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What is the metabolic syndrome?
Simon Thom
Lipid Update VIStratford-upon-Avon, 20/11/2006
Diabetes
ObesityHypertension
Overlap of diabetes2 obesity & essential 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 women2. Serum triglycerides 1.73. Blood pressure >130/854. HDL cholesterol <1.0 men
and <1.3 women5. Serum glucose 6.1 (5.6 may
be applicable)
WHO definitionDiabetes, 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 140/904. Urinary albumin excretion
>20 µg/min or albumin-creatinine ratio >30 mg/g
JAMA 2001; 285: 2486Circulation 2004; 109: 433 WHO Geneva 1999
16 potential defining combinations!
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.pdfAlberti KGMM et al. Lancet 2005; 366: 1059
Ha
zard
ra
tio
& 9
5%
CI
Total stroke Total IHD Cardiovascular death
Asia Pacific Cohort Studies Collaboration. Diabetes Care 2004; 27: 2836
Usual fasting glucose & risk of CV end points
237,468 participants (14,282 Chinese); ~1.2 million person-years follow-up1,661 strokes & 816 IHD events
Each 1 mmol/l ↓fasting glucose associated with ~20% ↓risk of CVD death
Usual fasting glucose, mmol/l
CHD: risk accumulates with additional CV risk factors
DyslipidemiaTC 260 mg/dL
X2.3
HypertensionSBP 150 mmHg
X1.5
Glucose intoleranceX1.8
X3.5
X6.2
X2.8 X4
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
ATP III definition; adapted from: Gu D. Lancet 2005; 365:1398. Eckel R. Lancet. 2005; 365:1415. Ford E. Diabetes Care. 2004; 27: 2444.
International prevalence of the metabolic syndrome
Reynolds K. Am J Med Sci, 2005; 330: 273
Does the metabolic syndrome predict CVD risk?
Sattar N. Circulation 2003; 108: 414
Kaplan-Meier curves for CHD events in men with zero, 1, 2, 3, or >=4 characteristics of the metabolic syndrome at baseline
Years
% w
ith
eve
nts
Metabolic syndrome: CHD death or non-fatal MI with different numbers of factors- 6000 men followed for 5 yrs
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.
Components of the ATP III metabolic syndrome
Haz
ard
ratio
*
The syndrome conferred no greater CHD risk than the sum of its components.
McNeill AM, ARIC, Diabetes Care 2005; 28: 385
The metabolic syndrome and 11-year risk of incident CVD in ARIC12,089 women & men followed for 11 years
Wannamethee S G et al. Arch Intern Med 2005; 165: 2644
Metabolic syndrome / Framingham risk score & measures of probability (%) for occurrence of CHD event & Type 2 diabetes
.... in recognising the undoubted risk factor clustering of the metabolic syndrome, we don’t appear to be identifying any particular risk enhancing interaction.
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
.... should this surprise us?
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 ……..
Sympatheticactivation
High cardiac ouput - ( adrenergic)
Inadequate vasodilatation - ( adrenergic)
Stimulated adrenergicreceptors
High bloodpressure
Insulinresistance
Vascular hypertrophyConversion to fast twitch fibres
Cardiovascular Skeletal muscle
Vascular rarefaction
Decreased substrateto muscles
Acu
teC
hro
nic
250
Basal MAP (mmHg)
75 85 95 105 11565
50
100
150
200
% in
crea
se in
leg
bloo
d flo
w
r = - 0.69p = 0.005
Relationship between BP & muscle blood flow during hyperinsulinemic clamp
Baron AD, Hypertension 1993; 21:129
LP Lipase activity (mU/g w.w.)
Ca
pill
ary
den
sity
/mm
2
Effect of training on skeletal muscle lipoprotein lipase activity- relationship with capillary density
Kiens B. JCI 1989; 83: 558 - 564
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
200
300
400
500
0 20 40 60 80
Prasad A. Circulation 2004; 110: 1507
Pathophysiology of CVD in the metabolic syndrome
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.
Kahn R, et al. Diabetes Care 2005; 28: 2289
Cause? Consequence?
Linked by association or by mechanism?
Ferrannini E. Am Heart J 1991; 121: 1274
- a genetic or environmental hook – or both?
DiabetesObesityHypertension
Overlap of diabetes2 obesity & essential 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
Diabetes
Obesity
Hypertension
?
Diabetes
Obesity
HypertensionPhysical inactivity
Metabolic syndrome – at least a prompt for action?
0
1
2
3
4
5
6
BP Cholesterol Sugar BMI
“Un
its”
Diagnostic / therapeutic threshold
Khunti K. BMJ 2005; 331: 1154Alberti KG. Lancet 2005; 366: 1056
Metabolic syndrome – at least a prompt for action?
0
1
2
3
4
5
6
BP Cholesterol Sugar BMI
“Un
its”
Diagnostic / therapeutic threshold
Khunti K. BMJ 2005; 331: 1154Alberti KG. Lancet 2005; 366: 1056
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
Metabolic syndrome - a clinically useful diagnosis?
Reaven GM. The metabolic syndrome: is this diagnosis really necessary?
Am J Clin Nutr 2006; 83: 1237
* IDF criteria
11.4 5.8
2.2 1.8
(mmol/l)
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
Metabolic syndrome: Deadly trigger – unidentified Magic bullet – ? … rimonabant, glitazones, telmisartan………
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
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
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
RR of hypertension by quartile of baseline fasting insulin278 adult women age 50, Gothenburg, 12 years follow-up
Adjusted for BMI, W/H ratio, weight changeAlso 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
Reaven G. Drugs. 1999; 58 (S): 19
BMI Central Adiposity
BMI Central Adiposity
GlucoseMetabolism
GlucoseMetabolism
Uric AcidMetabolism
Uric AcidMetabolism DyslipidemiaDyslipidemia HemodynamicHemodynamic Novel Risk
Factors
Novel RiskFactors
Insulin ResistanceInsulin Resistance
HyperinsulinemiaHyperinsulinemia+
TG PP lipemia HDL-C PHLASmall, dense LDL
± Glucoseintolerance
Uric acid Urinary
uricacid clearance
SNS activity Na retentionHypertension
CRP PAI-1
Fibrinogen
Coronary Heart Disease
Haffner S. Circulation 2003; 108: 1541
Age-adjusted prevalence of CHD in the US population >50 years with metabolic syndrome & diabetes
Malik S. Circulation 2004; 110: 1245
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)
Metabolic syndrome predicting mortality
Prediction of CHD prevalence using multivariate logistic regression
* Significant predictors of prevalent CHD.
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
Alexander CM. Diabetes 2003; 52:1210
The syndrome confers no greater information than the sum of its component risk factors.
Intracell Ca++ Vasculopathy*Constriction Rarefaction
Symp, Activity/Tissue
Reactivity
CentralObesitiy
Hyperinsulinemia
Insulin resistance
Hyperinsulinemia
Na+ Reabsorption* skeletal muscle
Genetics Nutrition
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
