Cardio–Renal–Metabolic Syndrome: Redefining Chronic Disease Through Integrated Treatment

Key Takeaways
CKM syndrome unifies cardiovascular, kidney, and metabolic diseases: The American Heart Association’s CKM framework recognizes shared pathophysiology linking obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD)
GLP-1 receptor agonists and SGLT2 inhibitors deliver multisystem benefits: These agents improve glycemic control, reduce cardiovascular risk, and slow CKD progression, supporting integrated cardio–renal–metabolic management
Finerenone and next-generation MRAs address inflammation and fibrosis: Non-steroidal mineralocorticoid receptor antagonists expand treatment options beyond traditional steroidal MRAs
Triple agonists and LPA1antagonists represent the next wave of innovation: Emerging pipeline therapies target multiple hormonal and fibrotic pathways simultaneously to improve outcomes across CKM conditions
Integrated care and cross-disciplinary collaboration are essential: Advancing CKM treatment requires coordinated research, physician education, and updated diagnostic and reimbursement frameworks.

What is Cardio–Renal–Metabolic (CRM or CKM) Syndrome

Cardiovascular, kidney, and metabolic diseases, such as diabetes, have traditionally been treated by physicians independently. However, as more has been learned about human biology and disease pathways, there has been growing recognition of the interconnectedness of these three groups of diseases.^1–5In response to this growing awareness, the American Heart Association introduced the concept of cardiovascular–kidney–metabolic (CKM) syndrome in 2023.^1,2 A proposal has been recently introduced to expand that to include the liver— cardiovascular–renal–hepatic–metabolic (CRHM) syndrome.

The evidence has mounted that CKM conditions involve common pathophysiological mechanisms and risk factors, with high levels of adipose (fat) tissue, including both normal and dysfunctional tissue, at the core. The latter is a key contributor to the development of insulin resistance and type 2 diabetes, conditions that lead to hyperglycemia, which in turn causes metabolic disturbances that result in increased risk of heart failure (HF) and various cardiovascular diseases (CVDs).

As a result, people with diabetes are at higher risk of developing HF, other CVDs, and chronic kidney diseases (CKD), while patients with HF are more likely to develop CKD and/or diabetes, and those with CKD have a higher potential to develop CVDs and various metabolic diseases.³

In addition to coronary disease, chronic heart failure, diabetes, and renal failure, other diseases linked to the CKM framework include hypertension, dyslipidemia, obstructive sleep apnea–hypopnea syndrome (OSAHS), polycystic ovarian syndrome, venous thromboembolism, and metabolic dysfunction–associated steatotic liver disease (MASLD)/metabolic dysfunction–associated steatohepatitis (MDAS).^1,4

The treatment challenge is significant, as over 1 billion people worldwide have been diagnosed with CKM conditions.⁶ Several new medications are helping address the issue, but with half the global population projected to be overweight or obese by 2035,⁷ there is urgent need for more progress.

Several New Treatment Options

Increased understanding of human genetics and disease biology has not only revealed the link between cardio, renal, and metabolic diseases, but also enabled the identification of new drug targets and the development of new, more effective treatments.⁸ Leaders include glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), mineralocorticoid receptor blockers, and new development agents.^2,9

GLP-1 agonists (e.g., semaglutide) are effective for weight loss and reduction of adipose tissues, but also have been shown to reduce the risk of cardiovascular events and improve kidney function in patients with diabetes and heart failure.⁹ Because they improve multiple disease factor, they can also help reduce polypharmacy for patients.¹ SLGT2is (e.g., dapagliflozin, canagliflozin, and empagliflozin) provide glucose control and benefit patients with HF, major adverse cardiovascular events (MACE), and CKD.1 Certain clinical trial data suggests that combined treatment with GLP-1Ras and SGLT2is results in even greater improvements.⁹

Mineralocorticoid receptor antagonists (MRAs) are diuretics that block aldosterone, reducing sodium/water retention, fibrosis, and blood pressure.¹⁰ First-generation products, such as spironolactone and eplerenone, are steroids. Finerenone is a non-steroidal MRA shown to exhibit potent anti-inflammatory and antifibrotic effects and in clinical trials has led to reduced risk of cardiovascular events and CKD progression. It is also being investigated as a treatment for patients with type 1 diabetes and CKD and in combination with empagliflozin in in CKD and type 2 diabetes.

Dual action GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) RAs (e.g., tirzeptaide) are additional, newer treatments shown to have significant benefits for patients that fall within the CKM framework.¹ GIP RAs enable greater weight loss and improved insulin sensitivity compare to GLP-1 RAs and appear to help patients with MASLD, OSAHS, and HF, as well as those with diabetes.

These newer medications are often used in combination with established therapeutics, such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor/neprilysin inhibitor (ARNIs), and beta blockers (BBs).³

New Promising Treatments in Development

Several newer therapies are in development that could provide even more treatment approaches for patients with CKM conditions.¹ Promising candidates, including triple receptor agonists, lysophosphatidic acid 1 (LPA1) receptor antagonists, second-generation MRAs and SGLT2i combinations, target various important pathways in CKM diseases, such as fibrosis, metabolic dysfunction, and renal protection, often simultaneously.

Triple hormone receptor agonists (e.g., retatrutide) activate GLP-1, GIP, and glucagon receptors of improved glycemic control, weight loss, and cardiovascular control. LPA1 receptor agonists reduce fibrosis, inflammation, and vascular dysfunction by blocking this G protein-coupled receptor (GPCR). One example is ACT-1016-0707.¹¹Other second-generation, non-steroidal MRAs, such as esaxerenone and balcinrenone, are more selective than first-generation products, while studies are confirming that combination therapies involving SGLT2is provide improved outcomes.

Challenges in Translation

While several newer therapies are progressing through the clinic, it can be challenging to translate early preclinical results into safe and effective treatments in humans.⁴ The industry has taken notice. For instance, Roche (and biologics business Genetech) announced in late 2025 that it is tackling this challenge with the establishment of a new Innovation Center for Cardiovascular, Renal, and Metabolic Disease that will “bring together discovery biologists, clinical experts, and computational scientists, as well as external academic collaborators” using an integrated, end-to-end approach across drug discovery and late-stage development.⁷

Complicating the development challenge is the need to educate physicians about the benefits of pursing a comprehensive treatment approach for CKM patients. Equally important is the need for adoption of a new disease code for diagnosis and reimbursement purposes that enables a single diagnosis for patients with comorbidities in the CKM syndrome, including obesity, diabetes, CKD, and CVD.³

Collaboration and Tailored Treatment Approaches Needed

The new Roche Innovation Center and its focus on bringing together scientists from multiple arenas⁷ reflects the growing recognition that collaboration across research fields and organizations will be essential to further advancing new safe and effective therapies for patients with CKM diseases. Given the complexity of the CKM framework and the number of interconnected and overlapping disease pathways, inter-disciplinary collaboration is crucial for expanding knowledge of how obesity and excess adipose tissue leads to CKM diseases, as well as how each influences development of the others. Integrated care and screening and personalized treatment are equally important.