Cardiovascular Risk Beyond Metabolic Syndrome: The Role of CKM and Icosapent Ethyl

Cardiovascular–Kidney–Metabolic (CKM) syndrome is a newly defined multisystem disorder that extends the traditional framework of metabolic syndrome by explicitly incorporating chronic kidney disease. CKM was formally introduced in a 2023 American Heart Association (AHA) Presidential Advisory Statement chaired by Chiadi Ndumele, MD, PhD. The construct recognizes the interdependence of metabolic dysfunction, renal impairment, and cardiovascular disease (CVD) across a continuum of risk.

What Is Cardiovascular–Kidney–Metabolic (CKM) Syndrome?

CKM syndrome reflects the progressive interaction between cardiometabolic risk factors and declining kidney function. Unlike metabolic syndrome alone, CKM emphasizes the incremental cardiovascular risk associated with even modest reductions in kidney function, commonly assessed by estimated glomerular filtration rate (eGFR). Importantly, CKM applies to patients both with and without diabetes, underscoring kidney disease as an independent and amplifying driver of cardiovascular risk.

REDUCE-IT CKM: Evaluating Risk Beyond Metabolic Syndrome

One month after publication of the AHA CKM advisory, we examined the prevalence of metabolic syndrome in the REDUCE-IT trial, a large randomized outcomes study evaluating icosapent ethyl (IPE) in statin-treated patients with elevated triglycerides and established cardiovascular disease or diabetes plus additional risk factors.

Our newly published analysis, REDUCE-IT CKM, focused on patients with established cardiovascular disease without diabetes at baseline, allowing assessment of the cardiovascular impact of renal impairment beyond metabolic syndrome alone.

Renal Dysfunction Magnifies Cardiovascular Risk

Compared with patients who had metabolic syndrome and preserved kidney function (eGFR ≥90 mL/min/1.73 m²), cardiovascular risk increased substantially as kidney function declined. CKM was associated with a:

• 44% higher risk of cardiovascular events when eGFR was <90 mL/min/1.73 m²
• 87% higher risk of cardiovascular events when eGFR declined below 60 mL/min/1.73 m²

Cardiovascular events included myocardial infarction, stroke, cardiovascular death, hospitalization for acute coronary syndrome, and coronary revascularization procedures.

These findings demonstrate that renal impairment markedly amplifies cardiovascular risk associated with metabolic syndrome, even in the absence of diabetes.

CKM Identifies a Very High-Risk Population

Notably, the annual cardiovascular event rate among CKM patients in REDUCE-IT approached 7%, a rate more than threefold higher than what is typically observed in patients with stable coronary artery disease. This observation highlights CKM as a powerful risk stratification construct that identifies patients with particularly aggressive atherosclerotic disease biology.

Icosapent Ethyl and Cardiovascular Risk Reduction in CKM

Treatment with icosapent ethyl produced a 44% relative risk reduction in cardiovascular events and an absolute risk reduction of 11.2%, corresponding to a number needed to treat of just nine to prevent one cardiovascular event.

These robust and clinically meaningful benefits support consideration of IPE therapy in CKM patients who meet REDUCE-IT eligibility criteria, reinforcing the importance of addressing persistent cardiovascular risk in this high-risk population.

Implications

CKM syndrome provides a clinically relevant framework for understanding cardiovascular risk that extends beyond metabolic syndrome alone. Recognition of renal dysfunction as a key risk amplifier has important implications for risk stratification and therapeutic decision-making. The REDUCE-IT CKM analysis suggests that patients with CKM may derive substantial benefit from targeted therapy with icosapent ethyl.

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Michael Miller, MD, MASPC, FACC, FAHA, FNLA
Cardiologist and Professor of Medicine, Hospital of the University of Pennsylvania Chief of Medicine, Corporal Michael J Crescenz VAMC (Philadelphia) Follow on X: @mmillermd1
Learn more: www.drmichaelmiller.net

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