Features of the metabolic syndrome commonly found among viscerally obese patients

1
Features of the metabolic syndromecommonly found
among viscerally obese patients
. Hypertriglyceridemia . Low HDL-cholesterol .
Elevated apolipoprotein B . Small, dense LDL
particles . Inflammatory profile
. Insulin resistance . Hyperinsulinemia . Glucose
intolerance . Impaired fibrinolysis . Endothelial
dysfunction
Genetic susceptibility to hypertension, type 2
diabetes and coronary heart disease ultimately
affects the clinical features of the metabolic
syndrome
2
The Québec Cardiovascular Study
3
The atherogenic metabolic triad
Hyperinsulinemia
The atherogenic triad
Small, dense LDL particles
Elevated apo B concentrations
Beyond LDL-cholesterol, blood pressure, type 2
diabetes ...
4
Risk of ischemic heart disease (IHD) according to
the cumulative number of traditional and
non-traditional risk factors The Québec
Cardiovascular Study
30
Traditional risk factors Non-traditional risk
factors
25
20.8 (lt0.001)
20
Odds ratio
15
9.1 (0.01)
10
4.4 (0.01)
4.7
2.8
5
1.8
1.0
1.0
0
0
1
2
3
Traditional LDL-cholesterol, triglycerides and
HDL-cholesterol Non-traditional Insulin,
apolipoprotein B and small, dense LDL
particles Odds ratios are adjusted for
systolic blood pressure, family history of IHD
and medication use
From Lamarche B et al. JAMA (1998) 2791955-1961
5
IHD risk ratio across subgroups of Framingham
score and carriers of features of the triad
6 plt0.0001
5 plt0.003
95 CI 3-13
3 plt0.003
95 CI 2-15
IHD risk ratio
95 CI 1-6
1.0
Framlt6
Framgt6
Framlt6
Framgt6
Triad (0-1)
Triad (2-3)
From Lemieux I et al. Eur Heart J (2001)
6
The hypertriglyceridemic waist
A screening tool for the metabolic syndrome?

7
Relationship between waist circumference and
visceral adipose tissue accumulation
Front
r 0.80
Visceral AT
Waist
Visceral AT (cm2)
Hip
Subcutaneous AT
Back
60
80
100
120
Waist circumference (cm)
Apo B (g/L)
Insulin (pmol/L)
Waist girth (cm)
Waist girth (cm)
8
The atherogenic triad of new metabolic risk
factors Importance of waist and fasting
triglycerides as screening tools
Small, dense LDL
Insulin
Apo B
Waist gt 90 cm (gt40 yrs)
Triglycerides gt 2.0 mmol/L
Adapted from Lemieux I et al.
Circulation (2000) 102179-184
9
of men with the metabolic triad among subjects
classified on the basis of waist girth and TG
levels
90
84
83
80
70
60
53
50
of men with metabolic triad
40
30
20
12
10
10
0
waist gt 100
90 lt waist lt 100
waist lt 90
Adapted from Lemieux I et al. Circulation (2000)
102179-184
10
Percentage of men with the constellation of risk
factors of abdominal obesity
Waist lt 90 cm gt 90 cm
Triglycerides lt 2.0 mmol/L gt 2.0 mmol/L

Good Bad
10 80
Adapted from Lemieux I et al. Circulation (2000)
102179-184
11
Clinical identification of the metabolic syndrome
according to NCEP-ATP III criteria

• Waist circumference
• Men gt 102 cm
• Women gt 88 cm
• Triglycerides ? 1.7 mmol/L
• HDL cholesterol
• Men lt 1.03 mmol/L
• Women lt 1.30 mmol/L
• Blood pressure ? 130/85 mm Hg
• Fasting glucose ? 6.1 mmol/L

Presence of 3 or more of the above risk
determinants
From JAMA (2001) 285 2486-2497
12
"Abdominal obesity is the form of obesity most
strongly associated with the metabolic syndrome.
It presents clinically as increased waist
circumference."
"ATP III recommended that obesity be the primary
target of intervention for metabolic syndrome."
From Grundy SM et al. Circulation (2004)
109433-438
13
Prevalence of CHD risk factors an evolving
landscape
Smoking Hypercholesterolemia Hypertension
Type 2 diabetes Abdominal obesity Metabolic
syndrome
1950 60
1990 00

• Statins
• HT medication
• Smoking cessation
• Sedentariness
• ? Energy density
• of food

14
HPS Effects of simvastatin allocation on first
major coronary event in patients with/without
type 2 diabetes according to HDL-cholesterol
levels
16.4
Placebo
Simvastatin
13.5
12.9
10.5
10.3
9.0
8.2
CHD event rate
7.3
HDL?0.9
HDLlt0.9
HDLlt0.9
HDL?0.9
mmol/L
No diabetes
Diabetes
The Lancet 361 June 14, 2003 (web)
15
Management of CHD risk in patients with type 2
diabetes or the metabolic syndrome
Beyond lowering LDL-cholesterol, blood pressure,
glycemia ...

Diet Physical activity
Weight loss

• Improve the ? TG - ? HDL-C
• small LDL dyslipidemia

- Fix a dysmetabolic state (including
inflammation)
16
Cumulative incidence of diabetes according to
study group
Placebo
28.8
Metformin
21.7
Cumulative incidence of diabetes ()
Lifestyle
14.4
Study year
From the Diabetes Prevention Program Research
Group NEJM (2002) 346393-403
17
Managing CVD risk in type 2 diabetic patients
and in nondiabetic abdominally obese subjects
with the metabolic syndrome
Before
After
. Moderate weight loss (5-10) by diet and/or
exercise can induce a substantial (30) loss
of atherogenic visceral fat and substantially
improve the risk profile status of these
patients. . Thus, the importance of waist rather
than weight management is emphasized.
18
Management of CHD risk in patients with type 2
diabetes or the metabolic syndrome
Beyond lowering LDL-cholesterol, blood pressure,
glycemia ...

Diet Physical activity
Weight loss

• Improve the ? TG - ? HDL-C
• small LDL dyslipidemia

- Fix a dysmetabolic state (including
inflammation)
19
Contribution of fibrate therapy to the prevention
of CHD among patients with the metabolic syndrome
Effect on inflammation?
20
Gemfibrozil and the Prevention of CHD in Men
(VA-HIT Study)
Baseline Characteristics of the Subjects
Mean standard deviation
From Rubins HB et al. N Engl J Med (1999)
341410-418
21
Diabetes, hyperinsulinemia (HI) and
recurrentcoronary events in the VA-HIT trial
? 25.2
Placebo
32.9
Gemfibrozil
? 30.5
25.6
? 27.3
24.6
23.1
? 7.8
5-yr CHD event rate ()
17.8
16.8
16.0
15.3
Diabetes HI
Diabetes no HI
No diabetes HI
No diabetes no HI
From Després JP, Lemieux I and Robins SJ Drugs
(2004) 642177-2198
22
Relation of the 5-year incidence of CHD events
to HDL-cholesterol values achieved with placebo
or gemfibrozil
25
22
Placebo
19
5-year CHD event rate ()
16
13
Gemfibrozil
10
24
28
32
36
40
44
HDL quintiles (mmol/L)
From Robins SJ et al. JAMA (2001) 2851585-1591
23
Effect of 6-month gemfibrozil treatment on plasma
C-reactive protein levels in abdominally obese
patients with the atherogenic dyslipidemia of
the metabolic syndrome
3.0
plt0.003 vs. baseline
2.5
2.0
CRP (?g/mL)

1.5
1.0
0.5
0.0
Baseline
Follow-up
Baseline
Follow-up
Adapted from Després JP et al. Arterioscler
Thromb Vasc Biol (2003) 23702-703
24
Changes in hsCRP following 8 weeks of
treatment with fenofibrate or simvastatin groups
NS
Changes in hsCRP (mg/dL)
Before
After
Before
After
Fenofibrate (n35)
Simvastatin (n35)
From Wang TD et al. Atherosclerosis (2003)
170315-323
25
New markers of CHD risk what to look for?
Atherogenic dyslipidemia ? Triglycerides ?
HDL-cholesterol ? Cholesterol/HDL-cholesterol
ratio "Normal" LDL-cholesterol but ? apo B
Small, dense LDL and HDL Postprandial
hyperlipidemia
Inflammation
Insulin resistance Insulin resistance Hyperinsulin
emia Hyperglycemia Type 2 diabetes
Lipid core
Thin fibrous cap
Thrombotic state ? PAI-1 ? Fibrinogen
CORONARY ATHEROSCLEROSIS UNSTABLE PLAQUE
Inflammatory state ? CRP ? Cytokines
? risk of acute coronary syndrome
Metabolic risk factors
Abdominal obesity
26
Hypertriglyceridemic waist
ATHEROGENIC TRIAD OF NEW METABOLIC RISK MARKERS
Small LDL particles
Apolipoprotein B
Insulin
Triglycerides gt 2.0 mmol/L
Waist circumference gt 90 cm
SCREENING TOOLS
27
The unknown MS patient
1958-2004
His LDL-C was on target