Transcript Slide 1

What is the metabolic syndrome?
Simon Thom
Lipid Update VI
Stratford-upon-Avon, 20/11/2006
Overlap of diabetes2 obesity & essential
hypertension
Diabetes
Obesity
Hypertension
Squares are roughly proportional to prevalence of the
3 conditions in a middle-aged westernized population
Ferrannini E. J Nephrol 1989; 1: 3-15
The metabolic syndrome / insulin resistance
syndrome / Reaven’s syndrome / syndrome ‘X’







Resistance to insulin-stimulated glucose uptake
Glucose intolerance
Hyperinsulinemia
VLDL triglyceride
HDL cholesterol
Hypertension
Central obesity,
waist-hip ratio
Reaven G, Diabetes 1988; 37:1595
Metabolic syndrome definitions
NCEP-ATP III definition
Any 3 or more of the following
criteria:
1. Waist circumference >102
men & >88 cm in women
2. Serum triglycerides 1.7
3. Blood pressure >130/85
4. HDL cholesterol <1.0 men
and <1.3 women
5. Serum glucose 6.1 (5.6 may
be applicable)
16 potential defining
combinations!
JAMA 2001; 285: 2486
Circulation 2004; 109: 433
WHO definition
Diabetes, IFG, IGT, or insulin
resistance (clamp studies) &
at least 2 of the following
criteria:
1. Waist-hip ratio >0.90 men or
>0.85 women
2. Serum triglycerides 1.7 or
HDL cholesterol <0.9 men &
<1.0 women
3. Blood pressure 140/90
4. Urinary albumin excretion
>20 µg/min or albumincreatinine ratio >30 mg/g
WHO Geneva 1999
IDF 2005 worldwide metabolic syndrome definition
 Central obesity
 Waist circumference ≥94 cm for men and ≥80 cm
for women (Europid values)
 Plus ≥2 of the following:
 TG level ≥150 mg/dL (1.7 mmol/L) or treatment for
hypertriglyceridemia
 HDL-C <40 mg/dL (1.03 mmol/L) in males and <50 mg/dL
(1.29 mmol/L) in females or treatment for reduced HDL-C
 Systolic BP ≥130 mmHg or diastolic BP ≥85 mmHg or
treatment for hypertension
 Fasting plasma glucose ≥100 mg/dL (5.6 mmol/L) or Type 2
diabetes
http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf
Alberti KGMM et al. Lancet 2005; 366: 1059
Usual fasting glucose & risk of CV end points
Total IHD
Hazard ratio & 95% CI
Total stroke
Cardiovascular
death
Usual fasting glucose, mmol/l
237,468 participants (14,282 Chinese); ~1.2 million person-years follow-up
1,661 strokes & 816 IHD events
Each 1 mmol/l ↓fasting glucose associated with ~20% ↓risk of CVD death
Asia Pacific Cohort Studies Collaboration. Diabetes Care 2004; 27: 2836
CHD: risk accumulates with additional CV risk factors
Hypertension
SBP 150 mmHg
X1.5
X3.5
X6.2
X2.8
Dyslipidemia
TC 260 mg/dL
X2.3
X4
Glucose intolerance
X1.8
Risk shown above is compared with baseline risk for a 40-year-old
male non-smoker with TC 4.7 mmol/L (185 mg/dL), SBP 120
mmHg, and no glucose intolerance, who is ECG-LVH negative and
whose probability of developing CVD is 15/1000 (1.5%) in 8 years
Kannel WB. In Hypertension: Physiopathology & Treatment 1977: 888–910
International prevalence of the metabolic syndrome
ATP III definition; adapted from: Gu D. Lancet 2005; 365:1398. Eckel R.
Lancet. 2005; 365:1415. Ford E. Diabetes Care. 2004; 27: 2444.
Reynolds K. Am J Med Sci, 2005; 330: 273
Does the metabolic syndrome
predict CVD risk?
Metabolic syndrome: CHD death or non-fatal
MI with different numbers of factors
% with events
- 6000 men followed for 5 yrs
Years
Kaplan-Meier curves for CHD events in men with zero, 1, 2, 3, or >=4
characteristics of the metabolic syndrome at baseline
Sattar N. Circulation 2003; 108: 414
The metabolic syndrome and 11-year risk
of incident CVD in ARIC
12,089 women & men followed for 11 years
Hazard ratio*
The syndrome
conferred no
greater CHD
risk than the
sum of its
components.
Components of the ATP III metabolic syndrome
HRs of CHD associated with the presence of 1, 2, 3, or 4+
metabolic syndrome components cf. no components;
*adjusted for age, race, LDL cholesterol level, and smoking.
McNeill AM, ARIC, Diabetes Care 2005; 28: 385
Metabolic syndrome / Framingham risk score & measures of
probability (%) for occurrence of CHD event & Type 2 diabetes
Wannamethee S G et al. Arch Intern Med 2005; 165: 2644
.... in recognising the undoubted risk factor
clustering of the metabolic syndrome, we don’t
appear to be identifying any particular risk
enhancing interaction.
.... should this surprise us?
At least 80% of major CHD events in middle aged
men can be attributed to the three strongest risk
factors (cholesterol, BP & smoking).
The residual variation may be explained once
changes in smoking habits & other established
risk factors such as physical inactivity & obesity
have been taken into account.
Emberson JR et al. E Heart J 2003; 24: 1719
Is there a unifying explanatory
mechanism for the metabolic syndrome?
Metabolic syndrome
- hypotheses for pathogenesis
 Sympathetic activation
 Inflammation
 Adiponectin deficiency
 Vascular rarefaction
 Sodium retention
 Leptin resistance
 ……..
Sympathetic
activation
Stimulated  adrenergic
receptors
Vascular hypertrophy
Chronic
High blood
pressure
Acute
High cardiac ouput
- ( adrenergic)
Inadequate vasodilatation
- ( adrenergic)
Decreased substrate
to muscles
Vascular rarefaction
Insulin
resistance
Conversion to fast
twitch fibres
Relationship between BP & muscle blood flow
during hyperinsulinemic clamp
% increase in leg blood flow
250
200
150
r = - 0.69
p = 0.005
100
50
65
75
85
Basal MAP (mmHg)
95
105
115
Baron AD, Hypertension 1993; 21:129
Effect of training on skeletal muscle lipoprotein lipase activity
- relationship with capillary density

Capillary density /mm2
500

8 wk exercise, one leg
opposite leg control
In trained muscle :
 LPL activity
 VLDL-TG uptake
 HDL chol production
 m-LPLA :: a-v D TG
400
300
200
0
20
40
60
80
LP Lipase activity (mU/g w.w.)
Kiens B. JCI 1989; 83: 558 - 564
Pathophysiology of CVD in the metabolic syndrome
Prasad A. Circulation 2004; 110: 1507
Summary of concerns regarding the
metabolic syndrome
1. Criteria are ambiguous or incomplete. Rationale for
thresholds are ill defined.
2. Value of including diabetes in the definition is
questionable.
3. Insulin resistance as the unifying etiology is uncertain.
4. No clear basis for including/excluding other CVD risk
factors.
5. CVD risk value is variable and dependent on the specific
risk factors present.
6. The CVD risk associated with the "syndrome" appears to
be no greater than the sum of its parts.
7. Treatment of the syndrome is no different than the
treatment for each of its components.
8. The medical value of diagnosing the syndrome is unclear.
Cause?
Consequence?
Kahn R, et al. Diabetes Care 2005; 28: 2289
Linked by association or by mechanism?
- a genetic or environmental hook – or both?
Ferrannini E. Am Heart J 1991; 121: 1274
Overlap of diabetes2 obesity & essential
hypertension
Diabetes
Hypertension
Obesity
Squares are roughly proportional to prevalence of the 3
conditions in a middle-aged westernized population
Ferrannini E. J Nephrol 1989; 1: 3-15
Diabetes
Hypertension
?
Obesity
Diabetes
Hypertension
Physical
inactivity
Obesity
Metabolic syndrome – at least a prompt for action?
6
Diagnostic /
therapeutic
threshold
5
“Units”
4
3
2
1
0
BP
Cholesterol
Sugar
BMI
Khunti K. BMJ 2005; 331: 1154
Alberti KG. Lancet 2005; 366: 1056
Metabolic syndrome – at least a prompt for action?
6
5
Diagnostic /
therapeutic
threshold
“Units”
4
3
2
1
0
BP
Cholesterol
Sugar
BMI
Khunti K. BMJ 2005; 331: 1154
Alberti KG. Lancet 2005; 366: 1056
Metabolic syndrome - a clinically useful diagnosis?
Case 1
Case 2
54
54
Gender
Male
Male
WC (cm)
93
94
Age
Glucose (mg/dl)
203
11.4
103
5.8
Trigs (mg/dl)
193
2.2
155
1.8
Metabolic
syndrome*
No
Yes
(mmol/l)
* IDF criteria
Reaven GM. The metabolic syndrome: is this diagnosis really necessary?
Am J Clin Nutr 2006; 83: 1237
Metabolic syndrome:
 Deadly trigger – unidentified
 Magic bullet – ? … rimonabant, glitazones, telmisartan………
Editorial accompanying ‘Nolan J. NEJM 1994;331:1188 - effect
of troglitazone on insulin resistance .......’
“Medical moralists will despair that
pharmacologic inventiveness may now allow
people to become even fatter and lazier
without having to face their metabolic
nemesis.”
Harry Keen, NEJM 1994
Points of agreement around the
metabolic syndrome:
 That certain “metabolic” / cardiovascular
risk factors associate with each other
more often than chance would dictate.
 That these factors taken alone or in any
possible combination are associated with
an elevated risk for CVD & diabetes.
 That there is no definitive treatment for
the “syndrome” per se.
Kahn R. Diabetes Care 2006; 29: 1693
Thank you for your attention.
[email protected]
Link between insulin resistance (IR) &
essential hypertension (EH)
 Patients with EH (as a group) are relatively insulin
resistant with compensatory hyperinsulinemia
 Normotensive 1st degree relatives of patients with
EH are more insulin resistant cf. control subjects
without FH of EH
 IR in population based studies predicts the
eventual development of EH
RR of hypertension by quartile of baseline fasting insulin
278 adult women age 50, Gothenburg, 12 years follow-up
Comparison
Q2 vs. Q1
Q3 vs. Q1
Q4 vs. Q1
Point estimate
1.0
1.0
3.2
95% CI
0.4 – 2.4
0.4 – 2.5
1.4 – 7.5
Adjusted for BMI, W/H ratio, weight change
Also significant relationship: baseline insulin & BP
Lissner L. Hypertension 1992; 20: 797
Defect in insulin action
Rising glucose
Stimulated insulin secretion
Homeostasis at price of
hyperinsulinaemia
Insulin resistance states:
 Obesity
 Hyperlipidemia
 High blood pressure
 IGT
 High triglycerides
 Diabetes type 2
 Smoking
 HAART for HIV
 …….
The metabolic syndrome:
a recent perspective
 BMI
 Central Adiposity
Insulin Resistance
+
Hyperinsulinemia
Glucose
Metabolism
Glucose
intolerance
±
Uric Acid
Metabolism

Uric acid
  Urinary uric
acid clearance
Dyslipidemia

TG
  PP lipemia
  HDL-C
  PHLA
 Small, dense LDL
Hemodynamic

SNS activity
  Na retention
 Hypertension
Novel Risk
Factors

CRP
  PAI-1
  Fibrinogen
Coronary Heart Disease
Reaven G. Drugs. 1999; 58 (S): 19
Age-adjusted prevalence of CHD in the US population >50
years with metabolic syndrome & diabetes
Haffner S. Circulation 2003; 108: 1541
Metabolic syndrome predicting mortality
Age- and gender-adjusted CHD, CVD, & total mortality rates in US adults with MetS
+/- diabetes & pre-existing CVD in NHANES II (n=6255; mean follow-up, 13.3 years)
Malik S. Circulation 2004; 110: 1245
Prediction of CHD prevalence using multivariate
logistic regression
Odds
ratio
Lower 95%
limit
Upper 95%
limit
Waist circumference
1.13
0.85
1.51
Triglycerides
1.12
0.71
1.77
HDL cholesterol*
1.74
1.18
2.58
Blood pressure*
1.87
1.37
2.56
IFG
0.96
0.60
1.54
Diabetes*
1.55
1.07
2.25
Metabolic syndrome
0.94
0.54
1.68
Variable*
*
Significant predictors of prevalent CHD.
The syndrome confers no greater information
than the sum of its component risk factors.
Alexander CM. Diabetes 2003; 52:1210
Vasculopathy*
Constriction
Rarefaction
Intracell Ca++
Hyperinsulinemia
Insulin resistance
Hyperinsulinemia
Symp, Activity/
Tissue
Reactivity
Central
Obesitiy
* skeletal muscle
Na+ Reabsorption
Cardiovascular benefits of exercise
blood pressure
peripheral resistance
sympathetic activity
fibrinogen & PAI-1
platelet aggregation
triglycerides & LDL
blood sugar
left ventricular mass
abdominal obesity
endothelial NO
HDL
insulin sensitivity
fibrinolytic activity
LV ejection fraction
haemodynamics in HF
psychological well-being
arrhythmia threshold
coronary flow
Proposed Role of RBP4 in the Pathogenesis of Insulin Resistance and Glucose
Intolerance.
Insulin resistance in adipose tissue is associated with reduced levels of glucose
transporter 4 (GLUT4), which results in the increased production of RBP4. This
increased production leads to elevated circulating levels of the protein that causes
insulin resistance in muscle, as well as elevated levels of the gluconeogenic enzyme
phosphoenolpyruvate carboxykinase and an increased rate of gluconeogenesis in the
liver, causing increased glucose production. These factors increase blood glucose
levels, leading to impaired glucose tolerance or diabetes.
Polonsky, KS. NEJM 2006; 354: 2596-2598
Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi:10.1038/nrd2005
Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi:10.1038/nrd2005
Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi:10.1038/nrd2005
Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi:10.1038/nrd2005
Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi:10.1038/nrd2005
Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi:10.1038/nrd2005
Scripps ghrelin vaccine was injected into male rats. Ghrelin secreted by the rats
when they had not eaten is sequestered by vaccine-induced antibodies, reducing
the ability of ghrelin to reach the brain, where it acts
Zorrilla E. (& Janda). Proc. Natl. Acad. Sci. USA, DOI:10.1073/pnas.0605376103