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From individual risk factors and the metabolic syndrome to global cardiometabolic risk
Jean-Pierre Després1,2,*, Paul Poirier1,3,4, Jean Bergeron5, Angelo Tremblay2,6, Isabelle Lemieux1 and Natalie Alméras6 1 Québec Heart Institute, Hôpital Laval Research Centre, Hôpital Laval, 2725 chemin Ste-Foy Pavilion Marguerite-D’Youville, 4th Floor, Quebec City, QC G1V 4G5, Canada
2 Division of Kinesiology, Department of Social and Preventive Medicine, Université Laval, Quebec City, QC, Canada
3 Institut universitaire de cardiologie et de pneumologie, Hôpital Laval, Quebec City, QC, Canada
4 Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada
5 Lipid Research Centre, CHUL Research Centre, Quebec City, QC, Canada
6 Hôpital Laval Research Centre, Hôpital Laval, Quebec City, QC G1V 4G5, Canada
* Corresponding author. Tel: +1 418 656 4863; fax: +1 418 656 4610. E-mail address: jean-pierre.despres@crhl.ulaval.ca
 | Abstract |
|---|
‘Traditional’ risk factors such as hypertension,
elevated cholesterol, smoking, and diabetes have long been linked
to cardiovascular disease (CVD). However, although remarkable
progress has been made in the management of these classical
CVD risk factors, obesity, the metabolic syndrome, and type
2 diabetes have reached such epidemic proportions that CVD remains
a major cause of morbidity and mortality worldwide. As obesity
rates soar, more and more patients are developing additional
metabolic abnormalities that raise their CVD risk. Though obesity’s
health hazards are well documented, physicians are sometimes
perplexed by the absence of complications in some very obese
patients. Equally perplexing is the fact that some moderately
overweight individuals are characterized by a whole cluster
of atherogenic and diabetogenic metabolic abnormalities. Because
body mass index (BMI) provides little information about the
location of body fat, calculating BMI as the ratio of weight
over height-squared is therefore only useful as an initial step
towards crudely classifying patients based on their relative
weight. In this regard, numerous studies in the last two decades
have confirmed that a high amount of abdominal fat, intra-abdominal
(or visceral) adipose tissue in particular, is linked to a cluster
of emerging metabolic risk factors/markers that may increase
the risk of type 2 diabetes, CVD, and related mortality beyond
excess body weight. The scientific and medical community’s
recent recognition of abdominal obesity (especially the form
characterized by excess visceral/ectopic fat) as the most prevalent
form of the clustering atherothrombotic-inflammatory abnormalities
associated with insulin resistance is an important conceptual
advance with very significant clinical and public health implications.
However, yet to be resolved is the extent to which the specific
clustering abnormalities of visceral obesity increase overall
CVD and type 2 diabetes risk estimated by traditional risk factors.
There is evidence to suggest that current risk assessment algorithms
may not accurately estimate the global CVD risk in patients
with visceral obesity. In light of this, better methods are
needed to assess the global risk of CVD and type 2 diabetes
in the presence of traditional risk factors and emerging markers
found in individuals with excess intra-abdominal adiposity and
a ‘dysfunctional’ adipose tissue phenotype. This
global risk is defined as cardiometabolic risk.
Key Words: Abdominal obesity • Cardiometabolic risk • Ectopic fat • Global CVD risk • Insulin resistance • Metabolic syndrome
| Introduction |
|---|
The recognition of the metabolic syndrome as a major and prevalent
cause of coronary heart disease (CHD) by the National Cholesterol
Education Program-Adult Treatment Panel III (NCEP-ATP III) has
helped turn a key concept based on pathophysiology (insulin
resistance) into a concrete entity that can be diagnosed by
primary care physicians.
1 NCEP-ATP III committee members recognized
the importance of insulin resistance as a core metabolic abnormality
associated with a constellation of atherogenic and diabetogenic
risk factors/markers, but they also emphasized that the most
prevalent form of insulin resistance in clinical practice was
abdominal obesity.
2 In patients likely to have excess abdominal
fat, the committee recommended that attention be paid to five
parameters (waist circumference, triglycerides, high density
lipoprotein (HDL)-cholesterol, fasting glycaemia, blood pressure)
in order to identify individuals with the metabolic syndrome,
prioritizing waist circumference over body mass index (BMI)
when estimating the amount of abdominal fat.
1 This recommendation
to measure waist girth in clinical practice was a giant conceptual
leap forward, as it recognized abdominal obesity as the most
prevalent form of the metabolic syndrome in affluent, sedentary
populations. The NCEP-ATP III guidelines also recognized the
importance of elevated triglycerides and reduced HDL-cholesterol
concentrations as useful lipid markers of the presence of an
atherogenic ‘dysmetabolic’ profile related to visceral
obesity and ectopic fat deposition.
1 These guidelines were therefore
an attempt to provide health professionals with simple tools
to screen for the clustering abnormalities of the metabolic
syndrome in primary care centres.
| Can the metabolic syndrome be diagnosed in clinical practice? |
|---|
It is important to point out that the five criteria and cut-off
values proposed by the NCEP-ATP III panel to diagnose the likely
presence of the metabolic syndrome were reached by expert consensus
and were not validated for their ability to provide an optimal
discrimination of individuals with both the metabolic syndrome
and a related increase in CHD risk.
3 Accordingly, since the
publication of NCEP-ATP III criteria, clinicians have often
confused the conceptual definition of the metabolic syndrome
with the proposed criteria themselves (waist, triglycerides,
HDL-cholesterol, glycaemia, blood pressure). These criteria
are in fact simple surrogate variables to be used in clinical
practice to identify high-risk individuals likely to have abdominal
obesity, insulin resistance, an atherogenic dyslipidaemic state,
as well as a pro-thrombotic, inflammatory profile that may or
may not be accompanied by hyperglycaemia and hypertension (
Figure 1).
Thus, NCEP-ATP III clinical criteria do not define the metabolic
syndrome but rather provide a simple way to help clinicians
who cannot assess insulin resistance, visceral adiposity, and
the complex features of the related atherogenic, pro-thrombotic,
and inflammatory profile.
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| Figure 1 (A) The metabolic syndrome as a concept, which includes a constellation of atherothrombotic, inflammatory abnormalities resulting from insulin resistance and most often observed among patients with abdominal obesity and/or dysfunctional adipose tissue. (B) Clinical variables [not to be confused with the definition of the metabolic syndrome in (A)] proposed by NCEP-ATP III and the International Diabetes Federation to identify a large proportion of patients with the metabolic syndrome. [1] Population-specific cut-off values have been proposed in the International Diabetes Federation guidelines. See reference 4 for further details, [2] or treatment of hypertriglyceridaemia, [3] or treatment for low HDL-cholesterol, [4] or treatment of hypertension, and [5] or treatment with a hypoglycaemic agent. | |
The recently published recommendations of an International Diabetes
Federation (IDF) working group placed further emphasis on abdominal
obesity as the most prevalent form of the metabolic syndrome
and, consequently, on the need to first have an elevated waist
circumference before being considered at risk of having the
metabolic syndrome.
4 Moreover, in light of compelling evidence
that the waist cut-off value proposed for men in NCEP-ATP III
(102 cm) is likely too high, waist values were reduced in the
recent IDF recommendations to 94 cm in men and 80 cm in women,
with emphasis on the fact that factors such as ethnicity and
age can also affect the relationship of waist girth to abdominal
visceral fat deposition and related abnormalities. The fact
that an elevated waist girth was included in the IDF guidelines
as the first criterion to identify individuals likely to have
the metabolic syndrome marked another step forward in showcasing
the importance of abdominal obesity as a common form of the
metabolic syndrome in clinical practice.
4 Several groups5–20 have found evidence that a simultaneous increase in waist circumference and fasting triglyceride levels (a condition that has been initially described as hypertriglyceridaemic waist)21 may be a relevant and simple screening phenotype to identify a subgroup of individuals at high risk of being carriers of features of the metabolic syndrome. This diagnosis can be confirmed by measuring additional and more sophisticated metabolic markers such as fasting insulin, apolipoprotein B, C-reactive protein, and adiponectin levels, to name a few.
However, the IDF committee has also identified knowledge gaps in their recommendations.4 Its ‘new’ and population-specific waist criteria should therefore be considered a ‘work in progress’ and will have to be validated for their ability to optimally discriminate for the subgroup of high-risk individuals who have features of the metabolic syndrome and are at increased risk of cardiovascular disease (CVD), beyond what can be predicted by classical CVD risk factors.3,22
| The type 2 diabetes epidemic and the metabolic syndrome: the importance of abdominal obesity |
|---|
Although the obesity epidemic has been the subject of intense
media coverage, too many physicians still fail to recognize
that the scores of type 2 diabetic patients they see in their
practice are caused by our sedentary and affluent lifestyle,
which promotes a positive energy balance, weight gain, abdominal
obesity, and the progressive development of a ‘dysmetabolic
state’ likely to become glucose intolerance and, eventually,
outright hyperglycaemia.
23 Citing obesity’s key role in
the aetiology of type 2 diabetes, Zimmet
et al.
24,25 foresaw
a rapid increase in the prevalence of type 2 diabetes worldwide.
Unfortunately, obesity has progressed so quickly that type 2
diabetes continues to spread worldwide at a brisk and alarming
pace.
24 This should give health-care authorities real cause
for concern, as type 2 diabetes is associated with major health-care
expenses
26 such as those related to retinopathy causing blindness,
nephropathy leading to end-stage renal disease and dialysis,
as well as to neuropathic complications, which are the leading
cause of amputations.
27 In addition to these health problems
caused by diabetic microcirculatory damage, type 2 diabetes
is also a major cause of atherosclerotic macrovascular disease,
with the majority of patients affected dying from CVD.
28–30 Diagnosing and treating type 2 diabetic patients is therefore
crucial given that roughly 10% of our population has this metabolic
disease, whose prevalence is largely underestimated and which
has been found to be even more prevalent in some populations
worldwide.
24 Although it has been shown that better glycaemic control can reduce microcirculatory damage-related complications, evidence proving that better glycaemic control has a significant impact on CHD prevention in diabetic patients is modest at best.31,32 Although type 2 diabetics are clearly at greater risk of CHD than non-diabetics, recent studies have shown that type 2 diabetes is a heterogeneous entity and that the more abdominally obese the type 2 diabetic patients are, the greater is the likelihood that they have the features of the metabolic syndrome.33 Consequently, type 2 diabetics with abdominal obesity and the related abnormalities of the metabolic syndrome have a higher risk of CHD than the less prevalent group of type 2 diabetics with abdominal obesity alone (Figure 2).
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| Figure 2 Schematic illustration of the heterogeneity of coronary heart disease risk in the presence of the metabolic syndrome and type 2 diabetes. There is considerable evidence that features of the metabolic syndrome increase coronary heart disease risk, even in non-diabetic individuals. Studies have also shown that coronary heart disease risk is heterogeneous in type 2 diabetes. Clearly, type 2 diabetic patients with features of the metabolic syndrome are at highest risk of coronary heart disease. However, debate is ongoing as to whether diabetes per se (in the absence of the metabolic syndrome) significantly increases coronary heart disease risk. These results emphasize the need to consider factors other than glycaemic control for the optimal management of coronary heart disease risk in type 2 diabetic patients. Reproduced with kind permission of Springer Science and Business Media.56 | |
| Insulin resistance, the metabolic syndrome, and abdominal obesity: the pioneers |
|---|
Since features of the metabolic syndrome appear to be more important
than glycaemic control in predicting CHD risk, even in the absence
of hyperglycaemia, non-diabetic, overweight, or obese individuals
with features of the metabolic syndrome have a significantly
greater risk of CHD.
34–37 The concept of a syndrome of
abnormalities linked to insulin resistance was first introduced
by Reaven in 1988,
38 who proposed that impaired
in vivo insulin
action was a central component of a cluster of metabolic abnormalities
that did not necessarily include classical risk factors such
as raised low density lipoprotein (LDL)-cholesterol but was
instead characterized by hypertriglyceridaemia, low HDL-cholesterol,
fasting hyperinsulinaemia, and elevated blood pressure. At the
time, because Reaven argued that he could find insulin-resistant
subjects among non-obese individuals, he did not include obesity
as a necessary component of ‘his’ insulin resistance
syndrome and still maintains that obesity is not a component
of the insulin resistance syndrome.
39 In light of this, Crepaldi
and coworkers
40 should be credited with the first report on
the simultaneous presence of obesity, hyperinsulinaemia, hypertriglyceridaemia,
and hypertension, whereas Vague
41,42 should be recognized as
the first to foresee the importance of abdominal or upper body
adiposity (he described this condition as android or male-type
obesity) as the obesity phenotype most often associated with
diabetes and CVD. Another pioneer was Morris, who reported in
the mid-1950s that sedentary London bus drivers were at greater
risk of CHD compared with more active bus conductors who had
to walk through the buses to collect fares during their shifts.
43 Long before obesity’s demographic explosion, Morris had
also documented that high-risk sedentary bus drivers had a higher
prevalence of abdominal obesity (as revealed by the size of
their trousers) than active bus conductors.
44 This report should
be considered one of the key early proofs linking a sedentary
lifestyle and abdominal obesity to CHD risk.
44 In the mid-1980s,
with the development of imaging techniques to measure abdominal
fat precisely and distinguish intra-abdominal (visceral) from
subcutaneous fat, several studies demonstrated that abdominal
fat accumulation accompanied by an excess of intra-abdominal
(or visceral) adipose tissue was predictive of the features
of the insulin resistance syndrome.
45,46 Furthermore, it has
now been shown that presumably normal weight individuals may
nonetheless have excess visceral adipose tissue.
47–50 These normal weight subjects with an excess of visceral adipose
tissue also display features of the metabolic syndrome. This
condition has been described as the normal weight, metabolically
obese patient.
49 The metabolic complications associated with overweight and obesity have been extensively studied over the last 20 years. Although population studies have documented that obesity is associated with co-morbidities, the fact that some normal weight individuals are insulin resistant whereas some obese patients are insulin sensitive has been a legitimate argument raised by some38 to exclude obesity as a correlate of insulin resistance. However, the use of better methods to measure total body fatness and abdominal fat accumulation (such as dual energy X-ray absorptiometry, computed tomography, and magnetic resonance imaging) has shown that irrespective of the absence/presence of clinical obesity (BMI above 30 kg/m2), individuals with a selective excess of intra-abdominal or visceral adipose tissue are not only at a substantially increased risk of being characterized by the cluster of metabolic abnormalities of syndrome X (hypertriglyceridaemia, low HDL-cholesterol, hyperinsulinaemia, hypertension) originally described by Reaven,38 they are also more likely to have the expanded features of the so-called metabolic syndrome (elevated apolipoprotein B, small dense LDL, pro-thrombotic profile, and elevated inflammatory markers, including elevated C-reactive protein and reduced adiponectin, to name a few).51–55
| Metabolic syndrome and CHD risk: beyond hyperglycaemia |
|---|
There is now evidence to suggest that features of the metabolic
syndrome commonly found in abdominally obese patients with an
excess of visceral adipose tissue increase CHD risk. In this
respect, our prospective study of middle-aged men living in
the Quebec City metropolitan area, the Québec Cardiovascular
Study, showed that the simultaneous presence of some of the
features of the metabolic syndrome—namely fasting hyperinsulinaemia
as a marker of insulin resistance in non-diabetic individuals,
elevated apolipoprotein B levels (a marker of atherogenic lipoprotein
concentrations), and the presence of small dense LDL particles—substantially
increased CHD risk, even in the absence of classical risk factors
such as raised LDL-cholesterol, hypertension, or smoking (
Figure 3).
36 Whether measuring additional metabolic syndrome markers—C-reactive
protein levels, for example—would further refine our understanding
of CHD risk will require further study. The proposed NCEP-ATP
III criteria were a significant conceptual leap forward in this
regard as they not only included some features of the insulin
resistance syndrome (such as triglycerides, HDL-cholesterol,
elevated blood pressure, and elevated fasting glucose as a crude
marker of an altered glucose homeostasis likely resulting from
an insulin-resistant state), but also recommended that waist
circumference be measured as an index of abdominal obesity.
1 The NCEP-ATP III criteria therefore recognize that abdominal
obesity is the driving force behind the metabolic syndrome epidemic,
a notion that should be strongly emphasized in clinical practice.
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| Figure 3 Some features of the metabolic syndrome, namely elevated apolipoprotein B (apo B) and insulin levels and small LDL particles (atherogenic metabolic triad)—largely resulting from abdominal obesity increase coronary heart disease risk beyond the contribution of traditional risk factors. | |
| Is waist circumference better than BMI? |
|---|
As shown in
Figure 4A, population studies show fairly good
correlations between BMI and waist circumference.
56 Given this,
it is often asked why waist circumference is preferable to BMI
(an internationally accepted index of adiposity). Looking more
closely at
Figure 4A, the strength of the association is
largely explained by the heterogeneity of weight in the population.
Figure 4B shows how waist circumference values vary within
each BMI quartile.
56 It is apparent that considerable variability
remains at any given BMI quartile. Thus, if waist girth and
BMI are not equally predictive of the features of the metabolic
syndrome, BMI cannot be considered a surrogate for waist circumference.
The findings presented in
Figure 5 lend further support
to this notion. They clearly indicate that for given BMI subgroups,
subjects with an elevated waist circumference have a much greater
accumulation of visceral adipose tissue,
56 a major factor involved
in the dysmetabolic profile associated with abdominal obesity.
53–55,57–59 Waist girth and BMI are therefore not comparable markers of
visceral obesity and they do not similarly predict the presence
of metabolic complications.
Figure 6 illustrates the well-documented
relationship between BMI and CVD morbidity and mortality. However,
given the heterogeneity of obesity as assessed by BMI, the model
shows that the impact of BMI on CVD mortality and morbidity
is largely (although not entirely) explained by the subgroup
of obese patients with excess abdominal fat and the related
features of the metabolic syndrome.
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| Figure 4 (A) Although there is a highly significant correlation between body mass index and waist circumference, this correlation is explained by the wide variation in body mass index values in the samples studied. (B) For instance, standard deviation values for given body mass index quartiles clearly show that waist circumference varies substantially for any given body mass index quartile. Waist circumference and body mass index are therefore not equivalent in clinical practice. Q1–Q3: different from the corresponding quartile; P <>2; 50th: 30.0 kg/m2; 75th: 33.0 kg/m2. Reproduced with kind permission of Springer Science and Business Media.56 | |
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| Figure 5 Average cross-sectional areas of visceral adipose tissue measured by computed tomography (expressed in cm2) among groups of men stratified according to median values of body mass index and waist circumference. For any given body mass index subgroup, subjects with a higher waist circumference have a much greater accumulation of visceral adipose tissue than men with lower waist girth values. BMI cut-off: 50th: 30.0 kg/m2; waist circumference cut-off: 50th: 103.5 cm. *Significantly different (P <>56 | |
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| Figure 6 Schematic illustration of the well-documented relationship between obesity, as crudely assessed by body mass index (BMI), and cardiovascular disease mortality and morbidity. The model emphasizes the notion that much of the increased cardiovascular disease risk associated with body mass index could be attributed to the subgroup of overweight/obese individuals characterized by excess visceral/ectopic fat and the related features of the metabolic syndrome. The model also acknowledges that an elevated BMI per se could yield a moderate increase in cardiovascular disease risk. | |
| The importance of assessing abdominal obesity when screening for the metabolic syndrome in clinical practice |
|---|
Although rare forms of insulin resistance not accompanied by
overweight or obesity can be found,
60 clinicians must recognize
the pivotal role played by abdominal obesity in elevating the
metabolic syndrome to epidemic status. To further emphasize
this point, a representative sample of the population of the
province of Québec, Canada—the Québec Health
Survey cohort—was stratified into various subgroups according
to the presence of various combinations of the NCEP-ATP III
metabolic syndrome criteria.
56 As shown in
Figure 7, some
combinations could not be found in sufficient prevalence in
the population. However, average waist circumference values
revealed that among combinations of criteria, even those that
did not take waist circumference into account, all had markedly
elevated waist girth values.
56 These results clearly indicate
the major role played by an expanded waistline as the most prevalent
form of the metabolic syndrome in a population-based study.
Waist circumference is therefore a crucial first step towards
identifying individuals likely to have features of the metabolic
syndrome. However, as discussed in the next section, elevated
waist circumference alone is not sufficient to diagnose high-risk
abdominal obesity associated with excess visceral/ectopic fat.
| Elevated waist girth alone is not sufficient to diagnose the metabolic syndrome |
|---|
Although measuring waist circumference is an essential first
step in clinical practice, the ability of this anthropometric
index to predict visceral fat accumulation and the presence
of the metabolic syndrome is limited. In this regard, we have
been interested in identifying a simple metabolic marker that
could help physicians identify individuals with the atherogenic
features of the insulin resistance syndrome. We found that Caucasian
middle-aged men with both an elevated fasting triglyceride concentration
(above 2 mmol/L) and a waist circumference of at least 90 cm
had a high probability (greater than 80%) of displaying features
of the metabolic syndrome (hypertriglyceridaemic waist).
21 Men
who had a waist circumference below 90 cm and a fasting triglyceride
concentration below 2 mmol/L had a very low probability (about
10%) of displaying features of the metabolic syndrome.
21 We
therefore proposed that waist circumference (as a marker of
abdominal obesity) and hypertriglyceridaemia (as a crude marker
of the related dysmetabolic, dyslipidaemic profile accompanying
excess visceral/ectopic fat) were the two key variables for
a simple and inexpensive screening of individuals at high risk
of having the metabolic syndrome.
21,22 Numerous studies have
since confirmed the relevance of hypertriglyceridaemic waist
as a simple clinical phenotype predictive of excess visceral
adiposity, insulin resistance, and features of the metabolic
syndrome.
5–20
| Can NCEP-ATP III criteria for the metabolic syndrome be applied worldwide? |
|---|
As a concept, NCEP-ATP III has recognized that some simple clinical
markers (including waist girth) can be used to identify individuals
likely to have the metabolic syndrome.
1 Furthermore, some studies
have shown that individuals meeting these criteria have a higher
prevalence of CHD than subjects who do not meet NCEP-ATP III
metabolic syndrome criteria.
35,37,61 However, we do not know
whether the cut-offs proposed by NCEP-ATP III provide an optimal
discrimination of CHD risk. Additional data must be generated
so that diverse cut-offs can be used to verify which values
provide optimal sensitivity and specificity in discriminating
for clinical events. There is also evidence that there are population
differences in susceptibility to visceral fat deposition and
to the development of complications for any given level of abdominal
visceral fat.
62–65 For instance, Blacks are less prone
to visceral adipose tissue accumulation than Whites for any
given level of total body fat or waist circumference, and we
had previously reported that Blacks’ lower susceptibility
to visceral obesity was a key factor explaining their lower
triglyceride and apolipoprotein B levels compared with Whites.
64 Another obvious example of the need to develop population-specific
cut-offs is the Asian population, which develops type 2 diabetes
at much lower BMI (and therefore lower waist circumference)
values than the Caucasian population.
66 NCEP-ATP III guidelines are a remarkable advance in that they provide clinicians with simple metabolic syndrome markers that have been shown to be associated with CHD. However, further study of all world populations is clearly warranted to further refine NCEP-ATP III criteria and cut-off values for optimal assessment of metabolic syndrome-related risk. The IDF’s recent ethnicity-specific waist circumference cut-offs were an attempt to address this question, but their validity will have to be probed further.4
| Managing CHD risk in patients with the metabolic syndrome: towards what goal? |
|---|
The features of the metabolic syndrome increase relative CHD
risk whether or not classical risk factors are present.
67,68 However, the 1.5- to 2-fold increase in CHD risk that the metabolic
syndrome generally entails only provides an index of relative
risk and is therefore not sufficient to assess absolute risk,
which is the crucial information that clinicians need. To assess
absolute CHD risk, physicians must consider classical CHD risk
factors such as age, sex, blood pressure, lipids (LDL-cholesterol,
HDL-cholesterol), smoking, and diabetes and should also use
the global CHD risk calculators such as those provided by the
Framingham or PROCAM algorithms.
69,70 It has been suggested
that the metabolic syndrome could represent one more ‘building
block’ contributing to global CHD risk.
22 The overall
risk of CHD resulting from traditional risk factors and the
potentially additive contribution of the metabolic syndrome
is known as global cardiometabolic risk (
Figure 8).
22 Under
the cardiometabolic risk model, the metabolic syndrome could
further increase the absolute risk associated with modifiable
risk factors such as hypertension, diabetes, elevated LDL-cholesterol,
reduced HDL-cholesterol and smoking. These conventional risk
factors should certainly be managed in patients with the metabolic
syndrome. However, treating classical risk factors is unlikely
to eliminate the risk specifically resulting from features of
the metabolic syndrome. The results of the Heart Protection
Study (HPS) in diabetic patients provide a simple illustration
of this notion.
71 Although all diabetic patients in the HPS
benefited from simvastatin therapy, statin-treated patients
with low HDL-cholesterol levels (presumably resulting from the
presence of abdominal obesity and hypertriglyceridaemia, the
most common form of low HDL-cholesterol in our population) remained
at higher risk of CHD events and related mortality than type
2 diabetic patients with normal HDL-cholesterol levels (presumably
less abdominally obese and likely to have lower triglyceride
levels) who received a placebo.
71 Although it has obvious clinical
benefits, statin therapy in type 2 diabetic patients with low
HDL-cholesterol (and presumably the metabolic syndrome) does
not ‘normalize’ their CHD risk. These results suggest
that it may be necessary to manage the additional features of
the metabolic syndrome in order to further reduce CHD risk in
these high-risk patients. But exactly which syndrome features
should be targeted to ‘normalize’ CHD risk will
require further study. Evidence from fibrate trials has suggested
that patients with obesity, hypertriglyceridaemia, and low HDL-cholesterol
(with either hyperinsulinaemia or type 2 diabetes) may particularly
benefit from fibrate therapy
72–75 but the equivocal results
of the Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) trial has raised doubts about a fibrate class effect.
76 Further data must be generated on the benefits of fibrates in
asymptomatic type 2 diabetic patients with abdominal obesity
and the metabolic syndrome. Furthermore, in very high-risk patients
with type 2 diabetes, CHD, and the metabolic syndrome, statin–fibrate
combination therapy must be tested in large trials for safety
and, more importantly, clinical benefits.
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| Figure 8 It is accepted that the metabolic syndrome increases relative risk of cardiovascular disease. Under this model, the metabolic syndrome is a new risk factor for cardiovascular disease. In clinical practice, the metabolic syndrome is often accompanied by insulin resistance and visceral obesity, the latter reflecting the presence of dysfunctional adipose tissue. With a classical approach, clinicians seeking to evaluate global cardiovascular disease risk will consider traditional risk factors and calculate a global risk score using algorithms such as the Framingham risk chart. However, because of the metabolic syndrome’s prevalence and its associated risk, it is also important to take into account the metabolic syndrome-related cardiovascular risk as well as the risk posed by traditional risk factors. Such global risk is described as cardiometabolic risk. Debate continues as to whether the metabolic syndrome adds to global cardiovascular disease risk assessed by traditional risk factors, and further work in this area is clearly warranted. | |
Of utmost importance, physicians need to emphasize the importance
of moderate weight loss in light of the spectacular results
of the Finnish and American prevention of diabetes studies,
both of which reported that minimal weight loss provided considerable
clinical benefits. This weight loss prevented (or at least delayed
by several years) the conversion to type 2 diabetes among high-risk
obese individuals with glucose intolerance.
77,78 Such lifestyle
modification programmes have also been shown to reduce the risk
of developing the metabolic syndrome.
79 Similarly, moderate
weight loss has been reported to induce a selective loss of
visceral adipose tissue.
80–82 This selective loss of visceral
adipose tissue could possibly explain the tremendous clinical
benefits of moderate weight loss in the Finnish and American
diabetes prevention trials.
77,78 Because excess visceral adiposity
is a key feature of the prevalent form of the metabolic syndrome,
therapeutic approaches that focus on reducing visceral adipose
tissue could have a major impact on the clustering abnormalities
of the common form of the metabolic syndrome.
| The endocannabinoid system: a new target for the treatment of visceral obesity? |
|---|
The discovery of the endocannabinoid (EC) system and its impact
on energy balance, body fat distribution, and lipid/carbohydrate
metabolism has been a fascinating breakthrough.
83,84 Recent
evidence has highlighted that viscerally obese patients are
the subgroup of individuals with an activated EC system.
85,86 Two research groups have independently reported that viscerally
obese patients have elevated plasma concentrations of 2-arachidonoylglycerol
(2-AG) (the most abundant EC in the blood) and that these elevated
2-AG concentrations were predictive of the features of the metabolic
syndrome.
85,86 It has been shown that using the CB1 antagonist rimonabant, which has been tested in phase III trials and approved for clinical use in Europe, to treat abdominally obese patients with the atherogenic dyslipidaemia of the metabolic syndrome can substantially reduce waist circumference and improve all features of the metabolic syndrome.87–90 Moreover, rimonabant treatment increased plasma adiponectin levels, the increase being greater than what could be predicted by weight loss.87 As CB1 receptors are found in adipose tissue as well as liver, gut, skeletal muscle, and beta cells, further studies will examine the tissue-specific effects of the CB1 antagonist rimonabant in viscerally obese patients with ectopic fat. In fact, rimonabant therapy may particularly benefit the subgroup of overweight/obese patients with excess visceral fat/ectopic fat by normalizing EC system activity. A study is currently ongoing to examine the effect of rimonabant on visceral/liver fat. Results from RIO-Lipids showing a reduction in ALT (a liver function marker that is elevated among patients with increased liver fat) are consistent with a CB1 antagonism effect on liver fat content and function.91 Figure 9 illustrates the potential of CB1 blockade in managing global cardiometabolic risk. The model highlights the added value of rimonabant while integrating current pharmacological approaches used to target other CVD risk factors.
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| Figure 9 Model showing the added value of targeting excess visceral fat/ectopic fat through healthy eating, physical activity, and if required, pharmacotherapy, on ‘drivers’ of global cardiometabolic risk. The model also recognizes the importance of managing ‘traditional’ risk factors. | |
| Conclusion |
|---|
Although the obesity epidemic has clearly modified the landscape
of CVD risk factors, obesity is a remarkably heterogeneous condition
that cannot be defined solely using relative weight indices
such as BMI. There is now compelling evidence that overweight/obese
patients with excess visceral fat/ectopic fat accumulation represent
the subgroup of individuals most likely to be insulin resistant
and have the related cluster of metabolic abnormalities commonly
referred to as the metabolic syndrome. Although the metabolic
syndrome increases relative CVD risk, its diagnosis is not sufficient
to properly assess global CVD risk, which must be first evaluated
using current algorithms based on established risk factors (age,
sex, blood pressure, LDL-cholesterol, HDL-cholesterol, diabetes,
smoking, family history of CHD, etc.). However, there is evidence
that the metabolic syndrome may further increase global CVD
risk beyond what could be estimated by traditional risk factors.
This global risk is defined as global cardiometabolic risk.
Under this model, targeting excess visceral fat/ectopic fat
through healthy nutrition, physical activity, and, if required,
pharmacotherapy, may be useful in further managing CVD risk
associated with the treatment of traditional risk factors (
Figure 9).
| 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 the Scientific Director of the International Chair on Cardiometabolic
Risk, which is supported by an unrestricted grant from Sanofi
Aventis awarded to Université Laval.
Conflict of interest: Dr Després reports having received consulting or lecture fees from Abbott Laboratories, AstraZeneca, Fournier Pharma, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sanofi Aventis and grant support from Fournier Pharma, GlaxoSmithKline, Innodia, Merck, Pfizer, and Sanofi Aventis.
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