'Metabolically Healthy Obese' Concept Again Challenged in Huge Cohort

September 14, 2017

WASHINGTON, DC — People who are overweight or obese by BMI criteria, even lacking several well-established cardiometabolic risk factors, are at significantly increased risk of coronary heart disease (CHD), cerebrovascular disease, and heart failure compared with normal-weight people without those risk factors, concludes a study using a massive UK primary-care database[1].

The finding, which appeared to be independent of sex, argues against the existence of a "metabolically healthy obese" (MHO) phenotype that numerous studies have either supported or refuted in recent years. The evidence also varies for the similar "fat-but-fit" condition that considers fitness, usually based on activity level or exercise capacity, more than metabolic markers.

Of the almost 3.5 million adults in The Health Improvement Network (THIN) database mined for the study, all of whom were initially without heart disease and tracked for an average of 5.4 years, about 15% were found to have the MHO phenotype at baseline—that is, they had a BMI of at least 30 and lacked the three studied cardiometabolic risk factors: diabetes, hypertension, and hyperlipidemia.

The analysis also showed people who were underweight by standard BMI criteria were at increased risk for heart failure and cerebrovascular disease compared with normal-weight people even if they were metabolically healthy by the study's criteria.

The study, which follows a recent finding from a smaller but still large European cohort, along with other studies, that the MHO remain at increased CHD risk over more than a decade, "robustly challenges the assertion that MHO is a benign condition," write the authors, led by Dr Rishi Caleyachetty (University of Birmingham, UK).

The report was published September 11, 2017 in the Journal of the American College of Cardiology.

Is "MHO" Really a Thing?

It's wrong to classify MHO people as "healthy," said corresponding author Prof G Neil Thomas (University of Birmingham). "I think the data show on a population level that that's not the case," he told theheart.org | Medscape Cardiology.

"If you are obese, even without the risk factors, over time you will go on and develop cardiovascular disease. The risk is quite increased," he said, pointing out that, consistent with obesity as a risk in and of itself, adipose tissue is metabolically active and a mediator of CV risk markers.

However, it's a major limitation of the analysis that it did not include data on physical activity, exercise, or fitness level, said Dr Carl J Lavie (Ochsner Clinical School-University of Queensland School of Medicine, New Orleans, LA), in commenting on the findings. But he "doesn't fault it for that" since such information wouldn't normally be available from standard health records for millions of people.

Still, "I'm almost positive if they had data on fitness, they would show that the people who were relatively fit, who are metabolically healthy, with obesity, probably would not have a significantly increased risk. Or if they did have it, it would be maybe just for heart failure," he said. "In studies that have factored both, they've generally showed that fitness is more important than fatness for predicting prognosis."

Lavie, who isn't involved in the current research but is vastly published on the subject, said that it shows "only a pretty small increase" in risk among the MHO for the outcome that is the most important at the population level. In it, "they actually have a lower risk of coronary disease than the normal-weight people who had just one risk factor."

Thomas acknowledged that exercise or fitness data for the MHO certainly weren't available in their data base but said it's worth looking into. If such information were added, "What I think it would do is probably stratify the risk more among those individuals, so those who are fitter are probably going to have less risk than those who are less fit. To what extent that reduces the risk, we don't know at the moment."

Also, among people classified as MHO, "those likely to be fitter are probably going to be younger," Thomas said. Few of them, even among those who are both obese and not fit, will have cardiovascular events while still young. But at the population level, he said, most will lose that protection as they age and their cardiometabolic markers will start looking less favorable.

About 15% Would Be Classified MHO

 At baseline for the 3,495,777 individuals in the THIN data analysis, 37.7% were normal weight (BMI >18 but <25 kg/m2) with no metabolic abnormalities, 25.7% were overweight (>25 but <30 kg/m2) with no metabolic abnormalities, and 14.8% were obese (>30 kg/m2) with no metabolic abnormalities.

Among those with none of the three metabolic abnormalities, those who were overweight had a CHD risk-adjusted hazard ratio (HR) of 1.30 (95% CI 1.27–1.34), and it was 1.49 (95% CI 1.45-1.54) for those who were obese, all compared with normal-weight persons without the three metabolic abnormalities.

The HRs were adjusted for age, sex, smoking status, and indices of "social deprivation" including income, education, and employment.

Those who were obese without metabolic abnormalities showed an HR for cerebrovascular disease of 1.07 (95% CI 1.04–1.11).

The HR for heart failure in the absence of the metabolic abnormalities was 1.11 (95% CI 1.06–1.16) for the overweight and 1.96 (95% CI 1.86–2.06) for the obese.

Also, 2.7% of the population were underweight (<18 kg/m2) with no metabolic abnormalities. Their adjusted HR for of cerebrovascular disease, compared with normal-weight people without the metabolic abnormalities, was 1.31 (95% CI 1.23–1.40) and for heart failure was 1.36 (95% CI 1.23–1.51).

The analyses also looked at the HR for peripheral vascular disease (PVD) by BMI category, which—compared with those of normal weight and in the context of zero metabolic abnormalities—were, interestingly, 1.49 (95% CI 1.36–1.63) for the underweight but 0.92 (95% CI 0.88–0.96) for the overweight and 0.91 (95% CI 0.86–0.96) for the obese.

The authors speculated that the increased risks for events among the underweight "may be related to smoking-related diseases such as COPD and lung cancer." So they ran an analysis limited to never-smokers. "The results were unchanged from the main results with the exception that underweight individuals with no metabolic abnormalities now had a nonsignificant risk for cerebrovascular disease."

The study "not only definitively countered the concept of metabolically benign obesity but also demonstrated great risk to normal-weight individuals if metabolic dysfunction is present," write Drs Jennifer Bea and Nancy K Sweitzer (University of Arizona, Tucson) in an accompanying editorial[2].

Still using normal weight with zero metabolic abnormalities for comparison, persons of normal weight with one or two metabolic abnormalities showed significant jumps in risk for all four clinical outcomes. The risks climbed even further when all three abnormalities were present.

Those risk increases in normal-weight people were comparable to the corresponding risk increases among people classified as overweight or obese, at least for three of the clinical outcomes; the obese consistently had a much higher risk of heart failure.

"Certainly, once the number of metabolic abnormalities reached three, the weight category was irrelevant for most outcomes," write the editorialists. "Thus, we would suggest an increased need for screening in the normal-weight population."

The authors of both the report and the editorial report that they have no relevant financial relationships. Lavie is the author of The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier (Avery, 2014).

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