The metabolic syndrome

Type 2 diabetes mellitus is becoming extremely common; its prevalence worldwide is expected to reach 5-7.6% by 2025.¹ Atherosclerotic cardiovascular disease is the principal cause of death, disability, and excess healthcare costs in diabetes. Cardiovascular disease may already be present at the time when diabetes is diagnosed,^w1 and patients with diabetes are more likely than their non-diabetic counterparts to die from a first event of cardiovascular disease.^w2 These realities point to prevention of type 2 diabetes as the route to prevention of its costliest complications. The close association of type 2 diabetes with cardiovascular disease led to the hypothesis that the two arise from a common antecedent;^w3 this concept has been codified by the World Health Organization and others as “the metabolic syndrome.”²

The diagnosis of the metabolic syndrome in patients might hold promise for enhanced prevention of diabetes and cardiovascular disease. However, substantial uncertainties remain about the clinical definition of the syndrome and whether risk factor clusters collectively indicate a discrete, unifying disorder. Most importantly, it is unclear whether diagnosing the syndrome will confer benefit beyond risk assessments or treatment strategies associated with diagnosing and treating the syndrome's component traits. The current focus on the metabolic syndrome will possibly prove to be a distracting detour on the route to encouraging more widespread application of evidence based practices to prevent diabetes and cardiovascular disease.

The metabolic syndrome is characterised by the co-occurrence of obesity (especially central obesity), dyslipidaemia (especially high levels of triglycerides and low levels of high density lipoprotein cholesterol), hyperglycaemia, and hypertension. As yet no consensus exists for specific thresholds for establishing the diagnosis of each of these traits as components of the syndrome. Inclusion of insulin resistance or diabetes itself as diagnostic components is also controversial. The individual traits of the syndrome cluster together to a notably greater degree than expected by chance alone, a fact that lends substantial support to the existence of a discrete disorder.³

It has long been thought that insulin resistance (primarily in skeletal muscle and liver) may be the unifying pathophysiology underlying the syndrome.^w4 However, although insulin resistance is a consistent early abnormality in the pathogenesis of type 2 diabetes, its association with cardiovascular disease is less certain.^w5 Further, obesity is a major driving force behind clustering of risk factor,³ yet not all obese subjects are insulin resistant.⁴ In addition factor analyses of traits of the metabolic syndrome consistently show that blood pressure elevation is not closely related to clustering of the other traits.⁵ The question then arises whether attempting to prevent diabetes and cardiovascular disease by treating the metabolic syndrome in itself will be as effective as prevention of obesity or interventions specific for the other constituent risk factors.

Evidence is accumulating that people with the metabolic syndrome are at increased risk of incident diabetes⁶ or cardiovascular disease relative to people without the syndrome.⁷ These findings do not come as a surprise, as the traits of the metabolic syndrome are each well established risk factors for diabetes and cardiovascular disease. The question is whether the metabolic syndrome increases risk for adverse outcomes to a greater degree than predicted by the presence of its individual components.

One recent analysis seems to indicate that syndrome traits interact to increase atherosclerosis of the carotid artery to a greater degree than expected solely by their additive effects.⁸ Another preliminary analysis of participants in the control arms of two large lipid lowering clinical trials shows that those with the metabolic syndrome and a Framingham risk score greater than 20% were at higher risk for cardiovascular disease events compared with participants with an elevated risk score but without the metabolic syndrome.⁹ Another recent analysis, however, did not find excess risk for cardiovascular disease associated with the syndrome after traditional risk factors for cardiovascular disease had been accounted for.¹⁰ Thus, although it is plausible to think that diagnosis of the metabolic syndrome will point us in the right direction for effective prevention of type 2 diabetes and cardiovascular disease, more definitive data on the outcomes and effects of interventions are required before we can confidently head along that route.

The goal of identifying metabolic risk factors is to prevent morbidity and mortality due to type 2 diabetes and cardiovascular disease. We already know that relatively modest lifestyle changes can substantially reduce risk for type 2 diabetes in mildly hyperglycaemic subjects.¹¹ We already know that control of raised blood pressure and blood lipids substantially reduces risk of cardiovascular disease events in patients with hypertension or hyperlipidaemia. Although insulin sensitisation in itself may be beneficial in preventing type 2 diabetes,¹² we do not know if this strategy will ameliorate all the metabolic disturbances of the metabolic syndrome or prevent cardiovascular disease.

The worldwide epidemic of type 2 diabetes is fuelled in large part by a parallel epidemic of obesity and physical inactivity, clearly pointing to prevention of obesity as the most direct route to prevention of the metabolic syndrome and its sequelae. From this perspective, perhaps the best reason to consider a diagnosis of the metabolic syndrome is to identify obese people who are most likely to benefit from aggressive efforts to achieve a healthy weight, physical activity habits, and normal risk factor levels. In the end, even modest changes towards a healthy lifestyle may be the most direct route to treating the metabolic syndrome and preventing its type 2 diabetes and cardiovascular disease outcomes.