Issue: August 2020

Park S, et al. Ann Intern Med. 2019;doi:10.7326/M19-0563.

Disclosures: Cho reports she is a special consultant to the FDA for an endometabolic lipid panel. Eckel reports he serves on scientific advisory boards for Kowa and Novo Nordisk. Handelsman reports he has received research grants, consultant and speakers fees or honoraria from Aegerion, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Boehringer Ingelheim/Lilly, Bristol-Myers Squibb, Eisai, Gan & Lee, Grifols, Hanmi, Intarcia, Janssen, Lexicon, Lilly, Merck, Novo Nordisk, Regeneron and Sanofi. Hawkins, Rodriguez, Subramanian and Wilson report no relevant financial disclosures.
August 17, 2020
10 min read

‘Metabolic syndrome’ label imprecise, but cardiometabolic risk is real

Issue: August 2020

Park S, et al. Ann Intern Med. 2019;doi:10.7326/M19-0563.

Disclosures: Cho reports she is a special consultant to the FDA for an endometabolic lipid panel. Eckel reports he serves on scientific advisory boards for Kowa and Novo Nordisk. Handelsman reports he has received research grants, consultant and speakers fees or honoraria from Aegerion, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Boehringer Ingelheim/Lilly, Bristol-Myers Squibb, Eisai, Gan & Lee, Grifols, Hanmi, Intarcia, Janssen, Lexicon, Lilly, Merck, Novo Nordisk, Regeneron and Sanofi. Hawkins, Rodriguez, Subramanian and Wilson report no relevant financial disclosures.
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The term “metabolic syndrome” has been used since the mid-1990s to describe a constellation of risk factors that predispose adults to develop diabetes, CVD or both.

These factors, many of which are linked to obesity, inactivity and unhealthy diet, appear to be on the rise in younger people. From 1988-1994 to 2007-2012, the prevalence of metabolic syndrome among U.S. adults rose from 25.3% to 34.2%, according to the CDC.

Metabolic syndrome — which can include abdominal girth, elevated triglycerides or BP, low HDL or glucose abnormalities — doubles risk for development of CVD and quintuples risk for development of type 2 diabetes in the 5 to 10 years after diagnosis, according to the International Diabetes Federation (IDF). Adults with components of metabolic syndrome are twice as likely to die of a CV event as those without the syndrome, regardless of a previous history of CVD.

Leslie Cho, MD, from Cleveland Clinic, highlights the cardiac risks for metabolic syndrome.

Source: Cleveland Clinic. Reprinted with permission.

“All metabolic patients are at risk for cardiac disease,” Leslie Cho, MD, professor of medicine and section head of preventive cardiology and rehabilitation in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic, told Cardiology Today. “It is especially important that we address these factors because we know that people with metabolic syndrome go on to have cardiac disease. Now, some people will say the definition of cardiometabolic syndrome is people with cardiac disease who also have metabolic syndrome, but all patients who have metabolic syndrome are cardiac patients waiting to happen. Addressing these factors is something we can do as physicians to prevent patients from going down that route.”

Today, the IDF identifies a person as having metabolic syndrome if they have central obesity, defined as an increased waist circumference with ethnicity- specific values, plus any two of the following four factors: triglyceride level of at least 150 mg/dL; HDL level of less than 40 mg/dL for men and less than 50 mg/dL for women; systolic BP of at least 130 mm Hg or diastolic BP of at least 85 mm Hg; and a fasting plasma glucose of at least 100 mg/dL.

According to the Adult Treatment Panel III criteria, although abdominal obesity is a component of the syndrome, it is not a prerequisite for its diagnosis. Any three components of the five will make the diagnosis. That distinction leads to a change in prevalence estimates depending on the criteria used, according to researchers.


“By using the definition of metabolic syndrome from the International Diabetes Federation and the National Cholesterol Education Program, the prevalence of metabolic syndrome is estimated at more than 30% in the United States; however, by using the Adult Treatment Panel criteria, prevalence is estimated at about 22%,” Justin Xavier Moore, MPH, a predoctoral fellow in the department of epidemiology at the University of Alabama at Birmingham, and colleagues wrote in the March 2017 issue of Preventing Chronic Disease.

Disagreement on definition

Despite such warnings, disagreement persists among international health groups about what specifically constitutes metabolic syndrome. In a 2009 consensus statement published in Circulation, six major associations, led by the IDF, endorsed harmonized criteria to define the syndrome more accurately, but clinicians and researchers continue to question what the label should mean for patients who receive a metabolic syndrome diagnosis.

Savitha Subramanian

Some experts contend that metabolic syndrome is not a “syndrome” at all.

“Metabolic syndrome is such an abstract concept,” Savitha Subramanian, MD, associate professor in the division of metabolism, endocrinology and nutrition and medical director of the Lipid Clinic at the University of Washington School of Medicine, told Cardiology Today. “It is not really a syndrome. One should think about it as a clustering of risk factors, which is how I explain it to students and residents and trainees who come through my clinic. Controversy still exists about this term.”

The definition of metabolic syndrome has been argued upon for decades, and debate continues with the definition of cardiometabolic syndrome, according to Robert H. Eckel, MD, emeritus professor of medicine in the divisions of cardiology and endocrinology, diabetes and metabolism, emeritus professor of physiology and biophysics and Charles A. Boettcher II Chair in Atherosclerosis at the University of Colorado Anschutz Medical Campus, past president of the American Heart Association and current president of medicine and science of the American Diabetes Association.

“This is a complex of many things, but the underlying theme is insulin resistance,” Eckel said. “The metabolic syndrome is defined, plus all these other components, but cardiometabolic medicine includes the relationship of a number of additional metabolic factors such as prothrombotic factors, inflammation and beyond to cardiovascular disease. What is so-called cardiometabolic medicine represents the composite of multiple things that are metabolic and include cardiovascular disease-related outcomes.”

History, controversies

Complicating efforts to better understand the public health burden of metabolic syndrome and identify prevention strategies is the lack of consistency in the clinical definition and categorical cut points for component conditions.


Debate also continues regarding whether a defined number of risk factors confers greater risk for developing CVD and diabetes than the individual components do, according to Peter W.F. Wilson, MD, professor of medicine in the division of cardiology at Emory University School of Medicine, professor of public health in the Rollins School of Public Health at Emory University and director of epidemiology and genomic medicine at the Atlanta VA Medical Center.

“In an analysis my colleagues and I did when I was participating in the Framingham Heart Study, we found that two out of five risk factors conferred about the same risk as three out of five,” Wilson told Cardiology Today. “Each of the individual risk factors conferred about a 50% increased risk for developing diabetes over time, or CVD, but there’s nothing magical about two out of five or three out of five. Each risk factor increases the risk for diabetes, and each one also increases the risk for heart disease.”

Meantime, the criteria omit other key risk factors clinicians should consider for CVD and type 2 diabetes, Valentina Rodriguez, MD, assistant professor of clinical medicine in the division of endocrinology, diabetes and metabolism at the University of Miami Miller School of Medicine, told Cardiology Today. These key risk factors include family history, physical activity, smoking, alcohol use and other inflammatory conditions, such as rheumatoid arthritis and thyroid disease, which confer their own independent risks for CVD.

Similarly, cutoff values for the individual risk factors — for example, a fasting glucose of 100 mg/dL or greater — should not be looked at as defining lines, Rodriguez said.

“I would argue that you always need to look at this as a continuum,” Rodriguez said. “If a patient has increased belly fat and their fasting glucose is 99 mg/dL and their BP is 134/84 mm Hg, they may not exactly meet the defined criteria for metabolic syndrome, but they are very close to it. That does not mean you do not have metabolic syndrome and your CV risk is not as great. What it means is we still have to be proactive about preventive care and discuss this again in the near future.”

Risk picture

According to the consensus worldwide definition of metabolic syndrome, the clustering of risk factors is now considered to be “the driving force for a new CVD epidemic.”

“Increased waist circumference, what we call atherogenic dyslipidemia, or slightly elevated BP, all of these are a reflection of your CV risk down the road as you get older,” Subramanian said. “These risks are precursors or markers for developing diabetes or hypertension, because it is still early. One could think of them as prehypertension or prediabetes. That’s the implication.”

Robert H. Eckel

In a study published in November in Annals of Internal Medicine, researchers found that patients who recovered from metabolic syndrome decreased their risk for major adverse CV events, whereas those who developed metabolic syndrome had an increased risk for events. Researchers analyzed data from 9,553,042 patients from the National Health Insurance Database of Korea and found that adults in the metabolic syndrome recovery group had lower risk for major adverse CV events (incidence rate, 4.55 per 1,000 person-years) compared with those in the chronic metabolic syndrome group (incidence rate, 8.52 per 1,000 person-years). Those who developed metabolic syndrome during the study had a higher risk for major adverse CV events (incidence rate, 6.05 per 1,000 person-years) compared with those who were free from the syndrome (incidence rate, 1.92 per 1,000 person-years; adjusted incidence rate ratio = 1.36; 95% CI, 1.33-1.39).

Unfortunately, some health care professionals do not see metabolic syndrome as that serious of a risk factor.

“A lot of people think of metabolic syndrome as a not-as-severe risk factor as having coronary artery disease or diabetes,” Cho said. “For those of us who treat patients with metabolic syndrome, some unfortunately go on to develop coronary artery disease and all the maladaptive manifestations of cardiovascular, renal and metabolic diseases like diabetes, CAD, chronic kidney disease, stroke, etc.”

Still, experts contend that predicting CV risk for a person with metabolic syndrome can be difficult.

“Can you say to the person in front of you, ‘You’re going to have a CV event in your lifetime, and I can give you this much assurance’? No, you can’t,” Meredith A. Hawkins, MD, professor of endocrinology, the Harold and Muriel Block Chair in Medicine and director of the Global Diabetes Institute at Albert Einstein College of Medicine, told Cardiology Today. “That is where the confusion lies. You can try to estimate risk, and with various studies you could come close, but one will never actually predict whether a person will have an actual event, ever.”

Management, prevention

Although there are no formal guidelines strictly dedicated to metabolic syndrome, cardiometabolic risk is dovetailed into the primary prevention guideline released by the American College of Cardiology and the American Heart Association in 2019. A guideline from the European Society of Cardiology in 2019 on diabetes, prediabetes and CVD does somewhat address this issue, but it does not call it “cardiometabolic syndrome” directly.

Cho said a collaborative effort is needed to create a cardiometabolic syndrome guideline.


“If the ACC or AHA come out with a guideline on this, they need to do it in conjunction with the Endocrine Society or American Diabetes Association (ADA) because those things make the most difference,” Cho said. “It would be powerful to do an ACC/AHA/ADA guideline on something like this.”

The metabolic syndrome criteria offer clinicians a simple method to assess risk — a blood test, BP and body weight and girth measurements — and determine whether the patient is more likely to develop CVD and diabetes, Yehuda Handelsman, MD, FACP, FNLA, FASCP, MACE, medical director and principal investigator of the Metabolic Institute of America in Tarzana, California, told Cardiology Today.

“The point is we have a clinical tool, and once you know how to predict risk, that is good,” he said. “Everything else is philosophical.”

Rodriguez said clinicians should assess each component of the syndrome and work to maximize treatment for those individual conditions.

Peter W.F. Wilson

“If BP is high, we reduce BP,” Rodriguez said. “If triglycerides are high or HDL is not at goal, we have medications for these things, but the first-line treatment is to begin a regimen for weight loss.”

“We’re certainly not all the way there yet in terms of being able to offer great cures,” Hawkins said. “We know that bariatric surgery works, but that comes with risk and incredible cost. A 5% weight loss truly does seem to be the magic number for a lot of different conditions and is probably our most promising treatment.”

Although cardiologists often see patients once they have been diagnosed with cardiometabolic syndrome, they can still play an important role in the care of these patients.

“It’s important we treat patients with cardiometabolic syndrome aggressively and we do risk factor modifications aggressively,” Cho said.

Yehuda Handelsman

Medical therapies

There are no FDA-approved drugs with an indication to treat prediabetes or metabolic syndrome. Metformin, approved for adults with type 2 diabetes, may serve as a useful off-label option to prevent progression to overt diabetes among people with metabolic syndrome, Wilson said. In the landmark Diabetes Prevention Program (DPP) study, participants with prediabetes or metabolic syndrome assigned to a metformin therapy arm were 30% less likely to develop diabetes compared with participants assigned to usual care.

“It’s never been fully considered a recommendation, but it is an expert opinion in the American Diabetes Association literature, and it essentially states that if there is a person who looks like they belong in the DPP, why not give them metformin?” Wilson said.


Hawkins said medical therapy, in particular weight-loss drugs, could help patients with metabolic syndrome who struggle to lose weight and keep it off.

“The good news is there are more and more pharmacologic approaches, and even endoscopic approaches,” Hawkins said. “We have to be cautious. All of these have possible adverse effects, but there are some very interesting combinations, like naltrexone/bupropion (Contrave, Nalpropion Pharmaceuticals). These get at new mechanisms, like looking at reward pathways.”

Nutrition, specifically the quality of the diet, should be focused on to reduce risk.

Valentina Rodriguez

“There are so many conversations today about what the best diet is,” Eckel said. “The best diet is whatever works best in terms of both quality of the diet and risk factors, and also weight reduction if that’s a goal for most of these patients, which it is.”

According to Subramanian, who said metformin for select high-risk patients is not a bad idea, medical therapy is still not as effective as lifestyle management. In the DPP study, participants assigned to a lifestyle intervention arm that included 16 sessions with counselors and dietitians reduced their risk for developing diabetes by about 70%.

Prevention as a team

When a person meets the criteria for metabolic syndrome, clinicians should not underestimate the role of positive coaching and motivational interviewing, Hawkins said. The diagnosis offers providers an opportunity to intervene early, set goals on the path to wellness and prevent associated diseases.

Several centers across the country have developed clinics that integrate cardiology and endocrinology, for example, for a more comprehensive approach to caring for patients with metabolic syndrome. This also allows the opportunity to consolidate clinic visits.

Meredith A. Hawkins

“If we have a primary care physician, an endocrinologist and a cardiologist, and patients are flipping back and forth between these three types of physicians for their care, I don’t think the patient likes that much, and most don’t,” Eckel said. “Ultimately in terms of the cost of the system, we think [consolidating clinic visits] would be a cost-saving kind of opportunity.”

Cho said the team at her institution includes a cardiologist who is boarded in endocrinology in addition to several endocrinologists to care for patients with cardiometabolic syndrome. She also recommended a nutritionist, exercise physiologist, psychologist and psychiatrist on this team to aid in weight management.

“We think it’s that important to work collaboratively because there are things we don’t know, and for us to think that we somehow know more than our endocrine colleagues in all of the subtleties of insulin resistance and insulin management, that’s silly,” Cho said. “It takes a village to treat metabolic syndrome.” – by Regina Schaffer and Darlene Dobkowski, MA