, and nephrologists quickly embraced these as tools for nephroprotection. Today, GLP-1 receptor agonists are in a similar position in that they provide renal benefits beyond glycemic control. Our approach must include embracing these agents as part of nephrology care, just as we routinely prescribe ARBs, which also have cardiovascular effects.

Certainly, interdisciplinary coordination remains important, especially for patients with complex glycemic needs or comorbidities. But ultimately, the availability of GLP-1 receptor agonists offers us more options to improve outcomes, a responsibility we should not shy away from as we focus on comprehensive nephrology care.

Conclusion
The introduction of GLP-1 receptor agonists to the CKD treatment paradigm marks a significant shift in nephrology. With compelling evidence from the FLOW trial, these agents offer hope for slowing CKD progression and addressing cardiovascular risks in patients with diabetes. However, as with any new therapy, questions about combining agents, class effects, the impact of obesity, and the role in CKD without diabetes will guide our application in practice. In time, further research will help refine our understanding, but the evidence already suggests these therapies can profoundly impact patient outcomes.

Your Thoughts
How are you currently integrating GLP-1 receptor agonists into CKD management for your patients with diabetes? Are there particular challenges or considerations you've faced in applying this therapy in practice? Let us know your experience and insights.

To learn more about this topic, join us for a live webinar on November 1, 2024, from 1:00-2:00 PM ET or November 6, 2024, from 12:00-1:00 PM ET where I will discuss this data in more detail with Dr Jennifer Green.

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With the new evidence supporting GLP-1 receptor agonists in CKD management for patients with T2D, how likely are you to incorporate these agents into your treatment plans for high-risk patients?

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