What Is Cardiovascular-Kidney-Metabolic Syndrome?

Cardiovascular disease often occurs with kidney disease and metabolic diseases, including obesity and type 2 diabetes. And having more than 1 of these conditions multiplies health and mortality risks, particularly due to cardiovascular disease. An American Heart Association (AHA) presidential advisory recently published in Circulation newly defines the adverse interplay among these conditions as cardiovascular-kidney-metabolic (CKM) syndrome.

The advisory provides guidance on how to stage CKM syndrome in patients, predict its cardiovascular outcomes, and effectively manage, prevent, and even reverse it in both adults and children. Evidence is detailed in a separate scientific statement. Together, the publications provide a framework for holistically and equitably improving CKM health in the population, according to the advisory. They also lay the groundwork for a new cardiovascular disease risk calculator that will incorporate the concept of CKM health for the first time.

The advisory notes that the mutually reinforcing harmful relationships among metabolic diseases, chronic kidney disease, and cardiovascular disease are known. However, opinions have varied on how or to what degree these conditions together constitute a syndrome, which suggests a common underlying pathophysiology.

“There has been increasing interest in the interplay among these conditions, but there has not been a clear definition,” Chiadi E. Ndumele, MD, PhD, the advisory writing committee chair, said in an interview with JAMA. This has impaired treatment that addresses the entire CKM syndrome–risk spectrum, added Ndumele, who is an associate professor and director of obesity and cardiometabolic research at Johns Hopkins University.

To address the high and increasing prevalence of poor CKM health, the AHA developed a consensus statement to clarify the definition of CKM syndrome and the tools to better detect, prevent, and manage it. They are included in the advisory and the scientific statement, which are the products of a multidisciplinary committee made up of 28 experts in cardiology, nephrology, endocrinology, primary care, and pediatrics.

The advisory attempts to bridge sometimes inconsistent specialty-specific recommendations, Ndumele said. “There was a lot of attention given to harmonization across current guidelines. Where there were gaps or a lack of clarity, we identified those areas and then tried to provide clarity wherever possible.”

Metabolic diseases—such as obesity and type 2 diabetes—and chronic kidney disease can damage nearly every major organ system. In particular, they increase the risk of cardiovascular diseases including heart failure, atrial fibrillation, coronary artery disease, stroke, and peripheral artery disease, as well as the chance of premature death. Collectively, heart disease, stroke, kidney disease, and diabetes directly accounted for more than 1 million deaths in the US in 2021, or about 29%. Indeed, the increasing prevalence of CKM-related risks has slowed 5 decades of decline in cardiovascular disease mortality, the advisory notes. And excess weight and its downstream comorbidities directly and indirectly cost an estimated $1.7 trillion annually.

“There was a lot of urgency around addressing this challenge, and, at the same time, a growing array of therapeutic options for addressing it,” Ndumele said. “The clear public health challenge and growing clinical options make this very timely.”

In lay terms, the advisory defines CKM syndrome as a health disorder due to connections among heart disease, kidney disease, diabetes, and obesity, leading to poor health outcomes. The syndrome increases the risk of development and progression of cardiovascular disease and includes both those at risk of and those with existing cardiovascular disease.

Adopting this definition helps clarify understanding of these adverse interactions and supports specific constructs for staging, screening, risk stratification, and prevention and treatment, Ndumele said. It also may help more effectively communicate metabolic health factors and their risks to patients in a nonjudgmental way, according to Ashish Sarraju, MD, a preventive cardiologist at the Cleveland Clinic, who was not involved in the advisory development.

The staging for CKM syndrome laid out in the advisory reflects its pathophysiology, risk factors, and opportunities for prevention and care:

• Stage 0: no CKM risk factors

• Stage 1: excess or dysfunctional adiposity—a source of proinflammatory and prooxidative secretions that cause tissue damage and reduce insulin sensitivity

• Stage 2: metabolic risk factors—specifically hypertriglyceridemia, hypertension, diabetes, and metabolic syndrome; or moderate- to high-risk chronic kidney disease

• Stage 3: subclinical cardiovascular disease with CKM syndrome or risk equivalents—specifically high predicted cardiovascular disease risk or very high-risk chronic kidney disease

• Stage 4: clinical cardiovascular disease with CKM syndrome

“The goal is to give more clarity on how to use these therapeutic tools and also better support prevention across the life course,” Ndumele said. “With substantial lifestyle changes and significant weight loss, we can even see regression in staging.”

Screening for risk factors should begin early in life, the advisory notes, and should increase in frequency if CKM syndrome stages progress. A new risk calculator soon to be published will incorporate CKM health to facilitate cardiovascular risk assessment and outcome prediction, which should start at age 30 for affected patients. Social determinants of health significantly affect risk and should be screened for and considered.

Excess body fat and related insulin resistance are the root cause of many harms from CKM syndrome, according to the scientific statement. They should be addressed through lifestyle modification and weight loss, the recommendations say. Early use of medications, including sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists, also may reduce cardiovascular disease risk. Education and support for healthful lifestyles may help improve CKM health in both individual patients and the population.

The advisory emphasizes that holistic care strategies, including value- and volume-based models that support interdisciplinary care, may help reduce care fragmentation and may improve treatment and outcomes. These strategies should address social determinants of health. Forming multidisciplinary teams and community partnerships can help mobilize resources for an effective response.

There’s strong evidence to support the idea that CKM syndrome raises health risks overall, according to the scientific statement. But there are major gaps in understanding.

The mechanisms linking CKM risk factors to cardiovascular diseases and chronic kidney disease, both individually and combined, are clearer in some cases than others. For example, inflammation, dyslipidemia, hypertension, and insulin resistance from CKM syndrome appear to accelerate atherosclerotic cardiovascular disease. By contrast, the mechanisms linking CKM syndrome to heart failure and arrhythmias are less well described, although inflammation is increasingly understood as a cause of heart failure with preserved ejection fraction. In addition, the relationship between cardiovascular disease and increased risk of later kidney disease is poorly understood, the statement notes.

Moreover, the biological and chemical mechanisms behind differences in presentation and progression by sex also are not well understood. Nor are the influences of genetic risk factors. CKM syndrome risks also differ substantially among racial and ethnic groups, with much of the difference related to social determinants of health. Individual risk is likely influenced by environmental, lifestyle, and epigenetic interconnections, the statement says.

And although evidence supports prevention and management approaches for CKM syndrome, there are gaps in understanding here too. These gaps include information on optimal structures for interdisciplinary teams and coordinators; early life and maternal interventions; weight loss approaches; use of SGLT2 inhibitors, GLP-1 receptor agonists, and lipid-lowering therapies; and cardiovascular disease management in patients with chronic kidney disease.

Additional research is needed to address these gaps, as is advocacy to promote insurance coverage of expensive medications, and adopting delivery models that support care integration, Ndumele said. “Implementation within and across health centers is a key part.”

According to Sarraju, the advisory’s value lies in its comprehensive and comprehensible approach to a complex problem. “This statement unifies a lot of individual concepts that physicians are already familiar with and provides an approach that is easier to implement and communicate with patients,” he said. “Hopefully, it will allow implementation of preventive and treatment measures earlier in life and in a more efficacious manner.”

Published Online: November 8, 2023. doi:10.1001/jama.2023.22276

Conflict of Interest Disclosures: Dr Ndumele reported receiving grant support from the National Institutes of Health and the AHA. No other disclosures were reported.