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Optimizing CKM Syndrome Care
Optimizing CKM Syndrome Care: Strategies for Employing Evidence-Based, Guideline-Recommended Therapies

Released: February 16, 2026

Michelle Kittleson
Michelle Kittleson, MD, PhD
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Key Takeaways
  • CKM syndrome is the result of heart disease, kidney disease, and metabolic disorders that occur together and worsen one another through shared pathways.
  • The treatment of CKM syndrome should first be informed by heart failure type in those with this disease and follow guideline-recommended algorithms.
  • Potential risk for volume depletion or genitourinary infection should not stop healthcare professionals from prescribing SGLT2 inhibitors to patients who would benefit from this therapy 

Cardiovascular–kidney–metabolic (CKM) syndrome should be explained to patients as a group of interconnected conditions that comprise heart disease, chronic kidney disease (CKD), and metabolic disorders like diabetes. These conditions often occur together and worsen each other through shared risk factors and biological pathways. The framework for this syndrome recognizes that CKM-related conditions are not separate problems; they are part of a systemic disorder that affects multiple organs simultaneously. The connection is the common underlying causes they share, such as obesity, which secretes inflammatory substances that damage arteries, the heart, and kidneys.

Other shared mechanisms in CKM syndrome create a vicious cycle where the impairment of 1 organ can accelerate the deterioration of others. For example, chronic kidney disease can cause worsening heart disease, and diabetes can damage both the kidneys and cardiovascular (CV) system. Thus, healthcare professionals (HCPs) must manage CKM syndrome not by focusing on 1 organ but via an integrated approach to care. That includes recognizing that a treatment (ie, lifestyle modifications) for 1 condition may help others; comprehensive screening for hypertension, dyslipidemia, diabetes, and chronic kidney disease (CKD), including microalbuminuria; and prescribing pharmacotherapy that simultaneously protects patients’ heart, kidneys, and metabolic health. Such therapies include sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists, which have demonstrated benefits across these 3 systems.

Treatment Strategies for CKM Syndrome
Treatment should first be informed by heart failure (HF) type—heart failure with preserved ejection fraction (HFpEF) vs heart failure with reduced ejection fraction (HFrEF). Let us start with HFrEF, as the 4 pillars of guideline-directed medical therapy (GDMT) have been shown to help these patients live longer, feel better, stay out of the hospital, and potentially improve their heart function. Treatment should include an angiotensin receptor-neprilysin inhibitor (ARNI) (or ACE inhibitor/ARB if an ARNI is contraindicated or intolerable); an evidence-based beta-blocker like bisoprolol, carvedilol, or metoprolol succinate; a mineralocorticoid receptor antagonist (MRA), including spironolactone or eplerenone; and an SGLT2 inhibitor, such as dapagliflozin or empagliflozin. When it comes to treatment sequencing, I personally am not a fan of simultaneous initiation because we are entering into a contract of trust when prescribing treatment to patients. We are telling them, “Take this pill, and you will feel better.” But if you prescribe too many pills at once and there are side effects, you will not know which specific medication caused it and you lose some of that trust. I think sequential and rapid sequence initiation with titration occurring every 1-2 weeks in the outpatient setting via telehealth is more appropriate.

Now in the case of HFpEF, there is strong evidence for improving quality of life and preventing HF hospitalizations with the use of SGLT2 inhibitors. In addition, emerging data are showing the same for finerenone, a nonsteroidal MRA. For patients who may not be able to afford finerenone, the cheaper, generic version of spironolactone is a reasonable second-best option. HCPs also must recognize that HFpEF, in particular, lives in the milieu of CKM syndrome because these conditions, particularly obesity, are typically associated with and/or drive HFpEF. Incretin-based therapies like the GLP-1 receptor agonist semaglutide and dual GLP-1/GIP receptor agonist tirzepatide are both safe and effective for inducing weight loss, improving quality of life, and for tirzepatide, potentially reducing worsening HF events among those with HFpEF and obesity. It also is important to remember that other therapies have a proven double-duty benefit. RAS inhibitors like ARNIs, ACE inhibitors, and ARBs; nonsteroidal MRAs; and SGLT2 inhibitors all benefit the kidneys in patients with diabetes. Incretin-based therapies and SGLT2 inhibitors both benefit the heart in patients with diabetes. Then, of course, statins reduce the risk of atherosclerotic cardiovascular disease in patients with or without diabetes. There are many overlapping circles with these foundational therapies. So when you think of HFrEF, know that minimal treatment comprises the 4 pillars of GDMT. In turn, when you think of HFpEF, baseline treatment should include an SGLT2 inhibitor and MRA (nonsteroidal is ideal). After initiating these agents, you can consider what other options might benefit those with obesity or diabetes, such as an incretin-based therapy, as well as those with chronic kidney disease and diabetes like RAS inhibitors and statins.

SGLT2 Inhibitors: Foundational in CKM Care
It is almost easier to ask which patients do not benefit from an SGLT2 inhibitor since the list of those who see benefit is significantly longer. Patients with HF across the ejection fraction spectrum benefit from the use of an SGLT2 inhibitor. These therapies reduce the composite endpoint of CV-related death and HF hospitalizations, which is particularly effective in HFpEF. Next, SGLT2 inhibitors are efficacious in those with CKD and albuminuria because they reduce the risk of disease progression, CV-related death, and HF. Finally, SGLT2 inhibitors are indicated to improve glycemic control in those with type 2 diabetes, and further benefits are especially apparent in those with comorbid CKD and/or CV disease. These are incredibly powerful data. If you are treating any patients with HF, CKD, including microalbuminuria, and/or diabetes, be sure to reach for an SGLT2 inhibitor.

There is hesitation among HCPs in using these novel therapies. Clinical inertia is a clear challenge as many HCPs struggle with prescribing these new agents because they have to learn about and become comfortable with using them. The hesitation, which was not necessarily born out of clinical trials, often regards the risk of volume depletion. In my experience, volume depletion is minimal, and sometimes I reduce the dose of the diuretic to counteract it. Other times, I tell my patients to play it by ear and give me a call if anything feels off to them. There is also the potential for genitourinary infections, such as yeast infections, with SGLT2 inhibitors. Therefore, it is important to let patients know that if they have any symptoms, such as perineal itching or discomfort, dysuria, or other concern for genitourinary infection, they need to call their HCP. But the potential for genitourinary infection should not be a deal breaker for HCPs to prescribe an SGLT2 inhibitor. Finally, there is the myth or misconception that SGLT2 inhibitors are associated with a higher risk of amputation. The current evidence is not consistent, nor does it solidify a causal relationship. So risk of amputations should not be of concern either. 

More specifically in CKD, HCPs may hesitate to use SGLT2 inhibitors because there will be a small decline in patients’ estimated glomerular filtration rate (eGFR) which generally resolves and leads to a reduction in CKD progression over time. When it comes to the kidneys, I typically say, "Do not just do something. Stand there." Meaning, HCPs should not just look at 1 laboratory value but think about outliers vs trends. That initial decline should resolve if patients look good, feel good, and their blood pressure is otherwise fine. Continue to monitor them, but do not hit the brakes too quickly just because there is a small, initial bump in their serum creatinine that is at or below 30%. Remember, SGLT2 inhibitors are safe to use and have been tested in patients with an eGFR up to 20 mL/min/1.73 m2.

RAS Inhibitors: Monitoring Kidney Function
It is critical for HCPs to not just look at the laboratory value when it comes using RAS inhibitors and monitoring patients’ kidney function. You must look at each patient individually, too. If there is a tiny initial bump in worsening kidney function, do not just act immediately. You should pause and think about it before pulling back on treatment. RAS inhibitors generally are acceptable to initiate in patients unless their eGFR is under 15 mL/min/1.73 m2. At that point, patients are at increased risk and there is no evidence of benefit for protecting the kidneys. Whenever HCPs initiate a RAS inhibitor, they should order a basic metabolic panel 2-4 weeks later to monitor patients’ potassium and creatinine levels. Do not be alarmed if there is a rise in creatinine of 30% or less; that is the cost of doing business. If their creatinine does increase, HCPs should check it again within the next 2-4 weeks, as it will likely settle. 

Then think about the context in which the potential worsening kidney function is occurring. Does the patient feel awesome? Is their blood pressure fine? If so, HCPs should have patients hydrate more and recheck their kidney function at the next follow-up visit. If patients are on the verge of fainting every time they stand up or their blood pressure significantly decreased after they started therapy, then maybe they are not the type of patient who is going to see benefit from this treatment. In addition, HCPs should determine if other agents may be confounding the issue. Are patients also taking a lot of NSAIDs? We know that these therapies can worsen kidney function and cause volume retention. Therefore, it is good practice to not initially blame the RAS inhibitor, as it may actually be beneficial. Rather, HCPs must determine if there are other factors that could be affecting patients’ kidney function.

Multidisciplinary Care Is Key
Finally, it is important to think about the collaboration between cardiology, nephrology, and endocrinology for patients with CKM syndrome. In these complex cases, communication can be hard. And as HCPs we are comfortable living in our own silos. Communication across specialties takes effort, yet it is much easier to do today within the electronic health record.

I have a rule: I never ask patients to be my messenger. We have played that game called telephone at some point in our lives. In it, you pass along a single message in a group of people and by the time it gets to the end, the message is completely garbled and unintelligible. That is why I never send messages through my patients. If I have to, I will type it out in a note and ask my patients to give the note directly to their nephrologist or endocrinologist. I never ask them to pass on a verbal message. Instead, I use the electronic health record to send messages if specialists are accessible in that way. If they are not in my system, I print out the note that includes my contact information and ask my patients to hand this note to their other specialist.

In my notes, I ask specific questions like, "Do you think this eGFR is okay? I really want to start an SGLT2 and/or RAS inhibitor. Are you okay with that?" Or “The patient’s eGFR decline was over 30%, but they look great to me. I just want to sit tight right now. Are you okay with that?” These are the things I may ask my patients’ nephrologist about. For endocrinologists, I might ask, "I want to start an SGLT2 inhibitor. Can you please adjust the patient’s other therapies for diabetes to make sure things remain in balance?” I would ask the same for those in which I am considering an incretin-based therapy. 

Simultaneously with this open communication, I still want to take ownership of each patient’s care. I do not want to wait to start a therapy. There is an old saying, it is better to ask for forgiveness than permission. This does not exactly apply in its entirety here, but I would rather start a therapy that I know the patient will benefit from and then check in with other specialties, rather than wait for them to start it.

Your Thoughts
How often do you prescribe SGLT2 inhibitors to your patients with diabetes, HF, and/or CKD? You can get involved in the discussion by answering the poll question and posting a comment below.

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