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Expert answers in CKM care
Optimizing CKM Syndrome Care: Expert Answers to Your Frequently Asked Questions

Released: April 29, 2026

Stephen J. Greene
Stephen J. Greene, MD
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Key Takeaways
  • NT-proBNP and UACR are 2 biomarkers that can inform the risk of cardiovascular–kidney deterioration before clinical events occur. 
  • Clinical inertia is the top reason gaps in GDMT persist across CKM conditions, and HCPs should be careful not to misconstrue clinical stability as low risk or justification to not escalate appropriate therapy.
  • Evidence supports consistent efficacy and safety of GDMT in patients who are older, frailer, or have multiple comorbidities.

In this commentary, Stephen J. Greene, MD, answers questions posed by healthcare professionals (HCPs) during a live symposium titled “Shifting Gears in Cardio–Renal–Metabolic Care: Harnessing Evidenced-Based Therapies to Optimize Patient Outcomes.” Learn about specific considerations for managing cardiovascular–kidney–metabolic (CKM) conditions and employing guideline-directed medical therapy (GDMT) early in personalized treatment plans.

What biomarkers signal early cardiovascular–kidney deterioration before overt decompensation occurs?

The 2 biomarkers that I use most frequently to monitor patients with CKM conditions are NT-proBNP and urine–albumin-creatinine ratio (UACR).

First, NT-proBNP is one of the strongest, most consistent prognostic factors that tells us when patients with established heart failure are at risk of poor outcomes. NT-proBNP can change over time, and increases in NT-proBNP signal to HCPs that they need to do something more—whether that is adding or escalating GDMT, escalating diuretics, or considering candidacy for other interventions. Although HCPs should already be escalating combination GDMT as tolerated in all eligible patients with heart failure, NT-proBNP can serve as a reminder to do so. Increases in NT-proBNP can signal to HCPs that they should evaluate patients for other heart problems. For example, you may need to look for a new valve lesion or a new electrical issue. That is why NT-proBNP is at the top of my list for remote monitoring of patients with CKM conditions.

The other biomarker is UACR (or albuminuria). First and foremost, measuring UACR is fundamental for diagnosing chronic kidney disease (CKD). HCPs often forget that CKD is defined as an eGFR less than 60 mL/min/1.73 m2 and/or a UACR of 30 mg/g or greater for at least 3 months. Data suggest that if you are only using eGFR to screen for CKD, you will miss more than 60% of all CKD cases. That is, many patients with CKD have a normal eGFR but abnormal UACR, and HCPs who do not use UACR alongside eGFR are often flying blind. UACR can also change dynamically over time, which informs patients’ risk and prognosis. From a prognostic perspective, UACR, like NT-proBNP, is a strong and consistent biomarker for measuring cardiovascular and kidney risk. Some might traditionally think of it as only a kidney-related measurement, but it has a huge impact on cardiovascular prognosis, too.

Gaps regarding the use of GDMT for CKM conditions are repeatedly shown. In your opinion, what are the reasons that these gaps exist?

In looking at real-world data, we can all agree that there are large gaps in the use of GDMT for heart failure, metabolic disease, and CKD. But what we do not agree on is the reason why. This is where the debate starts. Some say the reason is the high costs of GDMT, whereas others say it is the side effects or adverse events related to treatment. Others may point to the risk of polypharmacy and that patient preferences are such that they do not want to take multiple therapies at once. With so many different feelings about the top reason for these GDMT gaps, how are we ever going to figure this out?

I am going to address this step by step and use the current data on heart failure as an example. First, let me say the data are clear that patient out-of-pocket costs are not the dominant reason we have widespread, systemic underuse of GDMT. Yes, out-of-pocket costs of treatment can definitely be a barrier for select patients, but again, not the dominant reason for large-scale nationwide gaps in GDMT. How do I know this? Look at the Veterans Affairs hospital system as an example. This is a health system that provides US veterans with low-cost healthcare access, medications are either free or low cost to the patient, and all GDMT for heart failure are on formulary.  Yet they still report enormous gaps in the use of evidence-based GDMT among medically eligible patients, gaps that are really not significantly different than gaps we see in patients in other types of health systems.

Also, I will point out that if the issue was all about patient out-of-pocket costs, then why aren’t we prescribing our generic, inexpensive medications for heart failure? Generic triple therapy for those insured with Medicare would cost about $160 annually for 3 lifesaving agents, yet less than 1 in 3 patients with heart failure with reduced ejection fraction (HFrEF) in the United States are prescribed even generic triple therapy at discharge. Although costs certainly are a barrier for some, it is not the main reason for widespread gaps in GDMT use.

What about safety and tolerability concerns with GDMT? Even though there are concerns about blood pressure limitations and/or eGFR changes that make HCPs more hesitant to use certain guideline-recommended therapies, data show that the gaps in heart failure are pretty similar regardless of blood pressure or eGFR levels. As much as some HCPs reference blood pressure as the reason they do not want to use GDMT fully, data suggest that it is not truly an issue of blood pressure. Rather, it is much more an issue of quality of care.

Yes, a very low eGFR is a contraindication for certain GDMT in treating CKM conditions. But among those with HFrEF, the guidelines offer a class 1A recommendation that these patients get initiated on an MRA as long as their eGFR is greater than 30 mL/min/1.73 m2. One study found that only 44% of patients with HFrEF and CKD are prescribed an MRA despite having an eGFR of 45-60 mL/min/1.73 m2. Although a decreased eGFR is associated with a lower likelihood of using GDMT, this is usually inappropriate and not reflective of a true absolute contraindication. 

That said, there is a strong and growing body of evidence clarifying that the real reason for these gaps in GDMT is clinical inertia—or HCPs underestimating clinical risk and misconstruing patients’ current stability as an inappropriate justification to not start or escalate evidence-based therapy. This has been analyzed via audits of electronic health records. When asked to pinpoint the single reason they did not prescribe GDMT despite their patients being eligible, HCPs most frequently reported clinical inertia. That means HCPs inappropriately deemed patients as clinically stable on current therapy and not in need of escalated therapy. This ignores the simple fact that there is no such thing as a low-risk heart failure patient. If a cancer patient came to the clinic feeling well but still with active underlying cancer, that patient generally gets treated very aggressively. That same culture of care does not currently exist in heart failure, despite heart failure prognosis being very similar to many forms of cancer.

This serves as a call to action. We need to unify on the reason we do not prescribe GDMT as recommended. Hopefully, once all stakeholders agree on the reasons gaps in GDMT exist, we can move the ball down the field and make a big difference in getting evidence-based therapies to our patients in need. 

For older adults with multiple CKM conditions and who experience polypharmacy, how do you balance GDMT with tolerability and care goals?

In older and frailer adults with or without multimorbidity, of course, we talk about the importance of shared decision-making. But as much as well-intentioned HCPs often seek to personalize treatment, we should not let personalized treatment be an excuse to practice nonevidence-based medicine. The thing is, we need to take a data-driven approach to care, and among patients included in the clinical trials, there is generally consistent efficacy and safety across the spectrum of different subgroups. This includes older and frailer patients. Yes, patients and HCPs need to talk about side effects that could occur with medications. But they also need to talk about “side effects” of not trying evidence-based medications that patients are eligible for. When it comes to GDMT for CKM, the risks of omitting evidence-based medications include a higher risk of mortality, hospitalization, end-stage kidney disease, and worsening symptoms. Patients need to be well informed of these risks if they are truly to make an informed decision about a medication.

Looking at the different pivotal trials across the CKM landscape, the intervention and placebo arms report similar rates of serious adverse events and discontinuations. That includes among those who are older, frailer, and/or have comorbidities. Therefore, the data strongly support GDMT in general as having a strong safety and tolerability profile. The thing we have to realize is that high rates of “side effects” happen even among patients randomized to placebo.  In real-world practice, we are often quick to blame the medications patients are taking when bad things happen. But in the clinical trials where patients are blinded to what they are receiving, the rates of discontinuation of GDMT are generally no different than the rates of discontinuation for placebo.

The clinical trials that established the efficacy of GDMT included a high proportion of older/frail patients with comorbidities, which might come as a surprise for some HCPs. In these subgroups, the trials report consistent relative risk reductions. But of importance, because patients who are older, frailer, and/or have comorbidities see a higher underlying baseline risk, those same relative risk reductions actually equate to larger absolute risk reductions and a lower number needed to treat. We can make a huge difference in patients’ care by having the courage to treat older and frailer adults with evidence-based GDMT. On the other side, withholding GDMT among frail and older patients without absolute contraindications is a problem, because these are the patients who have the most to lose in terms of the absolute harms of not prescribing.

Sometimes our older patients tell us that they do not care as much about living longer, but that quality of life rather than length of life is their top priority. So, another thing to remember is that GDMT not only enhances clinical outcomes, such as survival and decreased hospitalizations, but it also improves patients’ quality of life. Even if patients do not care much about living longer, they probably care about feeling better. Therapies like SGLT2 inhibitors are an evidence-based approach to help patients with CKM conditions feel better, including among those who are older, frailer, and/or have comorbidities.

What recent data in the CKM landscape have influenced your practice the most, and in what area is the evidence still incomplete?

Several trials have not changed my practice, necessarily, but have validated it. Since 2021, I have been advocating for the simultaneous or rapid sequence initiation of GDMT in patients with heart failure. That means HCPs must be willing to start more than 1 therapy at the same time. We cannot say, "I am only allowed to start 1 agent at a time and have to wait 3 months before starting the next one." We are never going to complete our mission of getting people on combination GDMT if we go down that road.

Now 2 randomized clinical trials have directly tested this theory of starting medications simultaneously: STRONG-HF and CONFIDENCE. STRONG-HF evaluated the efficacy and safety of rapid GDMT up-titration among patients with acute heart failure, and CONFIDENCE evaluated the same concept with the simultaneous initiation of empagliflozin and finerenone in patients with CKD and diabetes. The take-home point is that we now have randomized clinical trial evidence that strongly supports both the efficacy and relative safety of initiating more than 1 GDMT at the same time in patients with CKM.

Although there are always exceptions and no absolutes in life, this is about the default approach that HCPs should take. HCPs must buy into the fact that there is no rule in the CKM handbook that says you are only allowed to start 1 therapy in a given visit. In addition, there is no rule that says you cannot initiate therapies remotely, assuming patients are feeling okay and have the appropriate laboratory follow-up. There must be a sense of urgency that shortening the time to combination therapy is important for patients with CKM conditions. Each of these therapies shows benefits within days to weeks of initiation, and the benefits are fully additive. And the status quo of starting 1 at a time has been proven to result in many patients never achieving appropriate combination therapy. This slow and steady approach needlessly exposes patients to excess clinical risk while their medications are gradually titrated, if at all.

Every day, we have people with CKM conditions dying or being hospitalized without the therapies that are proven to prevent those events. That is the risk of omission, unfortunately. I know we can do a whole lot better. HCPs must be willing to start and titrate multiple therapies at the same time as their default approach when caring for patients with CKM conditions.

Your Thoughts
How often do you use GDMT in your patients with CKM conditions? You can get involved in the conversation by answering the poll question and posting a comment below.

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How often do you use GDMT in your patients with CKM conditions?

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