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More Doubt for 'Metabolically Healthy Obesity'

Miriam E. Tucker
May 31, 2018

Obesity remains a risk factor for cardiovascular disease even among those who are otherwise "metabolically healthy," new data from the Nurses' Health Study suggest.

Nathalie Eckel, MSc, from the German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany, and colleagues report their findings in an article published online May 30 in The Lancet Diabetes & Endocrinology.

The analysis, which included 90,257 women followed for a median of 24 years, revealed that "metabolically healthy" women — that is, without baseline diabetes, hypertension, or hypercholesterolemia — had a significantly lower risk for cardiovascular disease (CVD) than did women with those conditions, regardless of body mass index (BMI).

However, even among those who were metabolically healthy, the women with overweight or obesity had a greater risk for CVD than did those of normal weight.

In addition, regardless of BMI, most women who were metabolically healthy at baseline did not remain so over time, and the transition to being metabolically unhealthy was associated with greater cardiovascular risk.

"These findings suggest that individuals who are metabolically healthy might benefit from early behavioral and medical management focusing on preventing progression to being metabolically unhealthy (eg, by improving overall diet and increasing physical activity)," Eckel and colleagues write.

In an accompanying editorial, Carl J. Lavie, from the University of Queensland School of Medicine in New Orleans, Louisiana, and colleagues, write, "The greatest contribution of this study is providing important insights about how changes or maintenance of weight and metabolic status affect the prognosis of cardiovascular disease."

However, the editorialists fault the study for not assessing physical activity levels "or, more importantly, the powerful contribution of cardiorespiratory fitness, which might be one of the strongest predictors of cardiovascular disease and all-cause mortality... We have argued that fitness is more important than fatness, and those with metabolically healthy obesity and decent levels of cardiorespiratory fitness have a quite good overall prognosis from cardiovascular disease and overall survival."

Even for 'Metabolically Healthy,' High BMI Worsens CVD Risk

The authors used data from the 1980 Nurses' Health Study questionnaire as baseline, when the participants were aged 30 to 55 years. The follow-up included questionnaires mailed every 2 years. Investigated outcomes were fatal and nonfatal myocardial infarction (MI) and stroke, and their combination as total CVD.

The women were classified into normal weight (BMI, 18.5 to 24.9 kg/m2), overweight (BMI, 25.0 to 29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). Metabolic health was defined by the absence of hypertension, diabetes, and hypercholesterolemia.

During a median follow-up of 24 years, there were 6306 cases of CVD, including 3304 myocardial infarctions and 3080 strokes.

Compared with patients with metabolically healthy normal weight (n = 50,336), the hazard ratios (HRs) for CVD were 2.43 for the 8629 women with metabolically unhealthy normal weight, 2.61 for the 5708 women with metabolically unhealthy overweight, and 3.15 for the 4252 women with metabolically unhealthy obesity, all statistically significant.

In the metabolically healthy group, women who were overweight or obese had significantly greater CVD risk than did those of normal weight (HR, 1.20 and 1.39, respectively).

Development of Metabolic Risk Worsens CVD Outcomes

After adjustments for age, race, and other variables, the development of diabetes or hypertension over time was associated with significantly greater CVD (MI and/or stroke) risk among all baseline BMI groups, but the risk was greater with higher BMI.

For example, compared with women of normal weight at baseline who didn't develop diabetes, the HRs among those who did develop diabetes were 1.29 for the normal weight category at baseline, 1.93 for overweight, and 2.17 for obese. The corresponding HRs for development of hypertension were 1.92, 1.87, and 2.03, respectively, all significant.

Interestingly, the same relationship was not seen with the development of hypercholesterolemia. "Whether this reflects effectiveness of initiated pharmacological treatment of hypercholesterolemia to reduce cardiovascular disease risk might be worthwhile to investigate in other study populations," Eckel and colleagues write.

Still, even without developing any of the metabolic risk factors, women with metabolically healthy overweight and obesity remained at increased risk compared with those with metabolically healthy normal weight, with multivariate-adjusted HRs of 1.20 and 1.39, respectively.

Few Remained Metabolically Healthy Over Time

Of the total 71,668 women who were metabolically healthy at baseline in 1980, 84% overall converted to metabolically unhealthy over the study period. The proportions remaining metabolically healthy by 2010 were 15.4% of those of normal weight, 7.9% overweight, and 6.1% obese.

Within each BMI group, those remaining metabolically healthy had substantially lower cardiovascular risk during follow-up than women who were metabolically unhealthy at any time point. But still, metabolically healthy obese women who remained so through the year 2000 were at 1.57-fold greater cardiovascular risk than those of normal weight who remained metabolically healthy.

Implication: Preventing Metabolic Syndrome Key

The findings suggest that "Current definitions of metabolic health are insufficient to identify a subgroup of obesity not at risk," Eckel and colleagues say.

In the editorial, Lavie and colleagues write that this study and others "strongly support preventing the development of metabolic syndrome, which can be accomplished by preventing weight gain with physical activity and exercise training, as well as incorporating dietary strategies of reduced caloric intake, possibly by reducing calories from simple sugars and carbohydrates."

Additionally, the editorialists say, "increasing physical activity and exercise to improve levels of cardiorespiratory fitness is especially important to lower the cardiovascular disease risk in almost all groups of patients, including women with obesity."

The study was funded by the US National Institutes of Health and grants from the German Federal Ministry of Education and Research to the German Center for Diabetes Research. Eckel has no further disclosures, and the editorialists have disclosed no relevant financial relationships.

Reviewed on 5/31/2018

SOURCE: Medscape, May 31, 2018. Lancet Diabetes Endocrinol. Published online May 30, 2018.

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