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

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. 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. 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.
European Union (EU) HEALTH-F2-2012-279233
European Research Council (ERC) 268834
Medical Research Council UK (MRC) G0800270 MR/L003120/1 MR/M012190/1
British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194
National Institute for Health Research (NIHR)
Regional Government of Asturias
Hellenic Health Foundation
German Cancer Aid, German Cancer Research Centre, German Federal Ministry of Education and Research
Cancer Research UK 570/A16491
Regione Sicilia
Associazione Iblea per la Ricerca Epidemiologica (A.I.R.E.) - ONLUS Ragusa
Associazione Volontari Italiani Sangue AVIS Ragusa
Compagnia di San Paolo
Human Genetics Foundation-Torino (HuGeF)
British Heart Foundation RG/13/13/30194 RG/08/014/24067
Cancer Research UK 16491
Medical Research Council UK (MRC) MR/L003120/1 G0800270 MC_UU_12015/1
National Institute for Health Research (NIHR) NF-SI-0512-10135 NF-SI-0512-10165
Novo Nordisk Foundation NNF17OC0026936