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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
4 Pillars of GDMT for HF
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC:
I am going to start by discussing the pillars of GDMT for HF. The latest guidelines for heart failure with reduced ejection fraction (HFrEF)—that is, an ejection fraction of 40% or less—strongly recommend treatment with quadruple therapy. These 4 pillars of GDMT include:
- Angiotensin receptor–neprilysin inhibitor (ARNI) (preferred); angiotensin-converting enzyme (ACE) inhibitor or ARB if ARNI is contraindicated, intolerable, or inaccessible
- β-blocker
- MRA
- SGLT2 inhibitor
Combining treatment with these agents offers patients greater potential for improved outcomes.1 For example, it has been estimated that quadruple therapy reduces patients’ mortality risk by 73% vs no therapy over 2 years.2 Furthermore, quadruple therapy may extend patients’ survival by 1.4-6.3 years compared with conventional treatment (ie, ACE inhibitor/ARB plus β-blocker).3
What about heart failure with preserved ejection fraction (HFpEF)? First, this categorization includes those with an ejection fraction of 50% or higher. Then there is the new categorization: heart failure with mildly reduced ejection fraction (HFmrEF). And this group includes those with an ejection fraction between 40% and 50%.
The guidance has been a little bit less clear for treating HFpEF and HFmrEF due to a lack of high-quality evidence for all GDMT drug classes. For this reason, the 2022 guidelines only reported 1 completed trial for SGLT2 inhibitors in this patient population. Although these agents got a 2-way indication for all of HF in the current guidelines, the evidence in HFpEF and HFmrEF is not as robust as HFrEF. Since then, another major trial evaluating SGLT2 inhibitors in HFpEF and HFmrEF has been completed. Therefore, it is likely the guidance will be updated to include a stronger recommendation for SGLT2 inhibitors in HFpEF and HFmrEF.4,5
In addition to the expansion of SGLT2 inhibitor use in HF, we have seen finerenone (a nonsteroidal MRA) receive FDA approval to treat adults with HF and an ejection fraction of 40% or greater.6 In patients with obesity and HFpEF, there are now several clinical trials looking at incretin-based antiobesity medications (AOMs) (ie, semaglutide and tirzepatide). These trials are showing incretin-based AOMs can improve quality of life as well as reduce worsening HF events and composite cardiovascular-related death or worsening HF in patients with HFpEF and obesity.7
As you can see, we are starting to move to a pillared approach as well in GDMT for HFpEF and HFmrEF, with SGLT2 inhibitors and nonsteroidal MRAs being foundational with the use of ARNIs. Perhaps, incretin-based AOMs will become foundational for patients with HFpEF and obesity.
That is a basic summary of current GDMT for HF across the ejection fraction spectrum. Dr Levin will discuss further to help us understand if these pillars apply for patients with CKD as well. I do know that the 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend SGLT2 inhibitors and ACE inhibitors or ARBs as first-line therapy for all adults with CKD regardless of their diabetes status.8 So those are potentially 2 pillars of GDMT for this population.
Finally, for patients with diabetic kidney disease (DKD) and albuminuria, there is now strong evidence from clinical trials that supports the use of nonsteroidal MRAs and GLP-1 receptor agonists as 2 additional pillars in DKD.9,10 So the concept of 4 pillars in GDMT for patients with CKD and T2D is starting to emerge as well.
Quadruple Therapy Saves Lives!
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC:
A key reminder in HF care—this is an extreme risk condition with prognosis similar to cancer. Therefore, healthcare professionals (HCPs) must harness the early and additive benefits of quadruple therapy. The guidance is to start all therapies, at low doses at least, either simultaneously or near simultaneously with rapid sequencing. Titrating to target doses is important, but HCPs should only do so after all 4 therapies are initiated.1
Stages of CKM Syndrome
Adeera Levin, MD, FRCPC:
Yes, the treatment landscape is expanding and evolving rapidly in the DKD and CKD space. KDIGO should revamp their guidelines to be inclusive of nonsteroidal MRAs and incretin-based AOMs due to an abundance of emerging data. These therapies have demonstrated improvements in key composite kidney endpoints, including in patients at high risk for HF. For HFpEF in particular, and as Dr Michos mentioned, finerenone and semaglutide have shown proven benefit in reducing risk of major adverse cardiovascular events (MACE) and, in some cases, mortality among patients with CKD and T2D.9,10 Therefore, the CKD guidelines need updating to include these data and emerging therapies.
SGLT2 Inhibitors: Cardiorenal Protection Mechanisms
Adeera Levin, MD, FRCPC:
Outside of treating patients with comorbid T2D, the data are not quite as strong for nonsteroidal MRAs and incretin-based AOMs as they are for SGLT2 inhibitors,8 but data on these therapies are emerging and evolving. In addition, I expect new trials to be reported on over the next 1-3 years, demonstrating the value of adding incretin-based AOMs and nonsteroidal MRAs to patients’ treatment plans.
What is most remarkable is how we traditionally use these therapies in CKD. The rapid, sequential addition of therapies and titrating them to their maximum dose has not been articulated as well within nephrology. I think cardiology has adopted this appropriately in HF care. Now, it is just a matter of applying this timing concept for CKD across nephrology.
There is some beautiful modeling that demonstrates up to a 40% risk reduction in cardiovascular, kidney, and mortality outcomes with quadruple therapy. The problem is that we do not know if every patient needs quadruple therapy initiated all at once or sequentially. In addition, the optimal time to add and subtract these therapies must be addressed. There is no question that chapter 3 of the CKD guidelines needs to be updated, which will be important for HCP adoption.
Unintended Harms of “First, Do No Harm”
Adeera Levin, MD, FRCPC:
In discussing the simultaneous and rapid sequencing of therapy, it is critical that HCPs avoid this whole notion that people are either “too sick” or “not sick enough” to receive these therapies. For example, decreased levels of proteinuria put patients at a lower risk for developing kidney disease, but studies of patients with this decreased risk do not always show the hard outcomes we want to see.
However, a negative change in eGFR trajectory is well established to correlate with kidney failure risk.8 Therefore, HCPs must be careful because these patients are at high risk for adverse cardiovascular and kidney events. Which one will occur first? We do not know.
The take-home message is this: if you think patients should be on a specific therapy, then you should find a reason to put them on it, not a reason to keep them off it. Why not use an SGLT2 inhibitor first thing? The other therapies can come after.
Dr Michos, is there a similar perspective shared in cardiology for treating HF?
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC:
Yes, unfortunately, there is an established risk–treatment paradox in HF, including among those with comorbid CKD. In basic terms, the patients who are at higher risk are less likely to be treated with evidence-based GDMT.
We now have data from clinical trials like SOLOIST-WHF and EMPULSE that support the safety and benefit of starting in-hospital SGLT2 inhibitors when patients are hospitalized with acute HF.11,12 In-hospital initiation of SGLT2 inhibitors helps break the clinical inertia burden and treats this high-risk population with the sense of urgency patients deserve.
There also is an ongoing trial called REDEFINE-HF (NCT06008197) that is evaluating the efficacy and safety of initiating finerenone in hospitalized patients with acute HF. Its eligibility criteria include those with CKD—their eGFR must be 25 mL/min/1.73m2 or higher and their potassium 5 mmol/L or less. So we should have data soon that will determine if starting finerenone in the hospitalized setting is recommended.
Of note, the benefits of GDMT are greater among patients who are older, frailer, and who have comorbidities. Across randomized, controlled trials, the relative risk reductions associated with GDMT are consistent across the spectrum of risk. Because these patients have a higher baseline risk, those consistent relative risk reductions translate to increased absolute risk reductions in general.13
Key Points for Treating HF
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC:
It is important that we treat patients with urgency, but there are studies showing that GDMT is underutilized in HF care.13,14 Although there may be some well-intentioned concerns held by HCPs, I think there are common misconceptions about overestimating the potential for adverse events and being overly concerned about an eGFR dip, rise in serum creatinine, or asymptomatic hypotension. These misconceptions can impede HCPs from prescribing Class I recommended therapies in HF.
It is true that many patients will tolerate all 4 pillars. If they do not, HCPs can always adapt to an individualized approach after taking the initial steps to start quadruple therapy at low doses at least.13
GDMT Considerations for Hyperkalemia Risk
Adeera Levin, MD, FRCPC:
Yes, I agree. One of the big concerns that HCPs get excited about is hyperkalemia. If you look at the studies, the absolute change in potassium is somewhere between 0.14 and 0.30 mmol/L. In understanding potassium physiology, HCPs should appreciate that much of this is transient and depends on serum vs plasma potassium, the outpatient vs inpatient setting, and whether patients have glycemic control or not.
This unbelievable aversion to starting a therapy that might fiddle with potassium levels slightly is something that we need more education about and help with. As Dr Michos said, a potassium less than 5 mmol/L is fine. Even if it stabilizes at 5.2 mmol/L but patients are seeing benefit with their therapy, that is okay.15
I also want to echo the concept of relative vs absolute risk. An exploratory analysis of the EMPA-KIDNEY trial demonstrated that the patients at highest predicted risk (ie, more frail, multimorbidity) saw greater benefit in terms of their hospitalization risk.16 So I think HCPs need to protect themselves from being both ageist and frailist in terms of what the potential benefit truly is for patients. People have a limited life span, and they do not want to live it in hospital or nursing home because their HF is so bad.
Again, HCPs must avoid the misclassification of “too sick” and check in on their concerns with eGFR dips as well as this obsession with checking potassium. That is because studies on finerenone did not measure potassium for the first month. Furthermore, hazard ratios for increased risk for elevated potassium above 5.5 mmol/L and 6.0 mmol/L were 2.16 and 2.07, respectively, vs placebo. However, following protocol-directed monitoring and dose adjustments, the clinical benefit of finerenone persisted even for patients with potassium above 5.5 mmol/L.17
This obsession with measuring potassium 1 or 2 weeks after initiation is interesting because the studies did not follow this guidance. So why we need to measure it more often is not clear to me. I think this is something that we need to do, but I also am keen on seeing the results of the REDEFINE-HF trial. It will greatly affect our practice.
Multidisciplinary Care in CKM Syndrome Management
Adeera Levin, MD, FRCPC:
That then brings us to a discussion on the role of the various HCPs (ie, specialists and primary care HCPs) in determining who is in charge of what. I generally follow the principle that whoever sees the patient first is in charge of initiating GDMT. If, in fact, you need to engage other HCPs, then do that. But this notion of, “I will wait until you see your next HCP before you start a life-saving myocyte- and nephron- saving medicine”—why would we do that?
If you were the patient, is that what you would want from your HCP? It is critical that HCPs engage appropriately with their interdisciplinary and multidisciplinary care teams. They may be different, but they are both valuable.
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC:
Yes, absolutely. We need to stop playing “pass the hot potato” and take ownership of the patients who are in our office. Waiting until another HCPs starts these therapies can contribute to clinical inertia.
This whole idea of the CKM syndrome paradigm requires us to shift away from treating each of these as individual diseases to a more holistic approach. Patients do not just have T2D, HF, or CKD; they can have all these diseases simultaneously. So improved communication and collaboration is necessary among HCPs to tackle the interconnectedness of these CKM conditions. That way we can treat the whole body more effectively.
Part of this involves patients at the center, of course, in shared decision-making, which helps empower them in their values of treatment choices. In addition, it is crucial to help with their adherence to GDMT. So we need to educate patients by having 2-way conversations—explaining what each of these therapies are for, their relative benefits, and safety concerns that might be anticipated—while also listening to their goals and concerns. Furthermore, HCPs should do what they can to simplify treatment regimens, address financial or socioeconomic barriers, provide reminders about prescription refills, and involve pharmacists and other specialists in helping to optimize patient care.5
The Take-home Message for Providing Guideline-Concordant Care
Adeera Levin, MD, FRCPC:
Patients need to understand that these therapies can change their lives, and different patients will require different amounts of information. I think the reason that cancer outcomes are better is because patients with cancer are well aware of how treatment will change their outcomes. Similarly, we need to educate the entire continuum of care in HF and CKD, starting with patients and their families for those who cannot advocate for themselves. Then add in their primary care HCPs so everyone is appreciative of the benefits that can be had if patients are on the appropriate constellation of therapy. I think deprescribing therapies that do not work well is something that we should pay attention to, alongside sick-day rules. But this requires a concerted effort among everyone.
Furthermore, if HCPs start these therapies while patients are in the hospital, that sends a message to primary care HCPs that you are not afraid of starting GDMT and ensuring patients tolerated it well. That way, when patients go home, no one asks, “Well, should I or shouldn’t I be taking these medications?”
It is complicated, but we are trying to treat a whole person who may have evidence of different organs being damaged at different points in time over their life course. This narrow idea of “my organ, my time vs your organ, your time” must be reconsidered.