Obesity, Metabolic Health Status, and Adverse Outcomes in Men and Women

Metabolically healthy obesity account for approximately one-third of individuals with obesity and could affect up to 300million individuals worldwide. Whether this is a truly benign cardiometabolic phenotype as the name suggests is incompletely defined, leading to uncertainty regarding the optimal risk stratification and management strategies for these individuals. To assess the sex-specific independent and joint associations of obesity and metabolic health status on cardiometabolic outcomes and death. A prospective cohort study of UK Biobank participants free from cardiovascular diseases and not underweight. Participants were divided by BMI into normal, overweight or obese, and the presence or absence of ≥1metabolic abnormality (hypertension, diabetes or dyslipidaemia). Exposures were assessed at baseline(2006-2010), with outcomes ascertained over a median follow-up of 12.9 years(IQR 12.6-13.3). Sex-specific outcomes were fatal or non-fatal atherosclerotic cardiovascular disease(ASCVD; a composite of coronary heart disease, ischaemic stroke, and peripheral artery disease), heart failure(HF), metabolic dysfunction-associated steatotic liver disease(MASLD), end-stage renal disease(ESRD) and all-cause mortality. Multivariable-adjusted cox regression models were used to estimate hazard ratio (HR) and 95%CI. Among 157,159 participants (mean age 56.5years SD 8.2; 55.6% women), 24.2% were obese and 68.2% had ≥1 metabolic abnormality. Compared to normal BMI and no metabolic abnormality (reference group), obesity was associated with increased risk of ASCVD(HR 1.46, 95%CI 1.24-1.73), HF(1.63,1.14-2.32), MASLD(2.37,1.22-4.61), all-cause mortality(1.36,1.10-1.69) but not ESRD in men without metabolic abnormalities, which increased when any metabolic abnormality was present: ASCVD(2.21,2.03-2.41), HF(2.91,2.41-3.50), MASLD(6.84,4.60-10.18), ESRD(5.42,2.94-10.02), and all-cause mortality(1.62,1.45-1.81). Corresponding risk from obesity in women without metabolic abnormalities were: ASCVD(1.34,1.14-1.58), HF(1.69,1.21-2.37), MASLD(4.44,3.00-6.59), and all-cause mortality(1.27,1.05-1.52) but not ESRD, which increased when metabolic abnormalities were present: ASCVD(2.51,2.30-2.74), HF(3.67,3.04-4.43), MASLD(8.17,6.13-10.89), ESRD(7.96,4.00-15.85) and all-cause mortality(1.67,1.51-1.85). Adverse outcomes increased with severity of obesity, the presence of central obesity, and with increasing numbers of metabolic abnormalities, with an effect modification by sex suggesting more harm from obesity, central obesity and metabolic abnormalities in women. Obesity without metabolic abnormalities is not benign and associated with multiple adverse cardiometabolic outcomes, further exacerbated when metabolic abnormalities occur. As 300million individuals may be considered metabolically healthy but obese, future studies should explore whether preventing or reversing obesity prior to the appearance of significant metabolic abnormalities results in improved health outcomes. This prospective-cohort study of over 1.9 million person-years follow-up demonstrates that obesity without metabolic abnormality increases the risk of ASCVD by 46% in men and 34% in women respectively, HF by 63% and 69%, MASLD by 137% and 344% and all-cause mortality by 36% and 27%, compared to those with normal BMI, with graded increase as severity of obesity increases. The presence of metabolic abnormality doubles event-rates associated with obesity, with risk increasing with number of metabolic-abnormalities present. These findings suggest that obesity without metabolic abnormality is not benign and support efforts to prevent or reverse obesity before overt metabolic dysfunction manifests.