Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis

$\textbf{Aims}$ The hypothesis of ‘metabolically healthy obesity’ implies that, in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk. We tested this hypothesis in a large pan-European prospective study. $\textbf{Methods and results}$ We conducted a case-cohort analysis in the 520 000-person European Prospective Investigation into Cancer and Nutrition study (‘EPIC-CVD’). During a median follow-up of 12.2 years, we recorded 7637 incident coronary heart disease (CHD) cases. Using cut-offs recommended by guidelines, we defined obesity and overweight using body mass index (BMI), and metabolic dysfunction (‘unhealthy’) as ≥ 3 of elevated blood pressure, hypertriglyceridaemia, low HDL-cholesterol, hyperglycaemia, and elevated waist circumference. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI) within each country using Prentice-weighted Cox proportional hazard regressions, accounting for age, sex, centre, education, smoking, diet, and physical activity. Compared with metabolically healthy normal weight people (reference), HRs were 2.15 (95% CI: 1.79; 2.57) for unhealthy normal weight, 2.33 (1.97; 2.76) for unhealthy overweight, and 2.54 (2.21; 2.92) for unhealthy obese people. Compared with the reference group, HRs were 1.26 (1.14; 1.40) and 1.28 (1.03; 1.58) for metabolically healthy overweight and obese people, respectively. These results were robust to various sensitivity analyses. $\textbf{Conclusion}$ Irrespective of BMI, metabolically unhealthy individuals had higher CHD risk than their healthy counterparts. Conversely, irrespective of metabolic health, overweight and obese people had higher CHD risk than lean people. These findings challenge the concept of ‘metabolically healthy obesity’, encouraging population-wide strategies to tackle obesity.EPIC-CVD has been supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270 and MR/L003120/1), the British Heart Foundation (SP/09/002 and RG/08/014 and RG13/13/30194), and the UK National Institute of Health Research. EPIC Asturias was also supported by the Regional Government of Asturias. EPIC-Greece is also supported by the Hellenic Health Foundation. EPIC- Heidelberg was also supported by the German Cancer Aid, German Cancer Research Centre, German Federal Ministry of Education and Research. EPIC-Oxford was also supported by the UK Medical Research Council (MR/M012190/1) and Cancer Research UK (570/A16491). EPIC-Ragusa was also supported by the Sicilian Government, AIRE ONLUS Ragusa, and AVIS Ragusa. EPIC-Turin was supported also by the Compagnia di San Paolo and the Human Genetics Foundation-Torino (HuGeF)