Statistical considerations and other issues
When designing any risk scoring system, those proposing such a score must weigh up various competing factors. Metabolic syndrome benefits from the inclusion of clear (and now unambiguous, with the exception of waist circumference) criteria. However equal weighting is given to the five criteria while it is known that they do not contribute equally to the development of cardiometabolic disease. As noted above, two of the five criteria are strongly linked to cardiovascular disease but only weakly to risk of developing diabetes. The converse is true of the other three variables. Secondly, consideration of any biomarker as a continuous variable adds predictive power while dichotomization of data limits power substantially. One component, serum triglycerides, has a moderately high within-subject biologic variability of 20% with the result that classification of individuals with triglyceride levels close to 1.7mmol L−1 may give different results from day to day . Other potential weaknesses include the reliance on fasting samples while there is a move towards using nonfasting sampling for both diabetes (HbA1c) and cardiovascular (lipids, HbA1c) risk estimation and diagnosis. Some also challenge the inclusion of those with established T2DM and/or cardiovascular disease in the metabolic syndrome based on the assertion that it adds little to their clinical management [38,40]. Finally, metabolic syndrome describes relative risk of cardiometabolic disease and not absolute risk.
Treatment of patients with features of the metabolic syndrome
The prevalence of individuals with the metabolic syndrome or components thereof is undeniably high and constantly increasing. Despite control of major cardiovascular risk factors such as LDL-cholesterol, blood pressure, and smoking, a combination of factors regularly leads to a failure to address obesity or improve glycemic control with a resultant residual higher cardiovascular risk than is observed in the normal population. Therefore, attention must be focused on what additional approaches can be brought to bear to reduce this residual risk. While an in-depth discussion of outcome trial data regarding drugs aimed at lowering triglycerides or increasing HDL-cholesterol is beyond the scope of this chapter, their results can be summarized as disappointing thus far. Whether we should target the hypothesized upstream insulin resistance, and if so with what tools, remains unproven for reducing cardiovascular risk. Those with impaired fasting glycemia and impaired glucose tolerance are not routinely prescribed glucose-lowering agents although cardiovascular endpoint trials of relevant therapies such as metformin are either underway or in feasibility studies. Lifestyle modification is commonly recommended and has been shown to reduce the development of T2DM in those at risk [61,62], but data supporting a reduction in cardiovascular outcomes remains elusive. Problematically, while intensive lifestyle advice can be provided in the context of a clinical trial, significant improvement remains difficult to achieve and sustain outside the research environment. Large observational studies of weight loss surgery strongly suggest a reduction in risk of developing diabetes  but access to such procedures is necessarily limited to a subset of the population based on availability of resources.
Current thinking regarding metabolic syndrome
In November 2008, a WHO Expert Consultation was undertaken to evaluate the utility of the concept of metabolic syndrome in four areas: pathophysiology, epidemiology, clinical work, and public health . Much of the ground addressed in the report of the consultation is covered in the earlier sections of this chapter. The consultation’s conclusions are ones which the authors of this chapter are in agreement with. They made the simple but important observation that while metabolic syndrome has gained traction as a widely recognized concept, a formal diagnosis of metabolic syndrome is seldom made and the condition is rarely included in guidelines for the treatment and prevention of cardiometabolic disease. The group rightly called for a halt to studies comparing different versions of the metabolic syndrome and also emphasized that research should be focused on identifying the mechanism or mechanisms underlying the clustering of metabolic risk factors, rather than attempting to further refine diagnostic criteria. The main conclusion was therefore that while metabolic syndrome represents a useful educational concept, it has limited practical utility as a diagnostic or management tool.
The terms “insulin resistance syndrome” or “metabolic syndrome” are widely used in clinical research but their precise definitions remain weakly defined and their clinical utility questionable. The present chapter has summarized numerous biomarkers associated with insulin resistance and attempted, where possible, to determine which may be causally linked to insulin resistance, and the directionality of such links. A minority of insulin resistance-associated risk factor perturbances (e.g. those related to NAFLD or PCOS) appear relevant to clinical practice whereas simple risk factors (age, gender, obesity, family history, and ethnic origin) predict type 2 diabetes well. Novel blood-based insulin resistance biomarkers seem unable to meaningfully (or cost-effectively) improve diabetes prediction. In terms of vascular disease, and contrary to popular belief, the current data do not support a strong association of insulin resistance (in the absence of diabetes) with cardiovascular disease and, similarly, metabolic syndrome criteria do not improve prediction beyond simpler nonfasting cardiovascular risk scores.