Objective: To evaluate the strength and certainty of the evidence underlying an association between increased adiposity, as assessed by body-mass index (BMI), waist circumference (WC), or waist-to-hip ratio (WHR) and identify the risk of incident cardiovascular disease (CVD) events or mortality Design: Umbrella review of systematic reviews and meta-analyses. Data sources: Google Scholar, PubMed, Embase, Cochrane Database of Systematic Reviews, and manual screening of retrieved references Eligibility criteria: Systematic reviews or meta-analyses of observational studies and Mendelian randomisation (MR) studies that evaluated the association between various obesity-related indices and the risk of developing CVD and/or mortality due to CVD Data synthesis: Eleven systematic reviews and 53 meta-analyses that investigated associations between obesity and cardiovascular outcomes were included. Results from recently published cohort studies were also incorporated into the existing meta-analyses to update them with more recent data. Thus, the present study compiled all the relevant evidence accumulated to date, encompassing a total of 488 cohorts and over 30 million participants. MR studies were collected to identify any causal relationship between obesity and various CVD outcomes, and to avoid reverse causality. The degree of obesity was measured with BMI, WC, and WHR. The evidence levels of pooled results were graded into high, moderate, low, and very low according to the Grading of Recommendations Assessment, Development and Evaluation framework. Results: An increase in BMI was associated with a higher risk of developing coronary heart disease, heart failure, atrial fibrillation, stroke, hypertension, aortic valve stenosis, pulmonary embolism, and venous thromboembolism; the study results corroborate the casual effect of obesity on the incidence of CVD, except stroke, based on MR studies. The increase in the risk of developing CVD for every 5 kg/m2 increase in BMI ranged from 7% (relative risk [RR], 1.07; 95% confidence interval [CI], 1.03 to 1.11) for stroke to 49% (RR, 1.49; 95% CI, 1.41 to 1.58) for hypertension. The risk of all-cause mortality and CVD-specific mortality increased with adiposity, which was supported by a high grade of evidence from observational analyses; however, the causal effect of obesity on mortality outcomes was not significant in MR studies. Conclusions: Only 15 out of the 53 associations (28%) reported for obesity and CVD outcomes were supported with high evidence levels from observational analyses. Although other reported associations might be valid, various degrees of uncertainty remain. The causal effect of obesity on 9 of the 14 CVD-related outcomes was corroborated by MR studies. As obesity is progressively increasing around the globe and because CVD remains a constant threat to public health, it is necessary to understand the gradient of evidence underlying the association between these two clinical entities. Any weak links in the association and causality discovered in this review should be reinforced with further scientific research, while high-certainty associations with established causality should be reflected in clinical practices and health policies.
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