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CE / CME
Navigating the CKM Axis: Improving CKD and HF Outcomes With Novel and Emerging GMDT
European Learners: 0.50 EBAC® CE Credit
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Nurse Practitioners/Nurses: 0.50 Nursing contact hour
Released: December 19, 2025
Expiration: December 18, 2026
Activity
Current Limitations and Future Advances in Treating CKM Syndrome
Stefano Del Prato, MD:
About 20 years ago, there was a major revolution in the field of diabetes, particularly DKD. That was the introduction of RAAS blockade with ACE inhibitors and ARBs. There was an incredible therapeutic opportunity discovered with this because of these agents’ ability to block the synthesis of angiotensin II and ultimately prevent the later effects of aldosterone.
However, with chronic RAAS inhibition, there is potential for the activation of some compensatory mechanisms that leads to the resurgence of circulating aldosterone. This is due to compensatory enzymatic activity, chymase, and other local tissue activity that leads to the generation of aldosterone. Because of this, some of the beneficial effects of RAAS inhibition are diluted or limited.18 Therefore, we need alternatives in terms of therapy to achieve a constant and more preserved effect with the inhibition of aldosterone.
This has been also shown in certain clinical trials. For example, the RALES and EMPHASIS-HF trials showed that there is residual cardiovascular risk despite use of an ACE inhibitor or ARB because they do not effectively suppress aldosterone alone. Something needs to be done here.
One approach to this is to directly reduce the activity of aldosterone, which can be achieved through the action of MRAs. These agents were initially developed as steroidal MRAs, including eplerenone and spironolactone. They have proved to be quite effective in reducing cardiovascular mortality in patients with HF.19,20
However, the use of steroidal MRAs—including in patients with CKD—has been undermined by a major side effect: hyperkalemia. To try to avoid this effect, a new, nonsteroidal MRA has been developed. Finerenone has proven to provide a similar effect without the need for discontinuation due to hyperkalemia.21 Furthermore, the FIDELIO-DKD trial found that finerenone lowered the risk of CKD progression and adverse cardiovascular events in patients with CKD and T2D.22 Another study found that finerenone is associated with a less than 2% discontinuation rate due to hyperkalemia in patients with type 1 diabetes and CKD.23
There are additional opportunities to block the synthesis of aldosterone instead of preventing its interaction with the receptor. I am not a nephrologist, but Dr Tuttle can provide a better view on what lies ahead regarding new therapies for CKD and HF.
Emerging Therapies Targeting the CKM Axis
Katherine R. Tuttle, MD, FASN, FACP, FNKF:
This idea has been around for a while; the problem was making aldosterone synthase inhibition practical. That is because aldosterone synthase has 95% homology with cortisol synthase. The early attempts at this were complicated by a high rate of hypercortisolism, and 1 of the early aldosterone synthase inhibitors in development was repurposed to treat Cushing's syndrome because of this phenomenon.
With the wonders of modern medicinal chemistry, we now have highly selective agents for inhibiting aldosterone synthase. The 3 agents that are currently being studied are vicadrostat, baxdrostat, and lorundrostat. These agents have a ratio of activity anywhere from a greater than 100- to greater than 300-fold selectivity for aldosterone synthase over cortisol synthase.
That is now the main blockade moving forward, and there is renewed interest in going back to more complete aldosterone inhibition, in addition to conventional RAAS inhibition. This approach addresses all limbs of the system controlled to protect the heart and kidneys.
In a phase II study of patients with CKD, vicadrostat was highly efficacious at reducing albuminuria. That is good readout for kidney protection because lowered albuminuria is likely to predict the prevention of true clinical endpoints, such as kidney failure, 50% eGFR loss, and cardiovascular complications. The interesting thing is that patients were first randomized to receive empagliflozin vs placebo and then randomized again to receive vicadrostat vs placebo. Empagliflozin is an SGLT2 inhibitor that also is a first-line therapy for CKD. Therefore, it is notable that this randomized trial showed that combination therapy was even more effective than either agent alone.
Vicadrostat is now being evaluated in a large, phase III trial called EASi-KIDNEY (NCT06531824). This study is enrolling patients with CKD with or without diabetes. All patients will receive empagliflozin and conventional therapy with an ACE inhibitor or ARB, then they will be randomized to treatment with vicadrostat vs placebo. The primary endpoint is time to first occurrence of composite CKD progression, HF hospitalization, or cardiovascular death. This is important because the pathophysiology, epidemiology, and risks associated with HF and CKD are being recognized. The populations are so similar, and they overlap so much that this trial was designed to win on either cardiovascular or kidney outcomes. Finally, vicadrostat is also being studied in patients with HF in the EASi-HF trial.
Moving on to baxdrostat, researchers have completed some nice studies in patients with resistant or uncontrolled hypertension. They are now looking at its benefit in patients with CKD and hypertension.
Finally, lorundrostat is another agent that is being studied for cardiovascular and kidney outcomes, although it has mainly been looked at in uncontrolled or resistant hypertension.24 I just got back from the American Society of Nephrology’s Kidney Week meeting, where researchers presented the results of the phase II Explore-CKD trial. In patients with CKD and hypertension, lorundrostat was highly effective at reducing albuminuria.25 That outcome should then take this agent onto phase III trials, so we will see what comes of that.
The take-home message here is that the field is moving very quickly across the CKD and HF space.
Real-world Data Supplement Lack of Active-Controlled Trials
Michelle Kittleson, MD, PhD:
That was such a beautiful overview because it takes the investigational and scientific discovery thrill and turns it into something that can help patients. Aldosterone is bad. So how do we get rid of the aldosterone effect? Well the MRAs that you both discussed do not do it completely. How cool is it that with more precise drug design, we can better target the aldosterone synthase inhibitor. That was a beautiful overview of decades of advances boiled down so nicely by our experts.
Because I am a bit of a curmudgeon and skeptic, my hesitation is when I think about the HF population. We know that these MRAs work. Is a placebo-controlled trial acceptable or should it be evaluated in an active-controlled trial? Even in hypertension or HF, should MRAs be compared with these novel aldosterone synthase inhibitors or placebo?
Katherine R. Tuttle, MD, FASN, FACP, FNKF:
From a clinical and scientific standpoint, that is an excellent idea. But from a practical standpoint, it could be a hard hurdle to overcome because comparative effectiveness studies require an enormous number of patients to have the power to show a difference between the 2 agents. Furthermore, both are likely to be highly effective.
That is where real-world data can help. Within the context of electronic health records, they have their warts and blemishes, but clinical trial emulations can allow us to look at large numbers of patients who are treated in real-world practice. In turn, however, you might ask if these patients are the most relevant to clinical practice. For example, that is what is being done for incretin-based medications with or without SGLT2 inhibitors in patients with obesity. It is how researchers are evaluating the impact of these agents on cardiovascular and kidney outcomes.26 That is because it is unlikely we could ever do a true prospective, randomized, and comparative effectiveness study.
Efficacy vs Safety of Novel Therapies
Stefano Del Prato, MD:
I also think that HCPs may not need to compare efficacy, but rather the safety of each agent. The first steroidal MRAs are quite effective in terms of efficacy. The problem was their safety and the risks associated with hyperkalemia.
The pharmacologic research is trying to provide the same effect without or with a greatly reduced degree/rate of adverse events and, in particular, hyperkalemia. The inhibition of the aldosterone synthase may be a way to achieve that because these agents can reduce the amount of aldosterone that is released. They do not, however, interact with the receptor, which is still available to interact with endogenously produced mineralocorticoids of different types. That may help in preventing hyperkalemia.24
I am also fascinated by the fact that we started off with RAAS inhibition, but now we have emerging aldosterone-specific treatment, incretin-based AOMs, and SGLT2 inhibitors. We diabetologists have contributed a little to the field of cardiology and nephrology with the discovery of SGLT2 inhibitors. Now there is growing interest in incretin-based AOMs, which is an interesting story. These therapies reduced the risk for MACE by 13% and composite kidney outcome by 18% in patients with T2D.27 So, I think there is more to come.
Going back to the point made about head-to-head trials, the pivotal SURPASS CVOT trial compared tirzepatide vs dulaglutide in terms of MACE risk reduction. GLP-1 has this mysterious effect on the kidneys; whether it is direct or indirect is a topic for debate. Dulaglutide is a GLP-1 receptor agonist, whereas tirzepatide is a dual GIP/GLP-1 receptor agonist. We have these 2 incretin-based AOMs, and we do not understand completely their potential direct effects on the kidneys. But with clinically relevant outcomes, initial data show that these agents provide some level of kidney protection.28,29
I think that we are facing a new world here, and it likely will evolve into a combination of different agents that will allow us to be more successful in preventing the progression of CKD and HF. As we have said, this is a dangerous interplay that we want to avoid.
Other Emerging Therapies for CKM Syndrome
Michelle Kittleson, MD, PhD:
We have touched on some of the agents that are under investigation, as well as popular classes like SGLT2 inhibitors and incretin-based AOMs. Are there other classes that we should look forward to?
Katherine R. Tuttle, MD, FASN, FACP, FNKF:
Regarding inflammation, there are anti-inflammatory agents that are being evaluated on their ability to reduce residual risk beyond RAAS, GLP-1, or SGLT2. There is particular interest in the anti-interleukin–6 pathway. Ziltivekimab is being tested in the ZEUS trial (NCT05021835) that is enrolling patients with CKD and elevated high-sensitivity C-reactive protein. The primary endpoint comprises a 3-point MACE, and the main secondary endpoint is a kidney outcome.30 I agree with Dr Del Prato, I see this moving into combination therapy.
One key point is that this is going to lead us into a precision era, where maybe not every patient gets the same 4 or 5 therapies. In addition, the expansion of these regimens starts to become unfeasible in terms of cost, complexity, and safety. But we can have better and more precise approaches to care. For example, patients must have elevated high-sensitivity C-reactive protein levels to enroll in ZEUS. That is not everybody, but it encompasses a lot of people. With this, I think we are moving into an exciting era where we will be able to better phenotype patients via conventional clinical characteristics and risk factors, alongside biomarkers and imaging. At the kidney level, we in nephrology are doing more biopsies now because there is so much heterogeneity at the structural level.
Another thing that Dr Del Prato pointed out that I think is vital is the safety piece of it. Regarding some of the combination therapies, they are not only being combined to increase efficacy but to also improve safety. One example that is particularly relevant is the combined use of RAAS and SGLT2 inhibition, as SGLT2 inhibitors are associated with a reduced risk of hyperkalemia (HR: 0.89). This has been consistent across both CKD and HF.31
The other exciting possibility is that we can keep more patients on an aldosterone blocker if they are also taking an SGLT2 inhibitor because the risk for hyperkalemia is substantially mitigated. It is a magical combination not only for efficacy but for safety, too. I think that is something that HCPs do not always appreciate. As Dr Del Prato said, if we have newer therapies that block aldosterone and produce less hyperkalemia and then we combine them with an SGLT2 inhibitor, we may be able to keep more patients on these kidney and heart protective therapies for longer.
Key Takeaways and Closing Thoughts
Stefano Del Prato, MD:
Although we may have more effective and safer therapies, we should not forget about prevention because many of these conditions are preventable. I think that HCPs should take advantage of these new opportunities, but they should also remember to support prevention as much as possible.
Katherine R. Tuttle, MD, FASN, FACP, FNKF:
I totally agree. I think having these novel therapies moves us in that direction. As we discussed, there are data that show SGLT2 inhibitors and incretin-based AOMs, especially in CKD, prevent the onset of albuminuria, which is the first sign of kidney disease. But we have to get up to the implementation phase so patients are treated right.
Another thing that I think is near and dear to both of us is glycemic control. Although these newer therapies have organ protective effects that are independent of glucose, glucose control is important, especially for patients with T2D. That is the best way to prevent complications, and I think that message gets lost. To the point about prevention, especially among those with T2D or hypertension, all of this needs to be done in the company of good conventional risk factor control.
Michelle Kittleson, MD, PhD:
I could not have asked for better takeaways myself. The importance of implementation, precision medicine, and ultimately prevention. Everyone reading this module should go outside right now and take a 30-minute walk because that will help us be healthier. I also want to highlight how incredible it is that we can integrate guidelines with these emerging therapies. But ultimately, it comes down to the patient sitting in front of you and how you interpret the pathophysiology, evidence, guidelines, and future to give them the best care.