Why Cardiovascular, Kidney, Metabolic Risk Must Be Managed Together, With Janani Rangaswami, MD, FAHA

An estimated 90% of US adults fall somewhere along the cardiovascular-kidney-metabolic (CKM) spectrum, a framework clinicians are increasingly applying as new therapies, including GLP-1 receptor agonists for CKD, expand options for managing overlapping risk.1,2

Introduced in a 2023 presidential advisory, the CKM model formalizes the interconnected relationship between cardiovascular disease, chronic kidney disease (CKD), obesity, diabetes, and metabolic dysfunction. Rather than viewing these conditions in isolation, the framework stages risk across a continuum from individuals without overt disease to those with advanced cardiovascular and kidney complications.1

The framework has gained additional urgency as new therapies, including GLP-1 receptor agonists recently approved for CKD, provide clinicians with more tools to address overlapping metabolic and cardiorenal risk.

For Janani Rangaswami, MD, FAHA, professor of medicine at George Washington University and co-chair of the advisory’s scientific writing group, the shift reflects what clinicians are already seeing in daily practice.

Here’s the Q&A with Rangaswami:

In routine clinical practice, where do you most often see cardiovascular disease, CKD, and diabetes converge in the same patients, and how does that overlap influence management decisions?

Rangaswami: So I think the overlap is so significant that after the framework of cardiovascular-kidney metabolic syndrome was put out by the American Heart Association — and I am co-chair of that scientific advisory group that wrote that presidential advisory in 2023 — the analysis of data in the United States shows that 90% of Americans are living with at least a stage of CKM syndrome. And you know, CKM syndrome encompasses the entire spectrum of risk, starting from people who have no risk factors or cardiovascular disease, going all the way through obesity, vascular risk factors, subclinical disease, and clinical cardiovascular disease.

And so in any healthcare setting — primary care, specialty care between cardiology, nephrology, and endocrinology — this is the bulk of practice. When you look at a specialty like in my practice, when I see individuals with kidney disease, diabetes alone is responsible for close to 50% of the cause behind that kidney disease. And then when you add in obesity and metabolic dysfunction and hypertension, all of these really come together very heavily. So that's why understanding that interconnectedness is so important between these three elements.

From a cardiorenal perspective, what did the approval of semaglutide in patients with CKD signal about how we are beginning to approach metabolic risk across both heart and kidney disease?

Rangaswami: I think that was such an important development, because with the new therapies, and particularly with the GLPs, our approach to the management of kidney disease has evolved. When we didn't have some of these foundational classes — you know, the SGLT2 inhibitors came first, we have non-steroidal MRAs, and of course the incretin class therapies — a lot of the management of coexistent metabolic factors like diabetes or obesity was just like controlling A1c or counseling about weight management, and fully recognizing that obesity played such an important piece. But there were really no definitive therapies the way we have today.

Now, the standard of care across these foundational classes of therapies goes beyond just treating the risk factor. So while the GLPs in semaglutide are very effective for A1c management and weight management, the FLOW trial — which was the pivotal trial that led to the labeled approval of semaglutide in kidney disease with type 2 diabetes — showed that this therapy saved lives, hearts, and kidneys.

In patients with high and very high-risk kidney disease who are high risk for both kidney failure and cardiovascular events, there was consistent benefit seen for prevention of worsening kidney function needing dialysis and transplant. There was also consistent reduction in rates of cardiovascular adverse events, and there was a mortality benefit. So now these therapies do multiple things — they address everything from improving lifespan to improving health outcomes, heart and kidney, and then even beyond.

Because as we now know, semaglutide, apart from the weight loss perspective, also has liver benefits. So in metabolic liver disease, that's another area where you see another organ benefit. And we also know that in people without diabetes, in the SELECT trial, there is a primary cardiovascular benefit in non-diabetic but overweight or obese individuals. So truly, it's like a whole health approach. Even if the label is for kidney disease, we're benefiting all of these different aspects.

Given that cardiology is often the first specialty managing metabolic risk, how have you seen clinicians currently incorporating GLP-1 receptor agonists when kidney disease is also present?

Rangaswami: Patients who may qualify for the kidney indication very likely also qualify for the other indications. If you look for the other indications, you will find them. It depends — sometimes patients in my practice have already been initiated, perhaps for weight management, or somebody has been screened for liver disease, and they have already been initiated on the therapy. Or sometimes I am the person initiating it for the kidney perspective.

We're also seeing that there's more liberal use now, with more access to therapy, so early on even if patients met the indication, access was a problem. Now we're seeing that improve, which is very reassuring. The nice thing about therapies like semaglutide is that there are multiple reasons, multiple clinical touch points, and multiple different types of clinicians who can initiate, and the benefits are still going to be accrued across multiple organ systems.

How do you clinically position GLP-1 receptor agonists alongside established therapies such as SGLT2 inhibitors and RAAS blockade in patients with both CKD and high cardiovascular risk?

Rangaswami: Not only do these therapies have multiple organ benefits, but patients with overlapping conditions, obesity, diabetes, kidney disease, and cardiovascular disease, will not just be eligible for one of these classes, but for multiple classes.

When you look at the design of the major trials that show these benefits, and the types of patients they included, there’s significant overlap. For example, in the FLOW trial, semaglutide was tested versus placebo on top of RAS inhibition and risk factor control. In the SGLT2 inhibitor trials, for the most part, that is true as well. There weren’t that many individuals in the GLP trials who were also on SGLT2 inhibitors, about 15%, but we know these therapies appear to be additive.

One plus one equals two. When we combine these therapies, we get the full benefit you would expect. In individuals at the very high end of the spectrum of risk, whether from a cardiovascular or kidney perspective, they are eligible for multiple therapies because they will still have adverse outcomes if left on just one class. This opens the discussion for a whole new era for the concept of combination therapies across multiple foundational classes, RAAS inhibition, GLPs, SGLT2 inhibitors, and non-steroidal MRAs, especially in type 2 diabetes plus kidney disease, all of which have high-level evidence for benefit.

Editor’s Note: Rangaswami reports relevant disclosures with the American Heart Association.

References

1. Chang R, Parekh T, Hagan KK, Javed Z, Ostrominski JW. State-Level Prevalence of Cardiovascular-Kidney-Metabolic Syndrome Stages in the United States, 2011 to 2023. JACC Advances. 2025;4(6):101754-101754. doi:https://doi.org/10.1016/j.jacadv.2025.101754

2. National Kidney Foundation. FDA Approves Ozempic for Type 2 Diabetes and Chronic Kidney Disease. National Kidney Foundation. Published February 20, 2025. https://www.kidney.org/news-stories/fda-approves-ozempic-type-2-diabetes-and-chronic-kidney-disease

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