What is the metabolic syndrome? Simon Thom

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What is the metabolic syndrome? Simon Thom
Lipid Update VIStratford-upon-Avon, 20/11/2006
2
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
3
The metabolic syndrome / insulin resistance
syndrome / Reavens 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 371595
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Metabolic syndrome definitions

• NCEP-ATP III definition
• Any 3 or more of the following criteria
• Waist circumference gt102 men gt88 cm in women
• Serum triglycerides 1.7
• Blood pressure gt130/85
• HDL cholesterol lt1.0 men and lt1.3 women
• Serum glucose 6.1 (5.6 may be applicable)

• WHO definition
• Diabetes, IFG, IGT, or insulin resistance (clamp
  studies) at least 2 of the following criteria
• Waist-hip ratio gt0.90 men or gt0.85 women
• Serum triglycerides 1.7 or HDL cholesterol lt0.9
  men lt1.0 women
• Blood pressure 140/90
• Urinary albumin excretion gt20 µg/min or
  albumin-creatinine ratio gt30 mg/g

16 potential defining combinations!
JAMA 2001 285 2486 Circulation 2004 109 433
WHO Geneva 1999
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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 lt40 mg/dL (1.03 mmol/L) in males and lt50
  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_d
efinition.pdf Alberti KGMM et al. Lancet 2005
366 1059
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Usual fasting glucose risk of CV end points
Total stroke
Total IHD
Cardiovascular death
Hazard ratio 95 CI
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
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CHD risk accumulates with additional CV risk
factors
Hypertension SBP 150 mmHg X1.5
Dyslipidemia TC 260 mg/dL X2.3
X3.5
X6.2
X4
X2.8
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 888910
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International prevalence of the metabolic syndrome
ATP III definition adapted from Gu D. Lancet
2005 3651398. Eckel R. Lancet. 2005 3651415.
Ford E. Diabetes Care. 2004 27 2444.
Reynolds K. Am J Med Sci, 2005 330 273
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Prevalence of the metabolic syndrome in USA
China
USA
China
Prevalence,
35 - 44
45 - 54
55 - 64
65 - 74
Gu D. InterASIA Lancet 2005 365 1398
Ford ES. JAMA 2002 287 356
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• Does the metabolic syndrome predict CVD risk?

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Metabolic syndrome predicts risk of CHD stroke
in healthy middle-aged men 22-Year follow-up,
Helsinki Policemen Study
CHD
Stroke
Kaplan-Meier curves for remaining free of CHD and
stroke by tertiles of insulin resistance
Pyorala M. ATVB 2000 20 538
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Metabolic syndrome CHD death or non-fatal MI
with different numbers of factors - 6000 men
followed for 5 yrs
with events
Years
Kaplan-Meier curves for CHD events in men with
zero, 1, 2, 3, or gt4 characteristics of the
metabolic syndrome at baseline
Sattar N. Circulation 2003 108 414
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The metabolic syndrome and 11-year risk of
incident CVD in ARIC 12,089 women men followed
for 11 years
The syndrome conferred no greater CHD risk than
the sum of its components.
Hazard ratio
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
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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
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.... in recognising the undoubted risk factor
clustering of the metabolic syndrome, we dont
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
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Is there a unifying explanatory mechanism for the
metabolic syndrome?
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Metabolic syndrome- hypotheses for pathogenesis

• Sympathetic activation
• Inflammation
• Adiponectin deficiency
• Vascular rarefaction
• Sodium retention
• Leptin resistance
• ..

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Sympathetic activation
Cardiovascular
Skeletal muscle
High cardiac ouput - (? adrenergic) Inadequate
vasodilatation - (? adrenergic)
Stimulated ? adrenergic receptors
High blood pressure
Acute
Insulin resistance
Vascular hypertrophy
Chronic
Conversion to fast twitch fibres
Decreased substrate to muscles
Vascular rarefaction
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Relationship between BP muscle blood flow
during hyperinsulinemic clamp
250
200
150
r - 0.69 p 0.005
increase in leg blood flow
100
50
95
115
75
105
65
85
Basal MAP (mmHg)
Baron AD, Hypertension 1993 21129
20
Effect of training on skeletal muscle lipoprotein
lipase activity - relationship with capillary
density

• 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

500
400
Capillary density /mm2
300
200
0
20
40
60
80
LP Lipase activity (mU/g w.w.)
Kiens B. JCI 1989 83 558 - 564
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Extension of metabolic syndrome on the basis of
resistance to the novel actions of insulin
Dandona P. Circulation 2005 1111448
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Pathophysiology of CVD in the metabolic syndrome
Prasad A. Circulation 2004 110 1507
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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
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Factor structure of the metabolic syndrome
C o n s e q u e n c e ?
C a u s e ?
Shen BJ. Am J Epi 2003 157 701
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Linked by association or by mechanism?
- a genetic or environmental hook or both?
Ferrannini E. Am Heart J 1991 121 1274
26
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
27
Diabetes
?
Hypertension
Obesity
28
Diabetes
Hypertension
Physical inactivity
Obesity
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Metabolic syndrome at least a prompt for action?
Diagnostic / therapeutic threshold
Units
Khunti K. BMJ 2005 331 1154 Alberti KG. Lancet
2005 366 1056
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Metabolic syndrome at least a prompt for action?
Diagnostic / therapeutic threshold
Units
Khunti K. BMJ 2005 331 1154 Alberti KG. Lancet
2005 366 1056
32
Metabolic syndrome - a clinically useful
diagnosis?
Case 1 Case 2
Age 54 54
Gender Male Male
WC (cm) 93 94
Glucose (mg/dl) 203 103
Trigs (mg/dl) 193 155
Metabolic syndrome No Yes
11.4
5.8
(mmol/l)
2.2
1.8
IDF criteria
Reaven GM. The metabolic syndrome is this
diagnosis really necessary? Am J Clin Nutr 2006
83 1237
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• Metabolic syndrome
• Deadly trigger unidentified
• Magic bullet ? rimonabant, glitazones,
  telmisartan

Editorial accompanying Nolan J. NEJM
19943311188 - 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
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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
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Thank you for your attention. s.thom_at_imperial.ac
.uk
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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

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RR of hypertension by quartile of baseline
fasting insulin 278 adult women age 50,
Gothenburg, 12 years follow-up
Comparison Point estimate 95 CI
Q2 vs. Q1 1.0 0.4 2.4
Q3 vs. Q1 1.0 0.4 2.5
Q4 vs. Q1 3.2 1.4 7.5
Adjusted for BMI, W/H ratio, weight change Also
significant relationship baseline insulin ?BP
Lissner L. Hypertension 1992 20 797
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Defect in insulin action Rising
glucose Stimulated insulin secretion
Homeostasis at price of hyperinsulinaemia
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Insulin resistance states

• Obesity
• Hyperlipidemia
• High blood pressure
• IGT
• High triglycerides
• Diabetes type 2
• Smoking
• HAART for HIV
• .

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The metabolic syndromea recent perspective
? BMI ? Central Adiposity
Insulin Resistance

Hyperinsulinemia
GlucoseMetabolism
Uric AcidMetabolism
Dyslipidemia
Hemodynamic
Novel RiskFactors

• ? TG
• ? PP lipemia
• ? HDL-C
• ? PHLA
• Small, dense LDL

• ? Uric acid
• ? Urinary uricacid clearance

• ? SNS activity
• ? Na retention
• Hypertension

• ? CRP
• ? PAI-1
• ? Fibrinogen

• Glucoseintolerance

Coronary Heart Disease
Reaven G. Drugs. 1999 58 (S) 19
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Age-adjusted prevalence of CHD in the US
population gt50 years with metabolic syndrome
diabetes
Haffner S. Circulation 2003 108 1541
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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 (n6255
mean follow-up, 13.3 years)
Malik S. Circulation 2004 110 1245
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Prediction of CHD prevalence using multivariate
logistic regression
Variable 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
Significant predictors of prevalent CHD.
The syndrome confers no greater information than
the sum of its component risk factors.
Alexander CM. Diabetes 2003 521210
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Nutrition
Genetics
Vasculopathy Constriction Rarefaction
Intracell Ca
Hyperinsulinemia
Insulin resistance
Hyperinsulinemia
Symp, Activity/ Tissue Reactivity
Central Obesitiy
skeletal muscle
Na Reabsorption
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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

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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
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Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006) doi10.1038/nrd2005
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Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006) doi10.1038/nrd2005
51
Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006) doi10.1038/nrd2005
52
Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006) doi10.1038/nrd2005
53
Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006) doi10.1038/nrd2005
54
Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006) doi10.1038/nrd2005
55
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, DOI10.1073/pnas.0605376103