Table 1.

Evidence map of the appraisal of the certainty of evidence (GRADE) of the association between obesity and each cardiovascular outcome

Main outcomes	Equivalent body fata		Central adipositya		Concordance (between observational and MR studies)b	Summary of evidencea	Interpretations and proposals for future study
	BMI category	BMI continuous (per unit increase)	WC	WHR
Risk for mortality
All-cause mortality	Moderate for overweight Moderate for obese High for severely obese	High for non-smokers Low for all population	—	—	No (not significant on MR study)	Moderate to high; no causality supported by MR study. Requires cautious interpretation	Results from meta-analyses of observational studies indicate an association; results of MR studies infer causality. Collective evidence suggested that adiposity may not be a causal risk factor for all-cause mortality despite solid associations with moderate to high certainty of evidence. Given that adiposity is a causal risk factor for CVD mortality, it is plausible that CVD mortality acted as a mediator between adiposity and all-cause mortality and complicated a thorough inspection of the actual relationship. Quantitatively synthesized evidence of the association between central adiposity (WC and WHR) and all-cause mortality is lacking, and future studies are required.
Heart failure	—	Not significant (very low)	—	—	MR study not reported	Very low	Heart failure-related death may have a very weak link with adiposity. Magnitude of the association and causality remains unsupported.
Coronary heart disease	—	High	—	—	Yes	High, with causality supported by MR study	Increased BMI is a causal risk factor for CHD mortality. However, to date, the association between CHD mortality and central adiposity (measured by WC and WHR) was studied at the individual study level, not in systematic reviews and meta-analyses; quantitative synthesis of evidence should be followed with the further accumulation of collective data.
Cardiovascular disease	—	High	—	—	Yes	High, with causality supported by MR study	The increase in BMI causes and escalates overall cardiovascular mortality. However, the association between CVD mortality and central adiposity (WC and WHR) is subject to future studies. It requires a further accumulation of collective data (in systematic reviews and meta-analyses).
All-cause stroke	—	High	—	—	No (not significant in MR study)	High, without causality supported by MR study. Requires cautious interpretation	MR study suggested no causal effect of adiposity on stroke-specific mortality; the result contradicts those of meta-analyses of observational studies. While adiposity may be associated with stroke death to some degree, more extensive studies may be required to resolve the disparity between the results of observational and MR studies. Prospective investigations on central adiposity (WC and WHR) will provide novel insight into the aetiology of stroke and stroke-specific death.
Sudden cardiac death	Low for overweight Low for obese	—	—	—	MR study not reported	Low level of evidence from observational studies; MR study not reported.	There is weak evidence that body fat increases the risk of sudden cardiac death, and the causal relationship remains unknown; future MR studies can elucidate the causality. The association between sudden cardiac death and central adiposity (WC and WHR) will be the subject of future studies.
Risk for developing CVD
Coronary heart disease	Very low for overweight Moderate for obese	High	—	—	Yes	Moderate in general, with causality supported by MR study	Collective evidence suggests that the increase in BMI is a causal risk factor for developing CHD. An association between the risk of CHD and central adiposity (WC and WHR) is the subject of a quantitative synthesis.
All-cause stroke	Not significant for overweight (low) Very low for obese	Low	—	—	Yesc (not significant in both observational and MR studies)	Low, without causality supported by MR study	Adiposity may not cause an all-cause stroke. Magnitude of association and certainty of evidence for the association were weak. An association between the risk of all-cause stroke and central adiposity (WC and WHR) is subject to quantitative synthesis.
Haemorrhagic stroke	—	Low	—	—	No (not significant in MR study)	Low, without causality supported by MR study	The MR study suggested no causal effect of adiposity on risk of haemorrhagic stroke; this result contradicts those of reports from the meta-analyses of observational studies. It should be noted that the association was borderline significant on the observational basis, and the directions of the adiposity effect on haemorrhagic stroke were opposite in Europe/North America/Australia vs. Asia, which further weakens the significant associations described in the meta-analysis of observational studies. It would be more reasonable considering that data from observational studies and MR studies are in concord against the association. An association between the risk of haemorrhagic stroke and central adiposity (WC and WHR) will be the subject of future studies.
Ischaemic stroke	—	High	—	—	No (not significant in MR study)	High, without causality supported by MR study	The MR study suggested no causal effect of adiposity on ischaemic stroke; this result contradicts those of the reports from the meta-analyses of observational studies. While adiposity may be associated with ischaemic stroke to some degree, more extensive studies may be required to resolve the disparity. The findings indicated that ischaemic stroke is more likely to be associated with adiposity than haemorrhagic stroke, which may suggest the underlying mechanism of the adiposity effect on stroke outcomes. Prospective investigations on the association between central adiposity and the risk of ischaemic stroke are necessary.
Heart failure	Not significant for overweight (very low) Low for obese Not significant for severe obese (very low)	High	High	Moderate	Yes	Heterogeneous for BMI, generally high for central adiposity; causality supported by MR study	Concerning the high level of evidence of the association between continuous BMI and heart failure, the association might indicate the dose–response relationship (inferring causality); however, the weak evidence level of the association between categorical BMI and heart failure might imply that the association is weak or inconclusive. Given the small number of studies investigating the association (≤10 studies), the latter would be more likely. Heterogeneous results across diverse adiposity indices complicate the interpretation and clarification of the association. Further studies should be performed to increase the level of evidence and minimize inconsistency.
Atrial fibrillation	Moderate for obese	High	High	Not significant (low)	Yes	Generally high, with causality supported by MR study	Collective evidence suggested that adiposity is a causal risk factor for developing atrial fibrillation. Of note, two central adiposity indices (WC and WHR) provided contradictory results, which should be addressed in future studies. This discrepancy may be partially attributable to the small number of studies; thus, an updated meta-analysis is necessary.
Aortic valve stenosis	Low for obese	—	—	—	Yes	Low, with causality supported by MR study	An increased BMI was associated with an increased risk of developing AVS. However, the magnitude of the association indicated by the meta-analysis of observational studies should be interpreted with caution due to the small sample sizes and cohorts. A prospective updated meta-analysis incorporating a larger number of studies is warranted. Moreover, evidence of the association between central adiposity (WC and WHR) and AVS is lacking, implying that this area requires future investigation.
Hypertension	—	High	High	High	Yes	High, with causality supported by MR study	The collective evidence suggested that adiposity is a causal risk factor for developing hypertension. The findings of equivalent body fat (BMI) and central adiposity (WC and WHR) consistently support this association. Both BMI and central adiposity may be reliable indicators for measuring risk and understanding the aetiology of hypertension.
Pulmonary embolism	High for obese	—	—	—	Yes	High, with causality supported by MR study	Adiposity might be a causal risk factor for developing PE. An association between the risk of PE and central adiposity (WC and WHR) will be the subject of future studies.
Venous thrombo-embolism	Moderate for obese	—	—	—	Yes	Moderate, with causality supported by MR study	Adiposity is likely a causal risk factor for developing VTE. For both PE and VTE, collective evidence of the effect of increased central adiposity (WC and WHR) is lacking.

GRADE (Grading of Recommendations, Assessment, Development, and Evaluation): High: The evidence provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low. Moderate: The evidence provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate. Low: The evidence provides some indication of the likely effect; however, the likelihood that it will be substantially different (a large enough difference that it might have an effect on a decision) is high. Very low: The evidence does not provide a reliable indication of the likely effect; the likelihood that the effect will be substantially different (a large enough difference that it might have an effect on a decision) is very high.

AVS, aortic valve stenosis; BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease (including CHD and stroke); MR, Mendelian randomization; PE, pulmonary embolism; VTE, venous thrombo-embolism; WHR, waist-to-hip ratio; WC, waist circumference.

^aHigh, moderate, low, and very low include outcomes with statistical significance.

^bResults from meta-analyses of observational studies indicate an association, while results of MR studies suggest causality.

^cThe association between BMI and the risk of stroke in overweight populations reported in observational studies and the risk of stroke reported in Mendelian randomization studies are consistently not significant..