Background: Little is known about the natural history of progression from a metabolically benign overweight/obese (MBO) to at-risk overweight/obese (ARO) phenotype. Improved understanding would help clinicians focus on controlling risk factors that predispose an obese individual to progression.Methods: Using discrete-time proportional hazard modeling on data from the Study of Women\u27s Health Across the Nation (SWAN), we examined the incident progression from MBO (less than two metabolic syndrome abnormalities) to ARO (two or more metabolic syndrome abnormalities) and factors associated with progression over a 7-year period.Results: Of 866 MBO women at baseline, 43% progressed to the ARO phenotype. Compared with those who remained MBO, those who progressed had higher baseline BMI and a higher prevalence of cardiometabolic abnormalities (elevated glucose, triglycerides, blood pressure and low high-density lipoprotein cholesterol). In multivariable analyses, an increase in body mass index was associated with a modest increase in the risk of progression. Although all cardiometabolic abnormalities were associated with an increased risk, the baseline impaired fasting glucose showed the strongest association with the risk of progression [hazard ratio 3.24; 95% confidence interval 2.10, 4.92; P \u3c .001]. Physical activity played a protective role in decreasing the risk of progression [hazard ratio 0.86; 95% confidence interval 0.80, 0.92; P \u3c .001].Conclusions: Increasing obesity and the presence of cardiometabolic abnormalities increase the risk of progression, whereas physical activity is the only lifestyle factor protective against progression from metabolically benign to the at-risk overweight/obese phenotype, a state that is unanimously associated with an elevated risk of cardiovascular morbidity and mortality
