Association between adiposity and cardiovascular outcomes: an umbrella review and meta-analysis of observational and Mendelian randomization studies

Abstract

Aims: The aim of this study was to investigate the causal relationship and evidence of an association between increased adiposity and the risk of incident cardiovascular disease (CVD) events or mortality.

Methods and results: Observational (informing association) and Mendelian randomization (MR) (informing causality) studies were assessed to gather mutually complementary insights and elucidate perplexing epidemiological relationships. Systematic reviews and meta-analyses of observational and MR studies that were published until January 2021 and evaluated the association between obesity-related indices and CVD risk were searched. Twelve systematic reviews with 53 meta-analyses results (including over 501 cohort studies) and 12 MR studies were included in the analysis. A body mass index (BMI) increase was associated with higher risks of coronary heart disease, heart failure, atrial fibrillation, all-cause stroke, haemorrhagic stroke, ischaemic stroke, hypertension, aortic valve stenosis, pulmonary embolism, and venous thrombo-embolism. The MR study results demonstrated a causal effect of obesity on all indices but stroke. The CVD risk increase for every 5 kg/m2 increase in BMI varied from 10% [relative risk (RR) 1.10; 95% confidence interval (CI) 1.01-1.21; certainty of evidence, low] for haemorrhagic stroke to 49% (RR 1.49; 95% CI 1.40-1.60; certainty of evidence, high) for hypertension. The all-cause and CVD-specific mortality risks increased with adiposity in cohorts, but the MR studies demonstrated no causal effect of adiposity on all-cause mortality.

Conclusion: High adiposity is associated with increased CVD risk despite divergent evidence gradients. Adiposity was a causal risk factor for CVD except all-cause mortality and stroke. Half (49%; 26/53) of the associations were supported by high-level evidence. The associations were consistent between sexes and across global regions. This study provides guidance on how to integrate evidence from observational (association) and genetics-driven (causation) studies accumulated to date, to enable a more reliable interpretation of epidemiological relationships.

Keywords: Cardiovascular disease; Coronary heart disease; Mendelian randomization study; Meta-analysis; Stroke; Umbrella review.

Observational studies (informing associations) and Mendelian randomization studies (informing causality) provided mutually complementary insight and enabled a more reliable interpretation of perplexing epidemiological relationships. This figure was constructed based on the summary of evidence shown in Table 1.

Figure 1

Flow diagram of the study search and selection process.

Figure 2

Collective results of observational studies. (A) Increased risk of cardiovascular events with elevated continuous and categorical body mass index. (B) Increased risk of death with elevated continuous body mass index. All results are based on random-effect models. The cohort and participant columns display the number of independent cohorts and the total number of participants incorporated in the meta-analysis for the outcome. The certainty of evidence underlying each association between body mass index and cardiovascular outcomes was evaluated using the GRADE framework. BMI, body mass index; ES, effect size; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; HR, hazard ratio; OR, odds ratio; RR, risk ratio or relative risk.

Figure 3

Collective results of Mendelian randomization studies. (A) Increased risk of cardiovascular events per 1 kg/m² increase in body mass index. (B) Increased risk of cardiovascular events per 5 kg/m² increase in body mass index. (C) Increased risk of death per 1 kg/m² increase in body mass index. All results are based on random-effects models. The cohort and cases columns display the number of independent cohorts and the number of cases incorporated in the meta-analysis for the outcome. BMI, body mass index; ES, effect size; HR, hazard ratio; OR, odds ratio; RR, risk ratio or relative risk.

Figure 4

Subgroup analyses of risk of cardiovascular diseases for central adiposity (A), categorical body mass index (B), and sex (C). All results are based on random-effects models. The cohort and participant columns display the number of independent cohorts and the total number of participants incorporated in the meta-analysis for the outcome. The certainty of evidence was evaluated using the GRADE framework. BMI, body mass index; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; RR, risk ratio or relative risk.

Figure 5

Risks of cardiovascular incidences and mortalities were re-analysed according to regions. BMI, body mass index; CVD, cardiovascular disease; CHD, coronary heart disease; ES, effect size; HR, hazard ratio; OR, odds ratio; RR, risk ratio or relative risk.