Obesity Severity Phenotypes, Relevant Biomarkers, and Cardiovascular Disease: The Cross-Cohort Collaboration (CCC)

Abstract

The global obesity pandemic is well documented and continues to pose a major public health threat. In 2022, the World Health Organization (WHO) classified more than 2.5 billion adults worldwide as overweight, including 890 million with obesity. In the U.S., projections indicate that by 2030, 1 in 2 adults will have obesity (BMI ≥30 kg/m²), and 1 in 4 will have severe obesity (BMI ≥35 kg/m²). Obesity is a well-established risk factor for numerous diseases, including type 2 diabetes mellitus, hypertension, obstructive sleep apnea, fatty liver disease, osteoarthritis, cancer, and cardiovascular disease (CVD), such as coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF). Using the Cross Cohort Collaboration (CCC), a harmonized dataset of 24 U.S.-based prospective cohort studies, we examined the relationship between BMI and CVD outcomes across a broad BMI spectrum, with a focus on severe obesity (Class II: BMI 35.0–39.9 kg/m²; Class III: BMI ≥40.0 kg/m²). Our findings show that while obesity was associated with increased risk for all outcomes, stratifying obesity into sub-classes revealed that relative risk increases with obesity severity, even after accounting for traditional CVD risk factors. We also evaluated the long-term impact of central adiposity on multiple CVD subtypes, with particular attention to discordant adiposity groups (e.g., normal BMI with elevated central adiposity). Our findings underscore the need to identify and address central obesity, even among individuals with a normal BMI. These results support incorporating central adiposity measures as routine clinical assessments to improve cardiovascular risk stratification. Finally, we explored the relationship between obesity and subclinical markers of inflammation, thrombosis, and atherosclerosis to better understand underlying mechanisms. Our results demonstrated a positive, graded association between BMI and elevated levels of these markers, with the strongest associations observed in Class III obesity.