4.1 Principal findings
In this perspective, observational study on a large Chinese cohort with long-term follow-up, we examined the prognostic association of DM with outcomes in patients with different degree of WC. Our results suggested that higher WC and diabetes were both significant and independent predictors of cardiovascular death (Figure 4a). In addition, our results suggested that patients with higher levels of WC coexist with diabetes had the worst outcome, the association is still significant after adjustment of other clinical confounders (Figure 4b). In summary, our results suggested that the addition of WC and diabetes to established cardiovascular risk factors may further improve risk stratification in general population. Our results provided updated information about the long-term prognostic role of WC and diabetes in general population.
4.2 Limitations of BMI
Adipose tissue is now considered to be a key organ for the fates of excessive dietary lipids, which may determine whether it will maintain body homeostasis (metabolic healthy obesity) or whether it will produce inflammation/insulin resistance, which can have harmful cardiovascular consequences. Obesity, especially visceral obesity, can also cause various structural adaptations/changes in the structure/function of CV. Adipose tissue can now be regarded as an endocrine organ that coordinates important interactions with vital organs and tissues (such as the brain, liver, skeletal muscle, heart, and blood vessels themselves).
The most commonly used anthropometric tool for assessing relative weight and classifying obesity is BMI, which is expressed as the ratio of total body weight to the square of height (kg/m2). Individuals with a BMI <18.5 kg/m2 are considered underweight, while individuals with a BMI between 18.5 and 24.9 kg/m2 are classified as normal or acceptable weight. Individuals with a BMI between 25 and 29.9 kg/m2 are classified as overweight, while those with a BMI of ≥30 kg/m2 are obese. BMI itself is associated with clinical outcomes and mortality in a U or J type . This inverse relationship has triggered controversy in the literature, called the "obesity paradox" . Compared with non-obese patients, patients with elevated BMI with chronic diseases have a higher survival rate and fewer cardiovascular (CV) events . Moreover, previous research reported that patients with an increased BMI were found to show lower mortality . In addition, BMI cannot distinguish between weight gain due to high levels of lean body mass and fat body mass. Generally, excess body fat (BF) is more often associated with metabolic abnormalities than high levels of lean body mass. Another explanation for this paradox is the lack of control over the main individual differences in the regional BF distribution. Therefore, more and more scholars believe that the BMI has its limitations to fully capture cardiometabolic risk. It is partially related to the fact that BMI in isolation is an insufficient biomarker of abdominal adiposity . By using the BMI, one must rely on the assumption that adipose tissue is distributed evenly over the body, which does not take into account the heterogeneity of regional body fat deposition .
The level of obesity must be considered in the risk stratification. In a recent meta-analysis of 2.88 million people, all levels of obesity combined were associated with increased mortality, with a hazard ratio of 1.18 (95% CI, 1.12-1.25). However, when analyzing separately, grade 1 obesity (table 1) is associated with a higher risk of death with a hazard ratio of 0.97 (95% CI, 0.90–1.04), compared with normal body weight. In contrast, serious obesity (grades 2 and 3) and risk of death (hazard ratio 1.34 – 95% CI, 1.21 – 1.47) . The prognostic value of BMI needs to pay attention to the length of follow-up time. There was a J-type association between BMI and sudden cardiac death, and the lowest risk was observed within the normal weight range. However, in studies with a longer follow-up period, the increased risk of low BMI was attenuated . In other words, the obesity phenotype may change over time to reflect the increase in abdominal obesity. For example, Ian Janssen and colleagues studied the changes in waist circumference for a given BMI over a 30-year period in a Canadian sample35. It is worth noting that for a given BMI, Canadians had a larger waist circumference in 2007 than in 1981. Specifically, the researchers observed that between 1981, men with a BMI of 25 kg/m2 increased their waist circumference by 1.1 cm, and women with a BMI of 4.9 cm and 2007. Similarly, Sandra Albrecht and colleagues studied 36 long-term changes in waist circumference in the United States (1988-2007), the United Kingdom (1992-2008), China (1993-2011), and Mexico (1999-2012), and reported significant statistics Academic significance in all countries and in most subgroups, waist circumference values have increased relative to BMI. The result of one study involving more than 58 000 elderly persons, during a 5-year-follow-up, showed that increased mortality risks for elderly people with an increased WC—even across BMI categories— and for those who were classified as ‘underweight’ using BMI. Part of the reason why BMI cannot fully capture cardiometabolic risks is that BMI alone is an insufficient biomarker for the whole body. More importantly, the central abdominal fat mass does not explain the extreme changes in intra-abdominal (visceral) fat mass. Fat distribution between individuals . Compared with BMI, waist circumference has a higher predictive value for cardiovascular death .
4.3 Visceral adipose tissue and the underlying mechanisms
Visceral adipose tissue has been proved to be independently associated with elevated CVD (cardiovascular disease) risk . Data from several past epidemiological studies 30 years of experience shows that VAT is an independent sign of morbidity and mortality . In some populations, WC has been found to be more predictive of overall mortality, coronary heart disease (CHD), and CVD mortality than BMI, However, prospective data on the impact of abdominal obesity on CVD incidence is still scarce. Many experimental studies support the potential connection between VAT and biological pathways that are important in the pathogenesis of multiple disease outcomes. Adipokines are biologically active molecules secreted by adipose tissue and are key components of these pathways, including inflammatory cytokines, angiogenic factors, lipid metabolites, and extracellular matrix components . The secretion of adipokines among specific fat depots appears to be different , and compared with subcutaneous adipose tissue (SAT), VAT exhibits more pro-inflammatory and pro-angiogenic gene expression. In addition, compared with SAT, small arteries in VAT are more likely to exhibit endothelial dysfunction , indicating that VAT has a potentially toxic effect on the vasculature. Visceral adipocytes differ from subcutaneous adipocytes in that they release secreted proteins that are known or potential risk factors for CHD. In at least one study, visceral fat expressed and released more plasminogen activator inhibitor-1, a fibrinolysis inhibitor, than subcutaneous fat . Angiotensinogen is a potential blood pressure regulator and is also highly expressed in visceral adipose tissue.
There are currently multiple methods to assess body fat distribution. The most accurate method is costly and time-consuming. It is not suitable for large-scale population research. Since routine access to CT, magnetic resonance imaging (MRI) may too expensive to be feasible for many clinicians, and the use of these methods to image visceral and ectopic fat has historically been reserved for research purposes, Perhaps the most widely used and these measurements are taken for waist circumference. Ashwell and colleagues were the first to show that there is a correlation between visceral fat mass and waist-to-hip ratio. However, compared with waist-to-hip ratio, waist circumference has a stronger correlation with visceral fat mass .
4.4 Obesities, Type 2 Diabetes Mellitus, and Cardiovascular Outcomes
Obesity is an important driving factor for the development of type 2 diabetes. Compared with BMI-matched non-type 2 diabetic patients, type 2 diabetic patients have a larger waist circumference and more VAT . A patient with VAT or severe obesity and type 2 diabetes is susceptible to cardiovascular abnormalities and cardiovascular disease; their simultaneous presence should further increase the risk of cardiovascular outcomes . The underlying mechanisms maybe ectopic and visceral obesity are related to insulin resistance, this may partially mediate the link between obesity, type 2 diabetes and cardiovascular risk. Metabolic syndrome and insulin resistance have been recognized as risk factors for cardiovascular morbidity and mortality . Studies have also shown that the presence of metabolic syndrome increases the risk of heart failure. The result of a cross-sectional study has shown that obesity and type 2 diabetes have an additive effect on left ventricular remodeling in normotensive patients. A recent study of patients with type-2 diabetes mellitus showed that compared with those in the first quartile of WC, male patients in the fourth quartile of WC (WC≥126) had a HR of 1.24 (95% CI 1.05–1.46) for major adverse cardiovascular events (MACEs); female patients in the fourth quartile of WC (WC≥122 cm) had an HR of 1.22 (95% CI 0.96–1.56) for MACEs . Our results suggested that patients with higher levels of WC coexist with diabetes had the worst outcome, the association is still significant after adjustment of other clinical confounders. Our results provided updated information about the long-term prognostic role of WC and diabetes in general population.
Limitations of our study
The limitation of our study is the relatively small cohort patients; therefore, a larger sample of research is needed. Another limitation would be the lack of "gold standard" methods for abdominal obesity, such as computed tomography (CT) or MRI, may be another limitation of current research. However, the effectiveness of WC has previously been confirmed in cross-sectional studies and prospective studies.