Metabolically healthy obesity, vitamin D, and all-cause and cardiometabolic mortality risk in NHANES III

Abstract

Background & aims: Previous studies assessing the prognosis of metabolically healthy obesity (MHO) have been limited by a lack of a harmonized definition of MHO phenotype. Furthermore, obesity is a risk factor for vitamin D deficiency and low vitamin D status has been associated with a higher risk of mortality; however, few studies have evaluated the joint association between vitamin D, metabolic health phenotype, and mortality risk. Using a harmonized definition, we investigated whether MHO is associated with subsequent all-cause and cardiometabolic mortality, and whether serum 25-hydroxyvitamin D [25(OH)D] modifies these associations.

Methods: This study included participants aged ≥20 years from the Third National Health and Nutrition Examination Survey (NHANES III). MHO phenotype was defined as a combination of obesity (≥30 kg/m²) and zero component of metabolic syndrome. Multivariable Cox regression was used to assess the risk of mortality across metabolic phenotypes, and the joint association between metabolic phenotype and 25(OH)D. Fine and Gray regression was performed to account for competing risk events.

Results: Among 11,333 participants, a total of 2980 deaths (937 cardiometabolic death outcomes) occurred during a median follow-up of 19.1 years. In the absence of any metabolic abnormality, obesity (MHO) was not associated with a higher risk of all-cause (hazard ratio [HR], 0.89 [95% CI, 0.52-1.51]) or cardiometabolic mortality (cause-specific HR, 1.21 [95% CI 0.33-4.46]). Similar results were obtained from competing risk analysis. No significant differences in average 25(OH)D levels were observed between MHO and non-MHO participants; however, there was a significant interaction between metabolic health phenotype and serum 25(OH)D in relation to cardiometabolic mortality such that levels of serum 25(OH)D < 50 nmol/L were associated with increased risk of cardiometabolic mortality, particularly in participants within the normal-weight and obese BMI ranges.

Conclusions: Our results support the hypothesis that MHO phenotype is a benign health condition. Vitamin D deficiency may exacerbate the risk of cardiometabolic death outcomes associated with metabolic dysfunction in normal weight and obese individuals. Further research is warranted to validate our findings.

Keywords: All-cause mortality; Cardiometabolic mortality; Metabolically healthy obesity; National Health and Nutrition Examination Survey III; Standardized serum 25-hydroxyvitamin D; Vitamin D.