The concept of cardiometabolic risk: Bridging the fields of diabetology and cardiology

Abstract

The lack of physical activity and the adoption of poor nutritional habits is the major cause of the obesity epidemic that is currently sweeping the world. The expansion of adipose tissue mass, especially of the visceral adipose tissue depot, is observed in the vast majority of individuals carrying the clinical features of the metabolic syndrome, an important (and reversible) risk factor of type 2 diabetes and cardiovascular disease. As waist circumference can be used as a crude estimate of visceral fat accumulation, its measurement provides further information on cardiovascular and type 2 diabetes risk, at any given body mass index value. However, an elevated waist circumference might also be the result of an increased ‘cardioprotective’ subcutaneous adipose tissue mass. We have proposed that the measurement of plasma triglycerides along with waist circumference, the so-called ‘hypertriglyceridemic waist’ might better quantify visceral obesity and its health hazards than waist circumference alone. “Hypertriglyceridemic waist” is thought to represent an altered, dysfunctional, and highly lipolytic adipose tissue that is a major culprit abnormality behind the metabolic syndrome and associated cardiometabolic risk, independently from classical cardiovascular disease risk factors such as age, sex, and plasma low-density lipoprotein (LDL) cholesterol levels.

• Cardiometabolic risk
• hypertriglyceridemic waist
• metabolic syndrome
• visceral adipose tissue

Introduction

At the landmark Banting Lecture Award that he delivered at the annual meeting of the American Diabetes Association in 1988, Gerald Reaven 1 proposed that insulin resistance was a core abnormality contributing to increasing not only the risk of type 2 diabetes but also of cardiovascular disease (CVD). In his seminal lecture, which would later be recognized for its tremendous impact on how we approach the pathophysiology of CVD, Reaven submitted the thesis that insulin resistance was at the center of a cluster of metabolic abnormalities which include hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, increased glycemia, and elevated blood pressure, such a constellation of abnormalities being described as syndrome X 1. Following this key early conceptual contribution, numerous studies have confirmed that insulin resistance is indeed associated with metabolic abnormalities which increase the risk of both diabetes and CVD 2–5. However, as measuring insulin resistance in clinical practice remains a challenge in the context of primary care practice, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) 6 proposed to the medical community very simple tools to identify, in clinical practice, individuals likely to be characterized by insulin resistance and by its related cluster of metabolic abnormalities: the ‘metabolic syndrome’ was born. Thus, the concept of the insulin resistance syndrome initially described as ‘syndrome X’ by Reaven and based on pathophysiological considerations had ‘evolved’ into an operational definition allowing its simple diagnosis in clinical practice. Since then, numerous studies have shown that individuals meeting the clinical criteria of the metabolic syndrome proposed by NCEP ATPIII are approximately by 1.5- to 2-fold at greater risk of CVD while being characterized by a 3- to 5-fold increase in their risk of type 2 diabetes 7–11.

Key messages

• Visceral obesity is the most prevalent form of the metabolic syndrome, a constellation of atherogenic risk markers that encompasses the presence of insulin resistance, dyslipidemia, increased blood pressure and a proinflammatory and prothrombotic profile.

• To identify the metabolic syndrome in clinical practice, health professionals should pay attention to the hypertriglyceridemic waist phenotype, a crude marker of visceral adiposity, ectopic fat deposition, and related cardiometabolic abnormalities.

• Beyond treatment of classical risk factors, a modification of nutritional and physical activity habits is essential to induce a mobilization of atherogenic and diabetogenic visceral fat.

The metabolic syndrome clinical criteria and the cutoff values have been debated by numerous groups and organizations, and, while not being perfect, these simple screening tools proposed by NCEP ATPIII have been shown to allow the identification in clinical practice of a subgroup of individuals showing an increased relative risk of diabetes and CVD. Because of the increased relative risk associated with its clinical diagnosis, the metabolic syndrome has received considerable attention from the scientific and medical communities, and some pharmaceutical companies have even attempted to make this condition a target for therapy. In 2005, a joint committee of the American Diabetes Association and from the European Association for the Study of Diabetes published a critical appraisal 12 of the metabolic syndrome concept, and they even questioned the relevance of the diagnosis of this entity in clinical practice. In their critical analysis, the authors emphasized the notion that the clinical diagnosis of the metabolic syndrome did not allow the proper assessment of global risk of CVD. Furthermore, they claimed that the physiological basis for the existence of a metabolic syndrome was not well established 12. Although this excellent critical paper raised several relevant issues, what was then discussed in the lay literature was sometimes abusive, and it unfortunately completely confused physicians and the population. In a nevertheless elegant editorial, Gale even proposed that the metabolic syndrome was a ‘myth’ and that its diagnosis was useless in clinical practice 13.

In order to hopefully clear such confusion, the American College of Endocrinology/American Association of Clinical Endocrinologists reaffirmed in 2006 14 their 2003 ACE Insulin Resistance Syndrome (IRS) statement 15. Their updated statement focused on the clinical relevance of using the term ‘syndrome’ without making the metabolic syndrome a disease by itself. Thus, the ACE/AACE focused on insulin resistance as a core feature associated with a constellation of abnormalities that they referred to as a syndrome. Thus, an attempt was made to go beyond the semantic aspects of the debate and to rather focus on the identification of patients with a cluster of metabolic abnormalities. Table I summarizes some of the advantages/limitations of the metabolic syndrome concept.

Table I.  Advantages and limitations of the clinical diagnosis of the metabolic syndrome.

Advantages	Limitations
• Independently from the clinical criteria used, metabolic syndrome is associated with a 1.5- to 2-fold increase in CVD risk.	• Clinical diagnosis of the metabolic syndrome does not assess global risk of CVD.
• Improves CVD risk prediction on top of currently available risk factors.	• Diagnosis of the metabolic syndrome does not appear to predict CVD risk beyond the sum of its individual components.
• Identifies high-risk subjects that are not necessarily identified by currently available risk algorithms.	• Treatment of the metabolic syndrome does not appear to be different than treatment of individual abnormalities.
• Independently from etiology, there is clear pathophysiological evidence linking features of the metabolic syndrome to atherogenesis.	• Etiology of metabolic syndrome is still unclear (debate between abdominal obesity and insulin resistance).
• Life-style interventions improve features of the metabolic syndrome and decrease CVD and diabetes risk	• No clear rationale for cutoff values of proposed clinical criteria for its diagnosis.
	• Severity of the syndrome not assessed by current approaches.
	• Added value questioned in clinical practice.

CVD: cardiovascular disease.

The International Diabetes Federation (IDF) also contributed to this conceptual debate in 2005 when they proposed similar clinical criteria to NCEP ATPIII to identify patients likely to carry this clustering of risk factors/markers 16. Contrasting with ACE/AACE ideology, IDF rather focused on abdominal obesity in opposition to insulin resistance as the fundamental pathophysiologic unifying component of the metabolic syndrome clinical manifestations. These metabolic syndrome clinical criteria proposed by IDF are identical to those of NCEP ATPIII with the exception of waist circumference cutoff values that are now lower and specific to different ethnic groups. The rationale behind these modified waist thresholds is that for a given waist circumference, Asians, blacks, and Caucasians show different levels of intra-abdominal adiposity, putting them at different risk levels of CVD and diabetes. Therefore, according to IDF criteria, to be diagnosed with the metabolic syndrome, one must be characterized by an elevated waist girth, as this is a mandatory criterion. Conceptually, IDF really emphasizes the notion that abdominal obesity is by far the most prevalent form of insulin resistance and of the metabolic syndrome.

In order to move the field forward and to develop an independent forum allowing the pros and cons of the metabolic syndrome concept to debate on its relevance, an international independent academic organization was created at the end of 2005, the International Chair on Cardiometabolic Risk 17. This multidisciplinary academic group meets on a regular basis and provides an unaligned platform for discussions of the concepts of abdominal obesity, metabolic syndrome, and global CVD risk (Figure 1). For instance, some authors have suggested that a portion of the risk resulting from the presence of the metabolic syndrome is already incorporated in the Framingham risk score because the latter algorithm takes into account some of the clinical criteria used to diagnose the metabolic syndrome such as blood pressure and HDL cholesterol levels. In this regard, it is important to raise two fundamental issues regarding the metabolic syndrome. First of all, as discussed in a previous issue of this journal 18, one must distinguish the conceptual definition of the metabolic syndrome from the clinical tools which are proposed to diagnose this condition 19. Therefore, as emphasized by the NCEP ATPIII guidelines, the metabolic syndrome is defined as a constellation of atherothrombotic and inflammatory complications in which insulin resistance plays a central role 6. Furthermore, the NCEP ATPIII committee recognizes that the most prevalent form of insulin resistance observed in clinical practice is found among patients with abdominal obesity 6. Therefore, although insulin resistance is not measured in clinical practice to diagnose the metabolic syndrome, NCEP ATPIII emphasizes that the presence of abdominal obesity accompanied by simple metabolic abnormalities can allow the identification of a very large percentage of individuals probably showing insulin resistance. In this regard, work conducted in our laboratory and by various research groups around the world has shown that the simultaneous presence of an elevated waistline (crude marker of abdominal obesity) accompanied by fasting hypertriglyceridemia can identify a large percentage of individuals showing insulin resistance and the accompanying atherothrombotic, inflammatory abnormalities of the metabolic syndrome 20–26. On the basis of these results, we have proposed that among the clinical tools used to diagnose the metabolic syndrome, the measurement of ‘hypertriglyceridemic waist’ (elevated waist circumference combined with increased triglyceride levels) could represent a simple but important clinical phenotype which should be incorporated in the evaluation of global cardiovascular risk 20. Data from various prospective studies have confirmed the relevance of paying attention to the presence/absence of ‘hypertriglyceridemic waist’ in clinical practice in order to refine the evaluation of global CVD risk resulting from the presence of classical risk factors 26, 27.

Figure 1.  Schematic representation of the assessment of global cardiometabolic risk using traditional risk factors and emerging cardiovascular disease risk markers.

Given the pivotal role of inflammation in atherogenesis, it has been proposed that C-reactive protein (CRP) should be added to currently available CVD risk algorithms 28, 29. Indeed, circulating CRP is a very good global marker of chronic inflammation, and the association of CRP with CVD risk has been clearly established in numerous publications over the past years 30, 31. It is also now well recognized that CRP levels are increased in obese patients and that they represent a good correlate of fat-mass and especially of abdominal adipose tissue accumulation 32, 33. Numerous studies have shown that the relationship between CRP expression from hepatocytes and therefore circulating CRP levels and abdominal obesity were likely mediated by an increased secretion of interleukin (IL)-6 by adipocytes from the enlarged intra-abdominal adipose depot which is infiltrated by macrophages 34, 35. Thus, it is reasonable to assume that adding CRP to traditional risk factor is likely to improve CVD risk prediction. However, after having added the ‘hypertriglyceridemic waist’ phenotype as an estimate of intra-abdominal adiposity (Figure 2), it is currently not clear as to what extent CRP may enhance CVD risk prediction. Further research will be needed to shed light on this question.

Figure 2.  Plasma: C-reactive protein (CRP) levels (top) and visceral adipose tissue accumulation measured by computed tomography (bottom) in men with the hypertriglyceridemic waist phenotype (waist ≥90 cm and triglycerides ≥2.0 mmol/L) and in men with both a low waist circumference and low plasma triglyceride levels.

Although the diagnosis of ‘hypertriglyceridemic waist’ allows the identification of a subgroup of patients who are probably insulin-resistant and who are at increased risk of being characterized by the features of the metabolic syndrome, it is once again very important to emphasize that the ‘hypertriglyceridemic waist’ clinical phenotype does not allow the proper evaluation of global cardiovascular risk. This question is at the heart of the debate and controversy around the metabolic syndrome. For instance, some scientists and clinicians have questioned the relevance of using too many clinical tools which would lead to the identification of possibly heterogeneous subgroups of individuals not necessarily sharing the same elevated CVD risk. Once again, it is important to emphasize that clinicians should always evaluate global risk of CVD first on the basis of classical risk factors using well established algorithms. However, the term ‘cardiometabolic risk’ has been proposed to capture the possibly additional CVD risk related to the clinical diagnosis of the metabolic syndrome, at any given level of global risk estimated by current risk assessment algorithms which are based on classical risk factors (Figure 1).

Abdominal obesity and metabolic syndrome: are they relevant in patients with type 2 diabetes?

Numerous epidemiological studies have shown that type 2 diabetes is associated with an increased risk of CVD 36, 37. However, the mechanisms responsible for the increased cardiovascular risk of type 2 diabetic patients are not fully understood. Of course, the presence of classical risk factors such as dyslipidemia and hypertension will increase the cardiovascular risk associated with a given hyperglycemic state 38. However, available evidence also suggests that the absence/presence of the metabolic syndrome could substantially modulate the CVD risk even among patients with type 2 diabetes 39, 40. Therefore, in a type 2 diabetic patient, it would be of utmost importance to measure waist circumference and to pay attention to the absence/presence of the other criteria of the metabolic syndrome. In this regard, abdominal obesity could even represent a new or additional therapeutic target for the optimal management of global CVD risk in patients with type 2 diabetes.

The effect of moderate weight loss on the glycemic control and insulin sensitivity of type 2 diabetic patients has been documented 41–45. As type 2 diabetic patients have generally high levels of intra-abdominal (visceral) adipose tissue 46, and as weight loss is generally associated with a preferential loss of visceral adipose tissue among viscerally obese patients 47, it remains to be tested whether a life-style modification program and/or pharmacotherapy leading to loss of visceral fat could reduce the global CVD risk of patients with type 2 diabetes beyond approaches aiming at the management of their hypertension, dyslipidemia, and their hyperglycemic state.

In addition, although the prediabetic state has been shown to be predictive of an increased risk of CVD 48, 49, work from our group and other laboratories around the world has also suggested that a dysglycemic state observed in isolation may not necessarily be considered as a serious independent risk factor for coronary heart disease in the absence of a diagnosis of abdominal obesity and of the metabolic syndrome 50. These results are consistent with the notion that the hyperglycemic state of the diabetic patient or the dysglycemic state of the prediabetic patient may only represent the tip of a large atherothrombotic inflammatory iceberg most frequently found among patients with abdominal obesity and with excess visceral/ectopic fat 51.

Assessing cardiometabolic risk, a matter of waist?

Despite the fact that it is now well established that an elevated waist circumference is predictive of an increased risk of CVD and type 2 diabetes for any given amount of total body fat 52–55, some investigators remain quite sceptical about the relevance of measuring waist circumference in clinical practice 56. For instance, it is often mentioned that it may be difficult for the clinician or the health professional to precisely measure waist circumference and that the added value of measuring waist circumference, once the body mass index has been assessed, is debatable. In this regard, the recently published results of the International Day for the Evaluation of Abdominal obesity (IDEA) study 57 have clearly shown that when primary care physicians are trained on how to properly measure waist circumference, such measurement predicts risk of CVD and diabetes beyond body mass index (BMI) and at any BMI level. Therefore, measuring waist circumference allows the evaluation of cardiometabolic risk associated with a given BMI to be further refined.

Waist circumference: always a marker of visceral adiposity?

Despite the relevance of measuring waist circumference in clinical practice, health professionals should keep in mind that an elevated waistline may not necessarily be a marker of visceral obesity as it could sometimes be the consequence of a substantial accumulation of total body fat. Thus, we should keep in mind that waist circumference is not only influenced by abdominal fat accumulation but that it is also a good marker of total adiposity 58. Therefore, among massively obese patients, an elevated waistline may not necessarily reflect a substantial accumulation of visceral or ectopic fat and may not always predict an altered metabolic risk profile 59. A frequently asked question in clinical practice is whether we can we refine the evaluation of visceral adiposity beyond waist circumference. In this context, we have proposed that fasting triglyceride levels may allow health professionals to distinguish visceral abdominal obesity from subcutaneous abdominal obesity. Thus, an elevated waistline not accompanied by hypertriglyceridemia could provide some evidence to the health professional that he/she is probably dealing with a subcutaneous form of obesity. On the other hand, for the same elevated waistline, the presence of hypertriglyceridemia may suggest to the physician that the elevated waistline of his/her patient is probably the result of an excess accumulation of visceral or ectopic fat (Figure 3). These findings further emphasize the importance of properly evaluating the presence/absence of ‘hypertriglyceridemic waist’ in clinical practice.

Figure 3.  The combination of an increased waist girth along with elevated plasma triglycerides is a good clinical marker of excess intra-abdominal adipose tissue accumulation and might represent a simple and inexpensive screening tool to identify patients with features of the metabolic syndrome.

Waist circumference and health risk: is there a threshold?

Another frequently asked question is whether or not there is a threshold above which we could identify patients with high-risk abdominal obesity. In this regard, it is very important to emphasize that the results of the large IDEA study have shown that there is a linear relationship between waist circumference and risk of diabetes and CVD 57. Therefore, to propose a cutoff value which would be considered as a therapeutic target is unrealistic. However, for the diagnosis of the likely presence of the metabolic syndrome, waist circumference values of 90 cm in men and of 85 cm in women have been suggested to be predictive of the presence of excess visceral fat only when those elevated waist circumference values are accompanied by hypertriglyceridemia (TG levels ≥2.0 mmol/L for men; ≥1.5 for women) 19, 20, 27, 60, 61. Therefore, health professionals should pay attention to waist circumference values above these thresholds and then consider the possible presence of hypertriglyceridemia, as this combination would suggest the likely presence of excess visceral adiposity, ectopic fat, and related cardiometabolic abnormalities.

Since the diagnosis of the ‘hypertriglyceridemic waist’ is dichotomic (absent versus present), it does not provide an indication about the severity of the metabolic syndrome regarding its relationship with CVD and diabetes risk. Obviously, all patients who are characterized by the ‘hypertriglyceridemic waist’ phenotype are not at equal CVD risk since they are likely to be characterized by different waist girths and/or triglyceride levels. This observation certainly represents a limitation of the diagnosis of ‘hypertriglyceridemic waist’ in clinical practice, and further work will be needed to capture this notion of ‘severity’ of metabolic syndrome in new global risk assessment algorithms.

Managing global cardiometabolic risk in patients with the metabolic syndrome: what should be our therapeutic targets?

The optimal management of global cardiovascular (cardiometabolic) risk in patients with the metabolic syndrome remains an open but important question. As previously mentioned, physicians should first properly evaluate global risk of CVD and target, when present, classical risk factors. In this regard, available algorithms such as those proposed by Framingham 62 or by the PROCAM 63 study are recommended. Therefore, among patients at high global CVD risk, it will be important to manage the traditional risk factors by following well established guidelines for the management of diabetes, hypertension, and dyslipidemia 19, 64–66. However, as the most prevalent form of the metabolic syndrome in clinical practice is associated with an excess of visceral and ectopic fat, health professionals should also focus on reshaping nutritional and physical activity habits of patients with high-risk visceral obesity. In this regard, management of the nutritional habits by a dietician and the recalibration of physical activity habits by kinesiologists are essential components of a successful life-style modification program in order to eventually produce loss of abdominal fat and improve cardiometabolic risk factors/markers which are not properly managed by current pharmacological approaches. In this regard, intervention studies have shown that a moderate weight loss induced among patients with abdominal obesity could lead to a selective mobilization of visceral fat and substantially improve the cardiometabolic risk profile of patients even in the absence of weight loss 47, 67–71. Furthermore, available evidence also suggests that abdominal visceral obesity associated with excess ectopic fat could also be related to an overactivation of the endocannabinoid system 72, 73. In this regard, randomized trials have shown that the use of an antagonist of the endocannabinoid system could lead to a substantial reduction in abdominal adiposity and to related improvement in the cardiometabolic risk profile 74. Additional studies are currently under way in order to test to which extent this selective mobilization of abdominal fat could prevent type 2 diabetes and/or reduce the risk of CVD. However, on the basis of the metabolic improvements associated with the loss of abdominal fat, it is proposed that targeting the endocannabinoid system should not be used to replace classical treatment of hypertension, dyslipidemia, and diabetes but that it should rather be considered as an approach to complete or potentiate the effects of current pharmacotherapies by targeting a component of global cardiometabolic risk which is presently not considered in current management strategies: abdominal visceral obesity.

In summary, despite the fact that it is more and more accepted that the metabolic syndrome is an important entity which should be evaluated, some specialists and experts around the world remain sceptical regarding the added value of a metabolic syndrome diagnosis in clinical practice and to which extent this may direct therapy. However, as the most frequently observed form of metabolic syndrome in clinical practice is found in patients with abdominal obesity and excess ectopic fat, it is proposed that high-risk abdominal obesity should be evaluated in clinical practice on the basis of the simultaneous presence of an elevated waistline and of hypertriglyceridemia. Therefore, the presence of the ‘hypertriglyceridemic waist’ phenotype exacerbates global cardiovascular (cardiometabolic) risk of patients, and it should require a more holistic therapeutic approach where not only classical risk factors are evaluated and managed but also nutritional and physical activity habits are reshaped in order to induce a mobilization of atherogenic and diabetogenic visceral fat.

As most type 2 diabetic patients are abdominally obese and are showing features of the metabolic syndrome, such a constellation of metabolic abnormalities puts them at high risk of CVD. Thus, diabetologists are confronted not only with the microvascular complications related to hyperglycemia but also with atherosclerotic macrovascular consequences of the metabolic syndrome. On the other hand, as the texture of risk factors for CVD has evolved from smoking, poorly managed hypertension, and elevated cholesterol to an epidemic of abdominal obesity, metabolic syndrome, and type 2 diabetes, cardiologists are also exposed to an expanding proportion of coronary artery disease (CAD) patients with metabolic syndrome and/or with type 2 diabetes. Thus, a dialogue between diabetologists and cardiologists and concerted actions are needed for the optimal clinical management of a rapidly growing population of abdominally obese patients.

Acknowledgements

The work of the authors has been supported by research grants from the Canadian Institutes of Health Research, the Canadian Diabetes Association, the Heart and Stroke Foundation and by the Foundation of the Québec Heart Institute. Dr. Després is Scientific Director of the International Chair on Cardiometabolic Risk, which is supported by an unrestricted grant from Sanofi Aventis awarded to Université Laval. Benoit J. Arsenault is recipient of a training scholarship from Hôpital Laval Research Centre. Mélanie Côté is supported by a scholarship from the Fond de la recherche en santé du Québec. Amélie Cartier is supported by the training program in obesity which is supported by the Canadian Institutes of Health Research.