Association of obesity–metabolic phenotypes with coronary artery disease prevalence: interaction and exploratory mediation analyses of high-sensitivity C-reactive protein

Objective To investigate the associations of obesity–metabolic phenotypes with coronary artery disease (CAD) prevalence and to evaluate the interaction between obesity and metabolic unhealthiness and the potential mediating role of high-sensitivity C-reactive protein (hsCRP). Methods A total of 860 participants were classified as metabolically healthy non-obese (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy non-obese (MUNO), or metabolically unhealthy obesity (MUO). Associations with CAD prevalence were estimated using modified Poisson regression with robust variance. Interactions between obesity and metabolic unhealthiness were assessed on multiplicative and additive scales. Subgroup and sensitivity analyses were performed, followed by an exploratory mediation analysis of hsCRP. Results Among 860 participants, 563 (65.5%) had CAD. After adjustment for age, sex, current smoking, alcohol use, family history of CAD, lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and estimated glomerular filtration rate (eGFR), the prevalence ratios for CAD were 1.51 [95% confidence interval (CI), 1.26–1.81] for MHO, 1.73 (95% CI, 1.48–2.02) for MUNO, and 1.79 (95% CI, 1.53–2.10) for MUO compared with MHNO (all P < 0.001). Negative interactions between obesity and metabolic unhealthiness were observed on both the multiplicative scale (interaction ratio, 0.69; 95% CI, 0.56–0.84) and the additive scale [relative excess due to interaction (RERI), −0.44; 95% CI, −0.79 to −0.13]. Results were consistent across sensitivity analyses. Exploratory mediation analysis showed average indirect effects through hsCRP of 1.94, 5.93, and 8.20 percentage points for MHO, MUNO, and MUO, respectively, corresponding to proportions mediated of 9.4%, 19.6%, and 23.6%. Conclusions MHO, MUNO, and MUO were all associated with higher CAD prevalence, with stronger associations observed for metabolically unhealthy phenotypes. Obesity and metabolic unhealthiness showed a negative interaction. Exploratory findings indicated an hsCRP-related indirect association, but causal mediation cannot be inferred from this cross-sectional study.