Abstract

Background and Aims Obesity is causally associated with multiple cardiovascular outcomes but effective population measure to control obesity is limited. This study aims to decipher to which extent excess atherosclerotic cardiovascular diseases (ASCVD) and heart failure (HF) risk due to obesity can be explained by conventional risk factors. Methods This is a prospective cohort study of 404,332 White UK Biobank participants. Participants with prior CVDs or other chronic diseases at baseline, or body mass index (BMI) <18·5 kg/m2 were excluded. Data were collected at the baseline assessment between 2006 and 2010. Linkage to death registrations and hospital admission records was used to ascertain ASCVD and HF outcomes up to late 2021. Obesity was defined as BMI ≥30 kg/m2. Candidate mediators included lipids, blood pressure, glycated haemoglobin (HbA1c), and liver and kidney function markers, which were chosen based on clinical trials and Mendelian randomisation studies. Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95% confidence intervals (CIs). Mediation analysis based on g-formula was used to separately estimate the relative importance of mediators for ASCVD and HF. Results Compared with people without obesity, obese people had an increased risk of ASCVD (HR 1.30, 95% CI 1.26–1.35) and HF (HR 2.04, 95% CI 1.96–2.13) after adjusting for sociodemographic and lifestyle factors and medications for cholesterol, blood pressure and insulin. The strongest mediators for ASCVD were renal function (eGFR: mediation proportion: 44.6%), blood pressure (SBP: 24.4%; DBP: 31.1%), triglycerides (19.6%), and hyperglycaemia (HbA1c 18.9%). These mediators collectively explained more excess risk of ASCVD than that of HF. Conclusions Interventions that help obese individuals to maintain healthy lipid concentrations, blood pressure, glycaemic control and kidney function could potentially alleviate a sizable proportion of the ASCVD burden. However, HF burden could not be meaningfully reduced without weight management.