1. Apex Block III, delkurs IV HT 2006
Metabola Syndromet
2006
Björn Carlsson
Apex Block III, delkurs IV HT 2006

2. INTER-HEART: Population-attributable risk of acute MI in the overall population
”Disease” related risk factors
Diabetes
Hypertension
Abdominal obesity
ApoB/ApoA1
Behaviour related risk factors
Alcohol intake
Exercise
Psychosocial stress
Current smoking

3. cardiac & cerebral events
Life style is a Driver of CVD
Stress
Smoking
Physical inactivity
Excessive food intake
Life style intervention
Hypertension
Diabetes
Dyslipidaemia
Obesity
Risk factor modification
Atherosclerosis
Chronic heart failure
Arrhythmia
Arterial & venous
thrombosis/
cardiac & cerebral events

4. Obesity in the US 1985

5. Obesity in the US 1990

6. Obesity in the US 1993

7. Obesity in the US 1998

8. Obesity in the US 2001
Today 30% of adults in the US are obese and >65% are overweight

9. Obesity is a major driver of obesity and diabetes
From Mokdad et al, JAMA 2003

10. Diabetes/obesity
Pandemic of obesity and type 2 diabetes mellitus continues
Foreseen effects in the USA
Life time risk of developing diabetes for individuals born in 2000
Men 32.8%
Women 38.5%
Life expectancy reduction if diabetes diagnosed at age <40
Men: loss of 11.6 life years
Women: 14.3 life years
Ref. JAMA. 2003;209:

11. Metabolic Syndrome 2005 A cluster of “non-typical” CV risk factors
Increases lifetime risk of developing type II diabetes and cardiovascular diasese
Controversial disease etiology
Insulin resistance
Visceral obesity

12. IDF Consensus definition ATPIII: the metabolic syndrome
WHO
(c)
EGIR
(d)
Hyper TG waist
(e)
AACC
(f)
International Diabetes Federation & input from IAS/NCEP
National Cholesterol Education Program – Adult Treatment Panel III
1999 World Health Organization definition of the metabolic syndrome
European Group for the Study of Insulin Resistance (IR)
The Hypertriglyceridemic Waist in Men
American Association of Clinical Endocrinologists**
Defined as abdominal obesity (as measured by waist circumference against ethnic and gender specific cut-points) plus any two of the following:
·    Hypertriglyceridemia (> 150 mg/dl; 1.7mmol/l)
·    Low HDLc (<40 mg/dl or <1.03mmol/l for men and <50 mg/dl or 1.29 mmol/l) for women) or on treatment for low HDL
·    Hypertension (SBP > 130 mmHg DBP > 85 mmHg or on treatment
·    Hyperglycemia – Fasting Plasma Glucose > 100 mg/dl or 5.6 mmol/l or IGT or pre-existing diabetes mellitus)
Diagnosis is established when > 3 of these risk factors are present
·      Abdominal obesity (waist circumference)
Men >102 cm (>40 in) Women >88 cm (>35 in)
·      Hypertriglyceridemia > 150 mg/dL
·      Low HDLc Men <40 mg/dL Women <50 g/dL
·      Hypertension >130/>85 mm Hg
·      Hypergylcemia Fasting Plasma Glucose >110 mg/dL
Defined as Insulin Resistance (IR)* plus any two of the following:
·   Obesity BMI (>30 kg/m2) and/or WHR (>0.90 in men, >0.85 in women)
·   Hypertriglyceridemia (>1.7 mmol/l) and/or low HDL cholesterol (<0.9 mmol/l in men, <1.0 mmol/l in women)
·   Hypertensive . antihypertensive treatment and/or elevated blood pressure (>140 mmHg systolic or >90 mmHg diastolic)
·   Microalbuminuria (urinary albumin excretion rate (AER) >30 µg/min
·   IR: Fasting insulin highest 25% of population
Plus two of the following:
·   Abdominal obesity (waist circumference) Men >94 cm: women >80 cm
·   Hypertriglyceridemia >2 mmol/l
·   And/or low HDLc <1 mmol/l
·   Hypertension >140/90 mm Hg
·   Hyperglycaemia Fasting plasma glucose >6.1 mmol/l
·  Triglyceride >2.0 mmol/l
·  Waist >90 cm
·   BMI >25 kg/m2
·   Tg >150 mg/dl
·   HDLcMen <40 mg/dl Women <50 mg/dl
·   Bp >130/85 mmHg
·   2 hours post glucose challenge BS >140 mg/dl
·   Fasting glucose mg/dl
·   Others
·   Family history T2DM, HTN or CVD
·   PCO
·   Sedentary
·   Advancing Age
·   Ethnic group at high risk

13. Targeting cardiometabolic risk in patients with intra-abdominal adiposity and related comorbidities

14. Summary
Despite therapeutic advances, cardiovascular disease remains the leading cause of death worldwide
Current treatments generally target individual risk factors and do not propose a comprehensive approach to the management of cardiometabolic disease
An increased risk of developing cardiometabolic disease can be attributed to abdominal obesity (as measured by waist circumference)
A major cause of cardiometabolic disorders (including dyslipidaemia, insulin resistance, type 2 diabetes, metabolic syndrome, inflammation and thrombosis) is thought to be intra-abdominal adiposity (IAA)
Waist circumference provides a simple and practical diagnosis of IAA in patients at elevated CV risk
Summary
Given the clinical importance of cardiovascular disease as the number one cause of death world wide, it is important that we seek underlying causes of cardiovascular morbidity and mortality. A comprehensive approach to cardiometabolic disease may yield greater clinical benefit than continuing to focus on managing individual risk factors.
Abdominal obesity, with its attendant intra-abdominal adiposity, is emerging as an underlying cause of multiple cardiovascular risk factors. Intra-abdominal adipocytes are active endocrine cells, secreting a range of substances that adversely affect cardiometabolic risk factors associated with the metabolic syndrome, such as lipid profiles, insulin sensitivity and glucose tolerance, and also emerging risk factors, including inflammation and altered haemostasis.
Recent research shows that over-activity of the endocannabinoid system, acting through the CB1 receptor, exacerbates multiple cardiometabolic risk factors. Selective CB1 receptor blockade provides a new therapeutic approach to the simultaneous management of multiple cardiometabolic risk factors, particularly in patients with intra-abdominal adiposity. These patients can be easily identified using standard waist measurement in conjunction with other cardiometabolic markers such as HDL, triglycerides, glucose or blood pressure.
This presentation reviews the relationships between abdominal obesity, intra-abdominal adiposity, and elevated cardiometabolic risk, and outlines the potential role of selective CB1 receptor blockade in the management of multiple cardiovascular risk factors.
theheart.org

15. Despite therapeutic advances, cardiovascular disease remains the leading cause of death (USA)5 10 15 20 25 30 35
Number of deaths (thousands)
Male
Female
% of all deaths (right axis)
No. of deaths (left axis)
% All deaths (male + female)
Despite therapeutic advances, cardiovascular disease remains the leading cause of death (USA)
Survey data from the Centers for Disease Control National Center for Health Statistics in the USA illustrate the continuing burden of mortality arising from cardiovascular disease.
The left hand axis shows the numbers of deaths attributed to specific conditions in men and women in The right hand axis expresses the number of deaths in men and women combined as a percentage of the total numbers of deaths during that year.
Cardiovascular disease remains the leading killer, with more impact on mortality rates than other major sources of mortality, such as cancer, respiratory disease, accidents, or diabetes.
National Center for Health Statistics. Health, United States, 2004 With Chartbook on Trends in the Health of Americans. Hyattsville, Maryland: 2004.
Data for 2002
National Center for Health Statistics 2004

16. Multiple cardiovascular risk factors drive adverse clinical outcomes
Increased Cardiometabolic Risk
Abdominal
obesity
Dyslipidaemia
Hypertension
Glucose intolerance
Insulin resistance
Multiple cardiovascular risk factors drive adverse clinical outcomes
Cardiovascular disease remains the number one cause of death despite recent advances in cardiovascular care, such as the introduction of new effective drugs for the management of individual cardiovascular risk factors.
The overall risk of an adverse cardiovascular event is often driven by multiple individual risk factors, including abdominal obesity, dyslipidaemia, insulin resistance/glucose intolerance and raised blood pressure.
Accordingly, new approaches that address these multiple sources of overall cardiometabolic risk, rather than individual risk factors, may be required for the next advance in cardiovascular and diabetes care.
Metabolic Syndrome

17. Substantial residual cardiovascular risk in statin-treated patients
The MRC/BHF Heart Protection Study 30
Placebo
Statin 20
Risk reduction=24%
(p<0.0001)
19.8% of statin-treated patients had a major CV event by 5 years
% Patients 10
Substantial residual cardiovascular risk in statin-treated patients
The MRC/BHF Heart Protection Study was one of the landmark trials that have established the place of statins in the management of hypercholesterolaemia. A population of 20,536 patients at high cardiovascular risk through the presence of coronary disease, other arterial disease or diabetes were randomly assigned to treatment with simvastatin or placebo for an average of 5 years.
The intervention was highly effective, with a significant reduction in the risk of cardiovascular events of 24%. However, a majority of cardiovascular risk remains unaffected after statin treatment, and almost 20% of patients in the statin group had a major cardiovascular event during the 5-year follow-up period.
Total-C and LDL-C were markedly reduced by treatment with the statin (mean changes from baseline of -1.2 mmol/L [-46 mg/dL] and –1.0 mmol/L [-39 mg/dL], respectively). However, other lipid components, such as triglycerides of HDL-C impact importantly on cardiovascular risk and were changed only slightly in the study (mean changes from baseline of -0.3 mmol/L [-27 mg/dL] and 0.03 mmol/L
[1 mg/dL], respectively).
We may need to look beyond effects on LDL-C to achieve greater results in the management of overall cardiovascular risk.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22. 1 2 3 4 5 6
Year of follow-up
Heart Protection Study Collaborative Group (2002)

18. Unmet clinical needs to address in the next decade
Major Unmet Clinical Need
Classical Risk Factors
Novel Risk Factors
Metabolic syndrome
Abdominal Obesity
HDL-C
TG
TNF IL-6
PAI-1
Glu
Insulin
 LDL-C
 BP
Smoking
T2DM
Unmet clinical needs to address in the next decade
The adverse effects of cardiovascular prognosis of the classical cardiovascular risk factors, hypercholesterolaemia, hypertension and smoking, are well understood. Our increasing understanding of the pathophysiology of cardiovascular disease is now defining the importance of a range of new cardiovascular risk factors.
Among these, abdominal obesity, low HDL-C, hypertriglyceridaemia and the hyperglycaemia associated with insulin resistance are all recognised criteria for the diagnosis of the metabolic syndrome. However, a range of important novel risk factors or risk markers for cardiovascular disease are also associated with the metabolic syndrome, although not yet included within its definition. These include chronic, low-grade inflammation, and disturbances in the secretion of bioactive substances from adipocytes (‘adipokines’) that influence cardiovascular structure and function.
The cardiovascular risk factors associated with the metabolic syndrome, whether included within its diagnostic criteria or not, contribute to the progression of atherosclerotic cardiometabolic disease, and represent an important clinical need inadequately addressed by current therapies.
CARDIOVASCULAR DISEASE

19. Management of the metabolic syndrome
Appropriate and aggressive therapy is essential for reducing patient risk of cardiovascular disease
Lifestyle measures should be the first action
Pharmacotherapy should have beneficial effects on
Glucose intolerance / diabetes
Obesity
Hypertension
Dyslipidemia
Ideally, treatment should address all of the components of the syndrome and not the individual components
Management of the metabolic syndrome
Aggressive intervention directed at underlying causes of cardiovascular morbidity and mortality is required to reduce the burden of cardiovascular disease. Addressing the underlying causes of cardiometabolic disease may yield greater clinical benefit than continuing to focus on managing individual risk factors.
Lifestyle intervention does address all of the components of the metabolic syndrome and must always be tried first. Where patients cannot or will not undertake sufficiently effective lifestyle intervention programmes, pharmacotherapy will be required. The ideal pharmacotherapy should address multiple components of the metabolic syndrome, and not its individual components.
International Diabetes Federation, 1st International Congress on “Prediabetes” and Metabolic Syndrome (2005)
International Diabetes Federation, 1st International Congress on
“Prediabetes” and Metabolic Syndrome (2005)

20. Abdominal obesity: required for diagnosing the metabolic syndrome
IDF criteria of the metabolic syndrome
High waist circumference
Plus any two of
 Triglycerides ( 1.7 mmol/L [150 mg/dL])‡
 HDL cholesterol‡
Men < 1.0 mmol/L (40 mg/dL)
Women < 1.3 mmol/L (50 mg/dL)
 Blood pressure  130 / >85 mm Hg‡
 FPG ( 5.6 mmol/L [100 mg/dL]), or diabetes
Abdominal obesity: required for diagnosing the metabolic syndrome
The new criteria of the metabolic syndrome from the IDF requires the presence of high waist circumference, along with two other cardiovascular risk factors.
Gender and ethnic-group specific values for waist circumference are provided on the next slide.
The IDF criteria are generally reminiscent of the current NCEP ATP-III criteria, except that the diagnostic cut-offs for abdominal obesity and FPG are lower in the new IDF criteria.
International Diabetes Federation.
‡or specific treatment for these conditions
International Diabetes Federation (2005)

21. Abdominal obesity and waist circumference thresholds
New IDF criteria:
Men
Women
Europid
>94 cm (37.0 in)
>80 cm (31.5 in)
South Asian
>90 cm (35.4 in)
Chinese
Japanese
>85 cm (33.5 in)
What is abdominal obesity?
This slide shows the diagnostic criteria for abdominal obesity, based on the measurement of waist circumference, from the metabolic syndrome as defined by the IDF and NCEP ATP-III criteria.
Anthropometric variables differ greatly between different ethnic groups. For example, certain Asian populations are at increased risk of cardiovascular events at lower values of BMI compared with Europid populations, so that waist circumference measurements may need modification for use in other populations. The new IDF criteria of the metabolic syndrome have addressed this issue.
National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Final Report. National Cholesterol Education Program, National Heart, Lung, and Blood Institute, National Institutes of Health. NIH Publication No September 2002.
International Diabetes Federation.
Current NCEP ATP-III criteria
>102 cm (>40 in) in men, >88 cm (>35 in) in women
NCEP 2002; International Diabetes Federation (2005)

22. High waist circumference is associated with multiple cardio vascular risk factors
US population age >20 years 30 20
Prevalence of high waist circumference associated with (%) 10
High waist circumference is associated with multiple cardiovascular risk factors
Abdominal obesity plays a major role in the development of multiple metabolic disorders, including dyslipidaemia1, insulin resistance2, type 2 diabetes3 and metabolic syndrome4 – all factors leading to the development of cardiovascular disease.
Analysis of data from the NHANES 1999–2000 cohort from the USA shows that high waist circumference (NCEP/ATP III definition) is commonly associated with other cardiovascular risk factors, as shown on the slide.5 Overall, 86% of abdominally obese patients had at least one other cardiovascular risk factor.5
1. Després JP et al. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis1990;10:497–511
2. Pouliot MC et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes1992;41:826–34
3. Kissebah AH et al. Health risks of obesity. Med Clin North Am1989;73:111–38
4.Turkoglu C et al. Effect of abdominal obesity on insulin resistance and the components of the metabolic syndrome: evidence supporting obesity as the central feature. Obes Surg 2003;13:699–705
5. NHANES 1999– Data downloaded September 2004 using SAS software (Data on file).
Low HDL-Ca
High TGb
High FPGc
High BPd
>2 risk factorse
a<40 mg/dL (men) or <50 mg/dL (women); b>150 mg/dL; c>110 mg/dL; d>130/85 mmHg; eNCEP/ATP III metabolic syndrome
NHANES 1999–2000 cohort; data on file

23. Unmet clinical need associated with abdominal obesity
CV risk factors in a typical patient with abdominal obesity
Patients with abdominal obesity (high waist circumference) often present with one or more additional CV risk factors
Unmet clinical need associated with abdominal obesity
Abdominal obesity (measured by high waist circumference) represents a major health threat, as it often presents in association with a cluster of cardiometabolic risk factors.
Indeed, 86% of abdominally obese subjects have one or more cardiovascular risk factors, and 24% have at least two additional cardiovascular risk factors that identify them as having the metabolic syndrome.1
Clearly, abdominal obesity signifies a marked increase in overall cardiovascular risk that is often driven by the progression of multiple risk factors.
New approaches to the management of cardiovascular risk that address this complex pathophysiology are needed.
1. NHANES 1999– Data downloaded September 2004 using SAS software (Data on file)

24. Abdominal obesity has reached epidemic proportions worldwide
Men (%) Women (%) Total (%)
USa
Spainb
Italyc
UKd
Francee – – 26.3
Netherlandsf
Germanyg
Abdominal obesity has reached epidemic proportions worldwide
Surveys in various countries suggest a high prevalence of abdominal obesity, using criteria similar to those used for the metabolic syndrome by NCEP/ATP III. Further details of the populations in each country are given below:
Country Year Age range studied
US 1999–2000  20
France 2003  15
Spain 1997–
Italy
Netherlands
UK 2000–
Germany 1994–5 25–74
Alvarez Leon EE, Ribas Barba L, Serra Majem L. Prevalence of the metabolic syndrome in the population of Canary Islands, Spain. Med Clin (Barc) 2003;120:172-4.
Charles MA, Basdevant A, Eschwege E. Prevalence of obesity in adults in France: the situation in 2000 established from the OBEPI Study. Ann Endocrinol (Paris) 2002;63:154-8.
Osservatorio Epidemiologico Cardiovascolare Italiano. Ital Heart J 2004,5(suppl.3):49-92.
Visscher TLS, Seidell JC. Time trends ( ) and seasonal variation in body mass index and waist circumference in the Netherlands. Int J Obes 2004;28:
Ruston D, Hoare J, Henderson L, Gregory J. The National Diet & Nutrition Survey: adults aged 19 to 64 years. Office of National Statistics (UK), 2004, National Diet and Nutrition Survey, vol. 4.
Ford ES, Mokdad AH, Giles WH. Trends in waist circumference among U.S. adults. Obes Res 2003;11:
Liese AD, Döring A, Hense HW, Keil U. Five year changes in waist circumference, body mass index and obesity in Augsburg, Germany. Eur J Nutr 2001;40:
High waist circumference: >102 cm (>40 in) in men or >88 cm (>35 in) in women except in Germany (>103 cm [41 in] and >92 cm [36 in], respectively)
aFord et al 2003; bAlvarez-Leon et al 2003; cOECI 2004; dRuston et al 2004; eObepi 2003; fVisscher & Seidell 2004; gLiese et al 2001

25. Growing prevalence of abdominal obesity
US National Health and Nutrition Examination Survey (NHANES)
NHANES III
(1988–1994)
NHANES
(1999–2000)
Relative change
Men
29.5%
36.9%
+ 28%
Women
46.7%
55.1%
+ 18%
Growing prevalence of abdominal obesity
The National Health and Nutrition Examination Survey is an ongoing observational study. The analyses shown in this slide have included 6346 men and women for the cohort and 1677 men and women for the 1999–2000 cohort.
The data shows clearly that the prevalence of abdominal obesity increased markedly in the USA between these two time points.
Ford ES, Mokdad AH, Giles WH. Trends in waist circumference among U.S. adults. Obes Res 2003;11:
Abdominal obesity defined as waist circumference: >102 cm (>40 in) in men or >88 cm (>35 in) in women
Ford et al 2003

26. Abdominal obesity increases the risk of developing type 2 diabetes24 20 16
Relative risk 12 8 4
Abdominal obesity increases the risk of developing type 2 diabetes
These data are from the Nurses’ Health Study,1 an observational study that followed a cohort of 43,581 women between 1986 and 1994 in the USA. The analysis presented here was designed to define the association between waist circumference and the risk of developing type 2 diabetes.
The risk of developing type 2 diabetes increased linearly with an increasing waist circumference. The relative risk for women at the 90th percentile of waist circumference (equivalent to a waist measurement of 92 cm [36 in]) was 5.1 (95% CI ) compared with women at the 10th percentile (waist measurement of 67 cm [26.2 in]). High waist circumference is a powerful predictor of an increased risk of developing type 2 diabetes.
Previous slides have defined the central role of abdominal obesity in the diagnostic criteria for the metabolic syndrome. People with the metabolic syndrome have a fold greater risk of developing type 2 diabetes, if not already present.2
1. Carey VJ, Walters EE, Colditz GA et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The Nurses' Health Study. Am J Epidemiol 1997;145:614-9.
2. Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM. Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Diabetes Care 2004;27:
<71
71–75.9
76–81
81.1–86
86.1–91
91.1–96.3
>96.3
Waist circumference (cm)
Carey et al 1997

27. Metabolic syndrome has a negative impact on CV health and mortality
No metabolic syndrome
Metabolic syndrome 25 25 *
*p<0.001 20 20
*p<0.001 * 15 15
Prevalence (%)
Mortality rate (%) * 10 10 *
Metabolic syndrome has a negative impact on CV health and mortality
Although it has been widely assumed that the metabolic syndrome is associated with an increased risk of cardiovascular disease, relatively little research has been done on the prevalence of cardiovascular morbidity and mortality in patients with the syndrome.
Isomaa and colleagues assessed cardiovascular morbidity and mortality in a cohort of subjects (N=3606; age, 35 to 70 years) participating in a longitudinal study in Finland and Sweden (the Botnia study). Median follow-up was years.
Subjects meeting the definition of metabolic syndrome were significantly more likely to have a history of CHD, myocardial infarction, and stroke than those without the syndrome. The presence of metabolic syndrome was associated with significantly increased risk of CHD (RR, 2.96, p<0.001), myocardial infarction (RR 2.63, P<0.001), and stroke (RR 2.27, p<0.001).
Overall, individuals with the metabolic syndrome were therefore 2–3-fold more likely to die from an adverse cardiovascular event than individuals without the metabolic syndrome.
People with the metabolic syndrome are at increased risk of being twice as likely to die from and tree times as likely to have a heart attack or stroke compared to people without metabolic syndrome.
Isomaa B, Almaren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24: * 5 5
CHD MI
All-cause
mortality
Cardiovascular
mortality
Stroke
Isomaa et al 2001

28. Abdominal obesity predicts the
Abdominal obesity: a major underlying cause of acute myocardial infarction
Cardiometabolic risk factors in the InterHeart Study 60 49
Abn Lipids
Abdominal obesity predicts the
risk of CVD beyond BMI 40
PAR (%)a 20
Abdom.
Obesity 18
HTN 10
Diabetes 20
Abdominal obesity: a major underlying cause of acute myocardial infarction
The INTERHEART Study was a case control study involving 29,972 participants in 52 countries. The study examined the contribution of various cardiometabolic risk factors to the risk of a first acute myocardial infarction (AMI). The study quantified the relationships between risk factors and AMI through calculation of the population attributable risk (PAR), which measures the proportion of AMI among those who have the risk factor which would be eliminated if the risk factor was removed.
Dyslipidaemia (raised ApoB/ApoA1 ratio) and smoking were associated with the highest PAR. However, the PAR for abdominal obesity was greater than either diabetes or hypertension. BMI showed a modest correlation with the risk of AMI, but this was not significant when abdominal obesity was included in a multivariate analysis.
Abdominal obesity is therefore an important predictor of adverse cardiovascular outcomes in its own right.
Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:
aProportion of MI in the total population attributable to a specific risk factor
Yusuf et al 2004

29. Abdominal obesity and increased risk of cardiovascular events
The HOPE Study
Tertile 1
Tertile 2
Tertile 3
Men
Women
<95
95–103
>103
<87
87–98
>98
Waist circ. (cm):
1.4
1.35
1.29
1.27
1.2
1.17
1.16
1.14
Adjusted relative risk 1 1 1 1
Abdominal obesity and increased risk of cardiovascular events
This analysis from the Heart Outcomes Protection Evaluation (HOPE) study evaluated the effects of abdominal obesity (tertiles of waist circumference) on the risk of all-cause or cardiovascular death, or myocardial infarction in 6620 men and 2182 women followed for an average of 4.5 years. Results were adjusted for BMI, age, smoking, sex, previous MI, stroke, peripheral arterial disease, microalbuminuria, use of antiplatelet agents, diuretics, lipid-lowering agents, and anti-hypertensives, history of hypertension, diabetes, or total cholesterol >5.2 mmol/L, or HDL <0.9 mmol/L.
The risk of cardiovascular death, MI, or death from any cause increased in line with increasing tertiles of waist circumference. These data from this major intervention study add to the growing database of evidence linking high waist circumference with a clinically significant increase in the risk of an adverse cardiovascular outcome.
Dagenais GR, Yi Q, Mann JF, Bosch J, Pogue J, Yusuf S. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. Am Heart J 2005;149:54-60.
0.8
CVD death MI
All-cause deaths
Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-C, total-C
Dagenais et al 2005

30. Abdominal obesity predicts adverse outcomes such as sudden death
The Paris Prospective Study 4 4
SAD is a better predictor of risk of sudden death than BMI
p for trend =0.0003 3 3
Age-adjusted relative risk
Age-adjusted relative risk 2 2 1 1 1 2 3 4 5 1 2 3 4 5
Abdominal obesity predicts adverse outcomes such as sudden death
The Paris Prospective study stratified 7079 asymptomatic, middle-aged men for sagittal abdominal diameter (SAD) and BMI, and followed them for clinical outcomes for an average of 23 years. The measured outcome was sudden death.
The risk of sudden death increased in parallel with increases in abdominal obesity (left panel). In contrast, the relationship between increasing BMI and risk of sudden death was flat for the first four tertiles, increasing only at the fifth, and highest tertile. These data suggest that SAD, the measure of abdominal obesity, was superior to BMI in predicting the risk of an adverse clinical outcome for most of the study participants.
Empana JP, Ducimetiere P, Charles MA, Jouven X. Sagittal abdominal diameter and risk of sudden death in asymptomatic middle-aged men: the Paris Prospective Study I. Circulation 2004;110:
Quintile of sagittal abdominal diameter (SAD)
Quintile of BMI
Quintile
SAD (cm) 12–19 20–21 22– –35
BMI (kg/m2) < – – – –47.7
Empana et al 2004

31. Abdominal obesity and increased risk of CHD
Waist circumference was independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other CV risk factors
3.0
2.44
2.5
p for trend = 0.007
2.31
2.06
2.0
Relative risk
1.5
1.27
1.0
Abdominal obesity and increased risk of CHD
The prospective Nurses Health Study set out to assess the impact of factors such as waist circumference in determining risk of CHD in a cohort of 44,702 US female registered nurses, aged 40 to 65 years, recruited between 1986 and Study subjects were free of prior CHD at baseline.
During 8 years of follow-up, there was a direct, independent and continuous relationship between waist circumference and age-adjusted risk of CHD.
Rexrode KM, Carey VJ, Hennekens CH et al. Abdominal adiposity and coronary heart disease in women. JAMA 1998;280:
0.5
0.0
< < < < <139.7
Quintiles of waist circumference (cm)
Rexrode et al 1998

32. Why is abdominal obesity harmful?
is often associated with other CV risk factors
is an independent CV risk factor
Adipocytes are metabolically active endocrine organs, not simply inert fat storage
Why is abdominal obesity harmful?
Abdominal obesity, driven by intra-abdominal adiposity, is not only often associated with other risk factors but is an independent and powerful predictor of adverse cardiovascular outcomes.
This is largely due to the highly active endocrine activity of intra-abdominal adipocytes.
The following slides explore the reasons for the adverse cardiovascular prognosis associated with intra-abdominal adiposity.
Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:
Wajchenberg 2000

33. Increased Cardiometabolic Risk
Health threat from abdominal obesity is largely due to intra-abdominal adiposity
Increased Cardiometabolic Risk
Abdominal
Obesity
Dyslipidemia
Hypertension
Glucose Intolerance
Insulin Resistance
Health threat from abdominal obesity is largely due to intra-abdominal adiposity
This slide summarises the relationships between intra-abdominal adiposity and increased cardiometabolic risk.
Intra-abdominal adiposity drives the progression of multiple risk factors directly, through the secretion of excess free fatty acids and inflammatory adipokines, and decreased secretion of adiponectin. The important contributions of intra-abdominal adiposity to dyslipidaemia and insulin resistance provide an indirect, though clinically important, link to the genesis and progression of atherosclerosis and cardiovascular disease.
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
Intra-Abdominal
Adiposity
Adapted from Eckel et al 2005

34. Intra-abdominal adiposity: a root cause of cardiometabolic disease
Intra-abdominal adiposity is characterised by accumulation of fat around and inside abdominal organs
Abdominal obesity
(High waist circumference)
Cardiovascular
risk factors
Indirect
Intra-abdominal adiposity: a root cause of cardiometabolic disease
Abdominal obesity is caused by intra-abdominal adiposity, I.e. an accumulation of fat around and inside the abdominal organs, such as the liver. This can directly influence the progression of cardiovascular risk, as shown in the InterHeart Study and also indirectly, through its effects on other aspects of metabolism. Cardiovascular risk factors that have been associated with abdominal obesity include:
 Low HDL-cholesterol  High triglycerides
 Elevated Apo B  Small, dense LDL
 Insulin resistance/hyperinsulinaemia  Hypertension
 Glucose intolerance  Chronic, low-grade inflammation
 Endothelial dysfunction  Impaired fibrinolysis
Despres JP, Lemieux I, Prud'homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 2001;322:
Frayn KN. Insulin resistance, impaired postprandial lipid metabolism and abdominal obesity. A deadly triad. Med Princ Pract 2002;11 Suppl 2:31-40.
Caballero AE. Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes Res 2003;11:
Misra A, Vikram NK. Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Nutrition 2003;19:
Intra-abdominal
adiposity
Direct
CV disease
Frayn 2002; Caballero 2003; Misra & Vikram 2003

35. The evolving view of adipose tissue: an endocrine organ
Old View: inert storage depot
Current View: secretory/endocrine organ
Fatty acids Glucose
Fed
Fasted Tg
Multiple secretory
products Tg Tg
Muscle
The evolving view of adipose tissue: an endocrine organ
Previously, adipocytes were considered to be little more than inert storage depots, storing fat as triglyceride in the fed state, and releasing fuel as fatty acids and glycerol in times of fasting.
It is now clear that adipocytes are highly active endocrine glands that secrete important hormones, cytokines, vasoactive substances, and other peptides. These exert marked influences on metabolic function and cardiovascular risk in a number of organ systems throughout the body. The following slides describe some of the principal adipocyte-derived agents, and summarise their metabolic and cardiovascular effects.
Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003;144:
Fatty acids Glycerol
Vasculature
Liver
Pancreas
Lyon CJ et al 2003

36. Intra-abdominal adiposity promotes insulin resistance and increased CV risk
 Secretion of metabolically active substances (adipokines)
 Hepatic FFA flux (portal hypothesis)
 Intra-abdominal adiposity
 suppression of lipolysis by insulin
 PAI-1
 Adiponectin
 IL-6
 TNFa
 FFA
 Insulin resistance
 Dyslipidaemia
Intra-abdominal adiposity promotes insulin resistance and increased CV risk
Intra-abdominal adiposity can promote insulin resistance and cardiovascular risk indirectly, though increased secretion of free fatty acids into the portal vein in the setting of insulin resistance, leading to increased hepatic triglyceride biosynthesis (the ‘portal hypothesis’). The direct adverse effects of intra-abdominal adiposity occur via the secretion of a range of bioactive substances. These include:
a) Increased secretion of plasminogen activator inhibitor-1 (PAI-1), the endogenous inhibitor of tissue plasminogen activator (tPA). Increased PAI-1 secretion increases the risk of an intravascular thrombus.
b) Adiponectin is a fat-derived hormone that protects the cardiovascular system. Decreased secretion of adiponectin in the setting of intra-abdominal adiposity implies increased cardiovascular risk.
c) Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFa) are inflammatory mediators. Intravascular inflammation is a key early event in atherogenesis.
Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004;28 Suppl 4:S12-21.
Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001;60:
Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord 2004;28:
Net result:
 Insulin resistance
 Inflammation
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004

37. Adverse cardiometabolic effects of products of adipocytes
↑ Lipoprotein lipase
Hypertension
↑ IL-6
↑ Agiotensinogen
Inflammation
↑ Insulin
Atherogenic dyslipidaemia
↑ FFA
Adipose tissue
↑ TNFα
↑ Resistin
↑ Leptin
↑ Adipsin (Complement D)
↑ Lactate
Type 2 diabetes
Adverse cardiometabolic effects of products of adipocytes
This slide shows a more complete list of the bioactive substances secreted by adipocytes, that modulate insulin resistance and cardiovascular risk.
Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003;144:
Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
↑ Plasminogen activator inhibitor-1 (PAI-1)
↓ Adiponectin
Atherosclerosis
Thrombosis
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

38. Properties of key adipokines
Adiponectin
 in IAA
Anti-atherogenic/antidiabetic:
 foam cells  vascular remodelling  insulin sensitivity  hepatic glucose output
IL-6
 in IAA
Pro-atherogenic/pro-diabetic:
 vascular inflammation  insulin signalling
TNFa
 insulin sensitivity in adipocytes (paracrine)
PAI-1
Pro-atherogenic:
 atherothrombotic risk
Properties of key adipokines
Here we examine key adipocyte-derived bioactive substances (‘adipokines’) in more detail.
Adiponectin exerts a number of protective actions in the vasculature, including inhibition of foam cell formation and vascular remodelling, both important steps in the formation of an atherosclerotic plaque. This hormone also improves insulin sensitivity and opposes the development of hyperglycaemia, and is therefore antidiabetic as well as anti-atherosclerotic in nature.
IL-6 is a systemic inflammatory hormone that exerts adverse, pro-atherogenic effects in the vasculature. IL-6 also exacerbates insulin resistance and is therefore both pro-atherogenic and pro-diabetic.
TNFa is a paracrine regulator in adipocytes. TNFa-induced reductions in insulin sensitivity in adipocytes are partly responsible for the increased free fatty acid production and hypertriglyceridaemia characteristic of abdominal obesity.
Increased PAI-1 secretion by intra-abdominal adipocytes shifts the balance of fibrinolysis towards a procoagulant state, increasing the risk of a morbid thromboembolic event.
Marette A. Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr Opin Clin Nutr Metab Care 2002;5:
IAA: intra-abdominal adiposity
Marette 2002

39. Suggested role of intra-abdominal adiposity and FFA in insulin resistance
 Hepatic insulin resistance
 Hepatic glucose output
 Small, dense LDL-C
Intra
abdominal
adiposity
Lipolysis
 TG-rich VLDL-C
 FFA
Portal
circulation
Low HDL-C
CETP, lipolysis
Systemic circulation
Suggested role of intra-abdominal adiposity and FFA in insulin resistance
Free fatty acids (FFA) are products of lipolysis of triglycerides from adipocytes. According to the portal theory, high concentrations of FFA from intra-abdominal adiposity reach the liver via the portal vein, where they impair metabolic function. Normally, the postprandial insulin rise suppresses lipolysis, but intra-abdominal adipocytes may be more insulin resistant than subcutaneous adipocytes. The excess portal FFA load induces hepatic insulin resistance, leading to increased hepatic glucose production and hyperinsulinaemia.
The hypertriglyceridaemia induces increased secretion of triglyceride-rich VLDL-cholesterol, which is converted to LDL-cholesterol in the circulation, as lipolysis degrades its triglyceride content. The relatively high original triglyceride content results in LDL particles that are smaller and denser than those present in an individual without intra abdominal adiposity and insulin resistance.
Cholesteryl ester transfer protein (CETP) exchanges cholesterol from HDL for triglycerides from VLDL and LDL. The high levels of triglycerides within VLDL-cholesterol will tend to increase the rate of exchange of cholesterol via CETP, and will result in the formation of triglyceride-rich HDL particles. As with LDL, these are subjected to lipolysis, resulting in small, dense HDL particles that are more rapidly catabolised. The net result is an overall reduction in HDL-cholesterol.
Lam TK, Carpentier A, Lewis GF et al. Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 2003;284:E
Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab 2004;89:
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
 Glucose utilisation
FFA: free fatty acids CETP: cholesteryl ester transfer protein
 Insulin resistance
Lam et al 2003; Carr et al 2004; Eckel et al 2005

40. Intra abdominal adiposity impairs pancreatic b-cell function
 FFA
Splanchnic & systemic
circulation
Intra abdominal
adiposity
Short-term stimulation of insulin secretion
Long-term damage to b-cells
Decreased insulin secretion
Intra abdominal adiposity impairs pancreatic b-cell function
The increased secretion of free fatty acids (FFA) from intra-abdominal adiposity also impairs b-cell function. Authoritative reviews on this subject conclude that a short-term stimulation if insulin secretion is followed by long-term damage to the β-cell and reduction of insulin secretion.
Excess FFA from intra-abdominal obesity can therefore induce both insulin resistance and impaired b-cell function – the primary metabolic defects that underlie type 2 diabetes.
Haber EP, Ximenes HM, Procopio J et al. Pleiotropic effects of fatty acids on pancreatic beta-cells. J Cell Physiol 2003;194:1-12.
Zraika S, Dunlop M, Proietto J, Andrikopoulos S. Effects of free fatty acids on insulin secretion in obesity. Obes Rev 2002;3:
FFA: Free fatty acids
Haber et al 2003; Zraika et al 2002

41. Systemic inflammation and adverse cardiovascular outcomes
Physicians' Health Study: 9-year follow-up
4.4
2.8
3.4
Relative risk of MI
2.5
2.8
1.3
1.1
Systemic inflammation and adverse cardiovascular outcomes
High-sensitivity C-reactive protein (CRP) is a marker of systemic inflammation that has been implicated in the progression of intravascular inflammation and atherogenesis. Elevated CRP levels have been observed in subjects with abdominal obesity.1
A 9-year follow up of participants in the Physicians’ Health Study2 evaluated the influence of CRP on the risk of experiencing a first MI. Subjects were stratified into tertiles of CRP, and also of total cholesterol/HDL-cholesterol ratio, as a marker of dyslipidaemia.
Elevated CRP conferred an increased risk of MI, irrespective of the severity of dyslipidaemia. The highest risk of MI occurred in subjects with high CRP and high total cholesterol/HDL-cholesterol ratio. Increased markers of inflammation, such as CRP, provide another causative link between intra-abdominal adiposity and cardiovascular disease.
1. Lemieux I, Pascot A, Prud'homme D et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol 2001;21:961-7.
2. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998;97:
1.2
1.0
High
Medium
hs-CRP
Low
Medium
High
Low
Cholesterol/HDL cholesterol ratio
Ridker et al 1998

42. Intra-abdominal adiposity and dyslipidaemia
310
248
186
124 62 60 45 30
mg/dL
Triglycerides
Lean
HDL-cholesterol
Visceral fat (obese subjects)
Low
High
Intra-abdominal adiposity and dyslipidaemia
The influence of regional adipose tissue distribution (measured by CT scanning) on lipid profiles was evaluated in 58 obese men. A further 29 lean men served as controls. Obese subjects were more likely to be hypertriglyceridaemic, and to have low HDL-cholesterol than lean subjects. Within the obese group, subjects with high intra-abdominal adiposity tended to have higher triglycerides and lower HDL-cholesterol than subjects with low intra-abdominal adiposity.
The degree of intra-abdominal adiposity (visceral fat area) was the most powerful predictor of adverse lipid profiles on univariate analysis.
Pouliot MC, Despres JP, Nadeau A et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes 1992;41:
Pouliot et al 1992

43. Intra-abdominal adiposity and glucose metabolism
Insulin 15 1
1,2
1200
1,2
1,2
Area
Area 12 1
1,2
1,2 1 1
1,2
800 9
1,2
mmol/L 1 1 1
pmol/L
1,2 1
1,2 6 1
400
1,2 3
1,2 60
120
180 60
120
180
Intra-abdominal adiposity and glucose metabolism
These data are from the study described in the previous slide.
Plasma glucose and insulin concentrations during an oral glucose tolerance test (the inset graphs show area under the plasma concentration-time curves) were broadly similar in lean subjects and in obese subjects with low intra-abdominal adiposity. The presence of obesity per se therefore did not appear to influence glycaemic status in these subjects.
In contrast, plasma glucose concentrations were significantly higher in obese subjects with high intra-abdominal adiposity, compared with the lean controls. While glucose levels generally differed little between obese subjects with high and low intra-abdominal adiposity, a markedly and significantly greater hyperinsulinaemia was required to maintain these glucose levels in the obese/high intra-abdominal adiposity group.
These results show that intra-abdominal adiposity is a more important cause of insulin resistance than obesity per se.
Pouliot MC, Despres JP, Nadeau A et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes 1992;41:
Time (min)
Time (min)
Non-obese Obese low IAA Obese high IAA
IAA: intra-abdominal adiposity Significantly different from 1non-obese, 2obese with low intra-abdominal adiposity
levels
Pouliot et al 1992 1

44. Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Cytokines
Adipocyte
Inflammatory markers
Monocyte/
macrophage
Insulin resistance
 Tg Metabolic syndrome  HDL
 BP
Atherosclerosis
Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease
A complex series of interactions of metabolic risk factors with genetic and environmental influences underlies the adverse influence of the metabolic syndrome on cardiovascular prognosis. Abdominal obesity is an important cause of multiple sources of cardiovascular risk within this system. Bioactive substances (adipokines, inflammatory cytokines and other agents) derived from intra-abdominal adipocytes, the liver and/or inflammatory cells help to drive the progression of the cluster of risk factors characteristic of the metabolic syndrome. In turn, exacerbation of these risk factors, in addition to the direct pro-atherogenic effects of adipokines, accelerates the atherosclerotic changes that increased the risk of an occlusive thromboembolic coronary event.
It is difficult to intervene successfully once the vicious cycle of promotion of cardiovascular risk factors and atherogenesis is established. Intervening at an earlier stage, for example to combat directly the development of intra-abdominal adiposity, may provide a more successful prospect for intervention to reduce the risk of a cardiovascular event.
Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation 2003;108:
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events

45. Summary
Despite therapeutic advances, cardiovascular disease remains the leading cause of death worldwide
Current treatments generally target individual risk factors and do not propose a comprehensive approach to the management of cardiometabolic disease
An increased risk of developing cardiometabolic disease can be attributed to abdominal obesity (as measured by waist circumference)
A major cause of cardiometabolic disorders (including dyslipidaemia, insulin resistance, type 2 diabetes, metabolic syndrome, inflammation and thrombosis) is thought to be intra-abdominal adiposity (IAA)
Waist circumference provides a simple and practical diagnosis of IAA in patients at elevated CV risk
Summary
Given the clinical importance of cardiovascular disease as the number one cause of death world wide, it is important that we seek underlying causes of cardiovascular morbidity and mortality. A comprehensive approach to cardiometabolic disease may yield greater clinical benefit than continuing to focus on managing individual risk factors.
Abdominal obesity, with its attendant intra-abdominal adiposity, is emerging as an underlying cause of multiple cardiovascular risk factors. Intra-abdominal adipocytes are active endocrine cells, secreting a range of substances that adversely affect cardiometabolic risk factors associated with the metabolic syndrome, such as lipid profiles, insulin sensitivity and glucose tolerance, and also emerging risk factors, including inflammation and altered haemostasis.
Recent research shows that over-activity of the endocannabinoid system, acting through the CB1 receptor, exacerbates multiple cardiometabolic risk factors. Selective CB1 receptor blockade provides a new therapeutic approach to the simultaneous management of multiple cardiometabolic risk factors, particularly in patients with intra-abdominal adiposity. These patients can be easily identified using standard waist measurement in conjunction with other cardiometabolic markers such as HDL, triglycerides, glucose or blood pressure.
This presentation reviews the relationships between abdominal obesity, intra-abdominal adiposity, and elevated cardiometabolic risk, and outlines the potential role of selective CB1 receptor blockade in the management of multiple cardiovascular risk factors.

46. cardiac & cerebral events
A Broad Approach to Prevention and Treament of Cardiovascular Disease
Stress
Smoking
Physical inactivity
Excessive food intake
Life style intervention
Hypertension
Diabetes
Dyslipidaemia
Obesity
Risk factor modification
Atherosclerosis
Disease intervention/ secondary prevention
Chronic heart failure
Arrhythmia
Arterial & venous
thrombosis/
cardiac & cerebral events

47. Can we change our life-style?
Of course, by changing our life-style we could have very large medical benefits. This has been proven very VERY difficult. One way forcing a life-style change is to buy a dog that has to be taken for a walk several times a day. However, the question is if this will do the job!
Buy a dog!

48. Thank you for your attention!