abdominal obesity ; the most prevalent caused of metabolic syndrome and cardiometabolic risk

Abdominal obesity: the most prevalent causeof the metabolic syndrome and relatedcardiometabolic risk

Jean-Pierre Despres*

Quebec Heart Institute, Laval Hospital Research Center, Universite Laval, 2725, chemin Ste-Foy, PavilionMarguerite-DYouville, 4th Floor, Ste-Foy, Quebec, Canada G1V 4G5

Abdominal obesity, due to intra-abdominal adiposity, drives the progression ofmultiple cardiometabolic risk factors independently of body mass index. This occursboth through altered secretion of adipocyte-derived biologically active substances(adipokines), including free fatty acids, adiponectin, interleukin-6, tumour necrosisfactor alpha, and plasminogen activator inhibitor-1, and through exacerbation ofinsulin resistance and associated cardiometabolic risk factors. The prevalence ofabdominal obesity is increasing in western populations, due to a combination of lowphysical activity and high-energy diets, and also in developing countries, where it isassociated with the urbanization of populations. The measurement of waist circumfer-ence, together with an additional comorbidity, readily identies the presence ofincreased cardiometabolic risk associated with abdominal obesity. For example,.80% men with waist circumference 90 cm and triglycerides (TG) 2 mmol/Lwere found to have an atherogenic triad of elevated apolipoprotein B, fasting hyper-insulinaemia, and small, dense LDL, which had been strongly associated with adversecardiovascular outcomes in a previous observational study. Accordingly, measurementof waist circumference should become a standard component of cardiovascular riskevaluation in routine clinical practice. Lifestyle modication remains the initial inter-vention of choice for this population, with pharmacological modulation of risk factorswhere this is insufciently effective. Looking ahead, the initial results of randomizedtrials with rimonabant, the rst CB1 receptor blocker, indicate the potential of cor-recting overactivation of the endogenous endocannabinoid system for simultaneousimprovement of multiple cardiometabolic risk factors.

KEYWORDSAbdominal obesity;

Adiponectin;

Cardiometabolic risk;

Inammation;

Metabolic syndrome

Introduction

Abdominal obesity is emerging as an important drivingforce behind the deterioration of cardiometabolic riskin the general population. Patients with evidenceof cardiovascular disease often display abdominalobesity,1,2 and observational studies have identiedabdominal obesity as a predictor of adverse metabolicor cardiovascular outcomes independently of body mass

index (BMI).313 Moreover, we have only recently begunto understand the important endocrine and paracrinefunctions of intra-abdominal adipocytes, and thecomplex interactions leading to a diabetogenic andatherogenic metabolic risk prole.14 The purposes ofthis review are to explore the pathophysiological linksbetween abdominal obesity and elevated cardiometa-bolic risk, to evaluate strategies to identify patientsmost at risk through the presence of intra-abdominaladiposity, and to consider the implications for interven-tion to improve cardiovascular outcomes in thesepatients.

& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected]

*Corresponding author: Tel: 1 418 656 4863; fax: 1 418 656 4610.E-mail address: [email protected]

European Heart Journal Supplements (2006) 8 (Supplement B), B4B12doi:10.1093/eurheartj/sul002

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Development of abdominal obesity

Typically, upper body obesity (android, apple shapeobesity) is more commonly found in men, whereaslower body obesity (gynoid, pear shape) is morecommonly found in women. Upper body obesity receivescontributions from adiposity in subcutaneous andintra-abdominal compartments. Intra-abdominal fat(visceral fat) has been dened as the fat locatedaround the viscera and within the peritoneum, thedorsal border of the intestines and the ventral surfaceof the kidney.15 Intra-abdominal fat accumulation canoccur in men or women, and BMI does not provide areliable indication of the extent of intra-abdominaladiposity. For example, Figure 1 shows computedtomography (CT) scans of two men with a similar BMIand with the same amount of total body fat.Nonetheless, the visceral fat area (VFA) on the CT scanin the subject of the top panel is .50% higher than theother man, despite similar BMI values. It is thereforeimportant to predict intra-abdominal adiposity carefullyin clinical practice in order to better assess the relatedcardiometabolic risk.Although there is solid evidence that body fat distri-

bution (and therefore intra-abdominal obesity) has avery signicant genetic basis, abdominal obesity willonly develop in the presence of a positive energybalance. Unfortunately, because of the toxic environ-ment that we have designed for ourselves, an increasingproportion of our population is sedentary and exposed toan energy-dense rened diet favouring the developmentof obesity. As a result, this increasing tendency towardssedentary habits and an excessive intake of high-energyfoods are efcient promoters of abdominal obesity.Recent evidence conrms a high prevalence of abdominalobesity among genetically susceptible individuals. In theUSA National Health and Nutrition Examination Survey

(NHANES) cohort examined between 1988 and 1994,30% of men and 46% of women were abdominallyobese,16 according to the arbitrary waist circumferencecut-offs of.102 cm in men and of.88 cm in women pro-posed by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III).17 By19992000, these gures had risen to 36 and 52%,respectively. In a European population comprising 9596participants within the WHO Monica Study, the averagewaist circumference increased by 1 cm between198990 and 199495, with the prevalence of abdominalobesity (dened as .80th percentile for men or women,equating to waist circumference .103 cm for men and.92 cm for women) increasing by .3% over this shorttime interval.18 Increasing urbanization of populationsin the developing world, associated with decreasedphysical activity and increased energy intake, is drivingan increased prevalence of diabetes and cardiovasculardisease and there is no evidence that this phenomenonwill plateau.1922

Abdominal obesity and elevatedcardiometabolic risk

Abdominal obesity, insulin resistance, andthe metabolic syndrome

The prognostic importance of high waist circumferencehas been recognized within the diagnostic criteria toidentify individuals with features of the metabolic syn-drome. The NCEP-ATP III criteria, dating from 2001,include high waist circumference (.102 cm for menand .88 cm for women) along with criteria relating toelevated TG, low HDL-cholesterol, high blood pressure,and high fasting plasma glucose (FPG).17 Patients needto meet any three of the ve criteria. The International

Figure 1 CTscans from two subjects with comparable BMI illustrating adiposity phenotypes characterized mainly by intra-abdominal adiposity (top panels)and subcutaneous adiposity (bottom panels). Subcutaneous fat is shown in black under the skin, and visceral fat area (VFA) in white. Scans were made at theL4-L5 level. Reproduced with permission from Tchernof A, Despres JP. Obesity and lipoprotein metabolism. In: Kopelman PG, ed. Clinical Obesity, UK:Blackwell Science Ltd; 1998. p176204.

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Diabetes Federation (IDF) has gone further and made thepresence of abdominal obesity a requirement for thediagnosis of metabolic syndrome, along with two offour other criteria similar to those used by the NCEP-ATP III.23 The IDF criteria use lower cut-off values forwaist circumference than earlier criteria, and ethnic-specic values are given based on some epidemio-logical evidence. These criteria are (men/women)94/80 cm for Europid subjects; 90/80 cm forSouth Asian subjects; 90/80 cm for Chinese subjects,and 85/90 cm for Japanese subjects, with criteria forEuropids to be used for other ethnicities in the absence ofspecic recommendations. Although it is clear that lowerwaist cut-offs are required in some populations of theworld such as Asia, the values proposed to dene abdomi-nal obesity have not been based on a rigorous analysisand comparison of standardized measures of visceraladiposity, except for Japan, and cardiometabolic riskfactors/markers across populations. Therefore, therecent IDF criteria will have to be subjected to furthervalidation against hard clinical endpoints.It is important to remember that the above clinical

variables are diagnostic criteria for and not denitionsof the metabolic syndrome.24 A number of other cardio-metabolic risk factors are associated with the metabolicsyndrome beyond these criteria, such as impaired brino-lysis and a hypercoagulable state,25 chronic low-gradeinammation,26,27 and the appearance of atherogenicsmall, dense lipoproteins.28 Many of these cardiometa-bolic risk factors are driven by a combination of insulinresistance and abdominal obesity resulting from excessintra-abdominal adiposity. For example, insulin resist-ance promotes the atherogenic dyslipidaemia that ischaracterized by elevated TG, low HDL-cholesterol, andsmall, dense LDL.29 The prognostic importance of thehigh TGlow HDL-cholesterol dyslipidaemic state hasbeen well described,17 whereas the small, dense LDLphenotype was shown to be signicantly associated withadverse cardiovascular outcomes in the QuebecCardiovascular Study.13 A shift towards small, denseHDL particles has also been identied as part of thecluster of cardiometabolic risk factors accompanyingabdominal obesity and insulin resistance.30

Measures of insulin resistance correlate signicantlywith the degree of intra-abdominal adiposity inhumans.31,32 In a study where obese men matched fortotal adiposity but with low and high intra-abdominal adi-posity were compared for glucose tolerance, it was foundthat plasma levels of glucose and insulin during an oralglucose tolerance test were similar in lean subjects andin obese subjects with low intra-abdominal adiposity.33

However, glucose tolerance was deteriorated onlyamong subjects with elevated intra-abdominal adiposity,indicating the presence of insulin resistance and glucoseintolerance. In another study conducted in older subjects(.60 years), it was also found that intra-abdominal adi-posity was associated with multiple adverse changes tothe lipid prole before and after adjustment for overalladiposity.34

Importantly, intra-abdominal adiposity appears tointeract with other cardiometabolic risk factors to

adversely inuence overall cardiometabolic risk. Ananalysis from the Quebec Health Survey stratied sub-jects for BMI and then for waist circumference andstudied the relationships between indices of obesity,hyperinsulinaemia, and blood pressure in the resultingsubgroups.12 Variations in waist circumference, ratherthan BMI, were found to explain the well-known relation-ships between obesity, insulin resistance, and hyperten-sion. In another study, stratication of 569 men for FPGrevealed no signicant association between the presenceof impaired fasting glucose (IFG) (FPG 6.16.9 mmol/L)and the presence of coronary artery disease (CAD) oncoronary angiography in subjects without abdominalobesity.13 In contrast, subjects with IFG, abdominalobesity, and hypertriglyceridaemia were more thaneight-fold more likely to have CAD than subjectswithout these risk factors. Thus, it appears important inclinical practice to consider additional risk factors, suchas abdominal obesity and TG, when evaluating theimportance of dysglycaemia as a cardiovascular riskfactor.It should be noted, however, that the relationship

between abdominal obesity and insulin resistance is inu-enced by genetic factors. South Asians, for example, tendto display insulin resistance at all levels of abdominalobesity and these subjects will develop type 2 diabetesor coronary heart disease (CHD) at lower levels ofobesity than other populations.35 In this regard, there isan urgent need for good descriptive imaging and meta-bolic data to verify whether such greater susceptibilityto the comorbidities of abdominal obesity are explainedby a greater accumulation of visceral adipose tissue orby a more substantial metabolic deterioration for agiven level of intra-abdominal fat.

Direct modulation of cardiometabolic risk byintra-abdominal adiposity

Overview of adipokinesExcess intra-abdominal adiposity has the potential toinuence metabolism and cardiometabolic risk directly,through alterations in the secretion of adipokines(Table 1). Abdominal obesity promotes increasedsecretion of a range of metabolites and of biologicallyactive substances, including glycerol, free fatty acids(FFA), inammatory mediators [e.g. tumour necrosisfactor alpha (TNFa) and interleukin-6 (IL-6)], plasmino-gen activator inhibitor-1 (PAI-1), and C-reactiveprotein.14,36 The secretion of adiponectin, an apparentlycardioprotective adipokine, has been shown to bereduced in abdominally obese patients.14,36

Acute exposure of skeletal muscle to elevated levels ofFFA induces insulin resistance,37 whereas chronicexposure of the pancreas to elevated FFA impairs b-cellfunction.38 Observational evidence suggested a two-foldincrease in the risk of ischaemic heart disease associatedwith elevated plasma FFA (top vs. lowest tertile) aftercorrection for non-lipid risk factors, although furthermultivariate adjustment for lipid parameters and insulinweakened the association.39 The majority of circulating

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FFA originates from upper-body subcutaneous adipocytes,whereas intra-abdominal fat content has been positivelycorrelated with splanchnic FFA levels which may contrib-ute to the liver fat accumulation commonly found inabdominal obesity.40

Leptin is an adipokine involved in the regulation ofsatiety and energy intake.36 Levels of leptin in theplasma increase during the development of obesity anddecline during weight loss. However, the plasma concen-tration of leptin is not determined primarily by theamount of visceral fat present and correlates morestrongly with subcutaneous adiposity.41

Pro-inammatory adipokines and atherogenesisAtherosclerosis has been shown to have an inammatorycomponent,42 and pro-inammatory adipokines may beimportant mediators of atherogenesis in abdominallyobese subjects.43 Adipocytes, particularly visceral adipo-cytes, secrete numerous pro-inammatory adipokines,such as TNFa and IL-6. TNFa is a paracrine mediator inadipocytes and appears to act locally to reduce theinsulin sensitivity of adipocytes.36,44 This action wouldtend to exacerbate FFA release, inducing an atherogenicdyslipidaemia.29 TNFa also increases the secretion ofother inammatory mediators.36

IL-6 is a systemic adipokine, which not only impairsinsulin sensitivity, but is also a major determinant ofhepatic production of C-reactive protein,45 the mostimportant source of this inammatory marker. A studyin 16 well-controlled type 2 diabetes patients showed

that circulating levels of IL-6 correlate strongly withVFA, quantied by magnetic resonance imaging.45 Inaddition, the stiffness of the carotid artery, an index ofatherosclerosis, correlated with both VFA and withlevels of IL-6 and C-reactive protein in this study.However, the correlation with intra-abdominal adipositywas attenuated on multivariate analysis, when levels ofthe inammatory markers were included, whereas therelationship between carotid stiffness and IL-6 remainedstrong. Thus, intra-abdominal adipocyte-derived IL-6could be involved in the accelerated atherosclerosis oftype 2 diabetic patients. The prognostic importance ofIL-6 for cardiovascular outcomes was studied in acohort of 1982 men, free of ischaemic heart disease atbaseline and followed for 13 years, in the QuebecCardiovascular Study.46 An elevated IL-6 level (highestvs. lowest quartile) was associated with an increaseof 70% in the risk of a rst fatal ischaemic heartdisease event or a non-fatal myocardial infarction(MI), after extensive multivariate adjustment forC-reactive protein and brinogen levels, together withstandard cardiometabolic risk factors (age, BMI,systolic blood pressure, diabetes, smoking, medication,LDL-cholesterol, HDL-cholesterol, and TG).Circulating levels of C-reactive protein are elevated

in subjects with abdominal obesity, and conversely,subjects with elevated C-reactive protein tend tohave intra-abdominal adiposity (Figure 2).27 C-reactiveprotein was a signicant predictor of adverse outcomesin the analysis from the Quebec Cardiovascular Study,

Table 1 Overview of key adipokines

Adipokine Key properties Secretion inabdominal obesity

Adiponectin Anti-atherogenic, reduces risk of developing diabetes ## Differentiation of macrophages into foam cells# Atherogenic vascular remodelling# Hepatic glucose output" Insulin sensitivity

IL-6 Promotes inammation, pro-atherogenic, promotes diabetes "" Vascular inammation" Hepatic C-reactive protein production# Insulin signalling

TNFa Pro-atherogenic/pro-diabetic "Paracrine role in the adipocyte# Insulin signalling" Secretion of other pro-inammatory mediators

C-reactive protein Promotes inammation, pro-atherogenic "Marker of chronic low-grade inammationPredicts adverse cardiovascular outcomes

PAI-1 Pro-atherogenic, pro-coagulant "" Atherothrombotic risk

Resistin Exacerbates insulin resistance "# Insulin signalling# Endothelial function" Vascular smooth muscle proliferation

See text for explanation and references.




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described above, although adjustment for other riskfactors/markers markedly attenuated this relationship.46

Many other studies have also implicated elevated C-reactive protein concentrations as a marker of increasedrisk of CHD or stroke.47,48

PAI-1 is secreted from intra-abdominal adipocytes,although mainly from platelets and the vascular endo-thelium.36 This acute phase protein is elevated ininammatory states49 and promotes a pro-coagulantstate by inhibiting tissue plasminogen activator, thusincreasing the risk of an intravascular thrombus.50

Plasma PAI-1 levels are increased in abdominally obesesubjects51 and are predictive of adverse cardiovascularoutcomes.50

Adiponectin: a cardioprotective adipokinePlasma adiponectin levels have been shown to be inver-sely proportional to the severity of intra-abdominaladiposity.41,52 When a group of 196 men were stratiedinto lean and obese groups, and further stratied onthe basis of their VFA assessed by CT, it was found thatadiponectin levels were similar in the lean group and inthe obese group with low VFA.52 However, obese subjectswith high intra-abdominal adiposity were characterizedby markedly reduced plasma adiponectin levels(Figure 3). These data conrm the dependence of adipo-nectin levels on intra-abdominal adiposity, rather than onobesity per se. Indeed, intra-abdominal adiposity was theonly independent predictor of adiponectin levels in thisstudy.Adiponectin has been shown to have many favourable

metabolic properties. For instance, it improves insulinsensitivity and glycaemic control,52,53 and levels ofthis adipokine correlate positively with levels ofHDL-cholesterol and inversely with TG or PAI-1.52,54 Theanti-atherogenic actions of adiponectin appears to bemultifactorial, including inhibition of endothelial acti-vation, reduced conversion of macrophages to foamcells, and inhibition of the smooth muscle proliferationand arterial remodelling that characterizes the develop-ment of the mature atherosclerotic plaque.55 Lowadiponectin levels have been associated with adversecardiovascular outcomes. For example, in a 6-year

follow-up of subjects in the Physicians Health Study, therisk of MI increased as adiponectin levels decreased,with a doubling of adiponectin associated with a riskreduction of 20% after multivariate adjustment forlipids, HbA1C, C-reactive protein, age, smoking, monthof blood draw, BMI, family history of MI, history of dia-betes and hypertension, alcohol, and physical activity.56

Prognostic value of abdominal obesitybeyond BMI

The strong relationships between abdominal obesity,insulin resistance, and cardiometabolic risk factors,described above, are suggestive of an important rolefor intra-abdominal adiposity in the pathogenesis of car-diovascular disease. A link between abdominal obesityand increased cardiometabolic risk was suggestedalmost six decades ago by Vague as well as in twoelegant early epidemiological studies that investigatedthe links between occupational physical activity, adi-posity, and outcomes. Specically, bus drivers and busconductors in London, UK, were studied. The drivers

Figure 3 Plasma adiponectin levels in healthy non-obese controls and inobese men with either low or high levels of visceral fat area (VFA). Dataare from a study of 39 non-obese men and two groups of 15 obese menstratied for VFA measured using CT scanning. Reproduced with per-mission from Cote et al.52 Copyright 2005, The Endocrine Society.

Figure 2 Association of intra-abdominal adiposity (VFA on CT scans) with elevated C-reactive protein. Signicance of results: P, 0.0001 vs. (asterisk)quintile 1; (dagger) quintile 2; (double dagger) quintile 3. Reproduced with permission from Lemieux et al.27

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had an almost completely sedentary occupation, whereasconductors were more active, as they needed to walkaround the upper and lower decks of buses to collectfares and issue tickets. A markedly higher incidence ofearly (3 months) mortality following a rst CHD eventhad been observed among the sedentary drivers(Figure 4, right panel).57 A similar difference in thisoutcome was observed between sedentary telephoneoperators and more active postmen. A few years later,a study set out to investigate whether differences inthe body shape between these groups, using availablerecords of uniform sizes, might explain the differencein outcomes. This study demonstrated a clear differencein the waist circumference of drivers uniform trousers,which was indicative of upper body obesity and sugges-tive of abdominal obesity (Figure 4, left panel).58

The ve decades of clinical research undertakensince this pioneering study have conrmed theprognostic importance of abdominal obesity. An increasedwaisthip ratio was found to account for 20% of thepopulation-attributable risk of a rst MI after adjustment

for a range of other cardiometabolic risk factors in theINTERHEART study, a casecontrol study involving 29 972subjects from 52 countries.3 Other studies have shownabdominal obesity to be a signicant predictor of cardio-vascular mortality,5,8 the development of CAD,9,13 type 2diabetes,7,10,11 or the metabolic syndrome.6,9

Importantly, some of these studies have demonstratedthe adverse prognosis associated with abdominal obesity,independently of BMI. BMI did not predict signicantlythe development of major coronary events in a retro-spective cohort study in 756 patients undergoingcoronary angiography after adjustment for standardcardiometabolic risk factors and abdominal obesity(Table 2).5 In contrast, high waist circumference signi-cantly predicted the development of major coronaryevents after adjustment for the same standard cardiome-tabolic risk factors and BMI (Table 2). Similarly, an analy-sis from a large cohort of 44 702 women enrolled in theNurses Health Study, aged 4065 and free of CHD at base-line, stratied subjects into tertiles for BMI and waist cir-cumference.7 The age-adjusted risk of CHD during 8 years

Table 2 Prognostic value of high waist circumference beyond BMI: data from an analysis of 756 patients under-going coronary angiography.5

Men Women

Odds ratio (95% CI) P-value Odds ratio (95% CI) P-value

Vascular mortalityBMI 1.04 (0.621.73) 0.886 0.35 (0.101.20) 0.095Waist circumference 2.31 (1.164.60) 0.017 8.71 (1.7842.68) 0.008

Major coronary eventsBMI 0.99 (0.631.57) 0.965 0.47 (0.181.24) 0.128Waist circumference 2.05 (1.063.94) 0.032 4.55 (1.1218.48) 0.034

For BMI, data shown are standardized odds ratios adjusted for age, gender, smoking and total cholesterol. Similar adjust-ments were made for waist circumference including adjustment for BMI. Major coronary events were dened as fatal/non-fatal MI, sudden cardiac death, or mortality from congestive heart failure of ischaemic aetiology.

Figure 4 Associations between occupational physical activity, obesity, and mortality in the 3 months following a rst CHD event in transport workers inLondon, UK. Proportions with waist .36 in. were adjusted for subjects height; 36 in. is equivalent to 91.4 cm. Between 58 and 214 men were studied foreach age group in either occupation. Mortality data are standardized mortality rates for individuals aged 3564 for years 194952. Drawn from datapresented by Morris et al.57 and Heady et al.58




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of follow-up increased with increasing waist circumfer-ence for each tertile of BMI. The age-adjusted incidenceof CHD was similar between subjects with the lowestBMI and highest waist circumference (83/100 000 person-years) and subjects with the highest BMI and lowest waistcircumference (77/100 000 person-years). Subjects withboth high BMI and high waist circumference had thehighest cardiovascular risk, with an age-adjusted CHDincidence of 128/100 000 patient-years. There is nodoubt that measurement of waist circumference addsclinically signicant prognostic information to BMImeasurement relating to the risk of developing cardio-vascular disease.

Implications for therapy

Identifying high-risk patients for interventions

The evidence reviewed above shows that abdominalobesity is closely involved in the development of multiplecardiometabolic risk factors, including those associatedwith the metabolic syndrome. The large and growingabdominally obese population includes a substantialnumber of patients who are at increased risk of adversecardiometabolic outcomes. In this regard, the NCEP-ATPIII guidelines emphasized that the most prevalent formof the metabolic syndrome that physicians will encounteris associated with abdominal obesity.43 In relying on theclassical risk factors that dene the metabolic syndrome,however, we run the risk of missing important infor-mation captured by the presence of other potentiallyimportant cardiometabolic risk factors. For example, atriad of non-traditional cardiometabolic risk factors,elevated apolipoprotein B (ApoB), fasting hyper-insulinaemia, and small, dense LDL conferred a ve-foldelevation in the risk of developing ischaemic heartdisease, after adjustment for other lipid parameters,compared with subjects with not more than one ofthese risk factors, in a 5-year prospective casecontrolanalysis of the Quebec Cardiovascular Study.59

However, the above elements of the atherogenic triadare not measured in routine clinical practice, and a morepracticable means of identifying this high-risk subgroup isrequired. Accordingly, we have identied the hyper-triglyceridaemic waist, a combination of high waistcircumference and hypertriglyceridaemia, a straight-forward and useful means of identifying abdominallyobese patients with excess visceral fat and with theatherogenic triad. The utility of hypertriglyceridaemicwaist was determined in a study in 185 men withoutsymptoms of cardiovascular disease stratied for differ-ent values of TG and waist circumference.60 More than80% subjects with modest hypertriglyceridaemia(2 mmol/L) together with high waist circumference(90 or 100 cm) were found to have the atherogenictriad (Figure 5). In contrast, a waist girth below 90 cmcombined with TG concentrations below 2.0 mmol/Lwas associated with a low probability (10%) of beingcharacterized by visceral obesity and related metabolicabnormalities. Thus, measurement of waist

circumference and TG, two simple clinical measurementssuitable for routine clinical use, clearly identies a highproportion of a subgroup of individuals at markedly elev-ated cardiometabolic risk.

Interventions to manage cardiometabolic risk inabdominal obesity

When managing the prevalent form of the metabolicsyndrome, NCEP-ATP III recommend to treat abdominalobesity and its associated insulin resistance rst, asthese are root causes of the overall elevation of cardio-metabolic risk. Current management guidelines supportthe use of lifestyle interventions (diet and exercise), asthis strategy has the potential to improve all cardiometa-bolic risk factors.17 Where necessary, the individualcomplications of abdominal obesity and insulin resist-ance, such as atherogenic dyslipidaemia, hypertension,a pro-coagulant state, or inammation, can then bemanaged. However, lifestyle modications are oftenunsuccessful, due in part to insufcient patient compli-ance with these regimens to induce long-term weightloss and maintenance. Under such circumstances,pharmacotherapy can be justied to manage elevatedcardiometabolic risk.Recent research has identied overactivity of the

endocannabinoid system, acting via the CB1 receptor, asan important factor in the pathogenesis of cardio-metabolic risk.61 Rimonabant is the rst selective CB1blocker to undergo clinical evaluation and has beenextensively evaluated in patients with obesity and associ-ated risk factors within the Rimonabant In Obesity (RIO)trial programme. Table 3 shows the effects of rimonabanton key cardiometabolic risk factors in two of these trials,RIO-Europe62 and RIO-Lipids.63 RIO-Europe recruited apopulation of obese (BMI 30 kg/m2) or overweight

Figure 5 Prevalence of an atherogenic triad of elevated ApoB, fastinghyperinsulinaemia, and small, dense LDL according to the TG and waistcircumference. Reproduced with permission from Lemieux et al.60

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(BMI . 27 kg/m2) patients with at least one cardio-vascular comorbidity, whereas RIO-Lipids recruitedobese (BMI 30 kg/m2) or overweight (BMI . 27 kg/m2)patients with untreated atherogenic dyslipidaemia,dened by hypertriglyceridaemia or an elevated totalcholesterol:HDL-cholesterol ratio. These double blind,placebo controlled, randomized trials evaluated rimona-bant 5 and 20 mg once daily in addition to a mild hypo-caloric diet. Treatment with rimonabant 20 mg for 1year resulted in marked and signicant improvementsrelative to placebo in a number of cardiometabolic riskfactors, including waist circumference, body weight,HDL-cholesterol, TG, and blood pressure. Importantly,statistical analysis showed that about half of theimprovements in HDL-cholesterol and triglyceride levelswere independent of weight loss, consistent with adirect action of rimonabant on cardiometabolic risk. InRIO-Europe, indices of glycaemic control and insulinsensitivity also improved during treatment withrimonabant, and there was a 46% increase in plasmaadiponectin vs. placebo with rimonabant 20 mg inRIO-Lipids. Rimonabant 5 mg results were either similarto those of placebo or intermediate to those of placeboand rimonabant 20 mg. Rimonabant was generally welltolerated.

Conclusions

A growing database of clinical evidence implicatesintra-abdominal adiposity as a powerful driving forcefor elevated cardiometabolic risk. This associationappears to arise directly, via secretion of adipokines,and indirectly, through promotion of insulin resistance.Addressing intra-abdominal adiposity should play acentral role in future strategies aimed at improvingcardiovascular outcomes in patients with abdominalobesity and its associated cardiometabolic risk factors.

Conict of interest: J.-P.D. has received consulting or lecturefees from Abbott Laboratories, AstraZeneca, Fournier Pharma,

GlaxoSmithKline, Merck, Pzer, Pharmacia, and sano-aventisand grant support from Fournier Pharma, GlaxoSmithKline,Merck, Pzer, and sano-aventis. J.-P.D. is Scientic Directorof the International Chair on Cardiometabolic Risk which is sup-ported by an unrestricted grant awarded to Universite Laval bysano-aventis.

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Table 3 Mean placebo-corrected changes in cardiometabolicrisk factors during 1 year of treatment with once daily rimona-bant 20 mg in the RIO-Europe62 and RIO-Lipids63 studies

RIO-Europe RIO-Lipids

Waist circumference (cm) 24.2a 24.7a

Body weight (kg) 24.7a 25.4a

HDL-cholesterol (%) 8.9a 8.1aTriglycerides (%) 215.1a 212.4a

Systolic BP (mmHg) 21.2 21.8b

Diastolic BP (mmHg) 21.0 21.5b

Data are least-squares mean treatment differences or differencesbetween mean changes on placebo and rimonabant 20 mg from theintent-to-treat population of the trials. Patients were randomizedto receive placebo, rimonabant 5 mg (data not shown) or rimonabant20 mg for 1 year in addition to a mild hypocaloric diet (2600 kcal/day).

aSignicance vs. placebo, P, 0.001.bSignicance vs. placebo, P, 0.05.




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abdominal obesity ; the most prevalent caused of metabolic syndrome and cardiometabolic risk

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