1
The Metabolic Syndrome:
Neil J. Stone MD, MACP, FACCProfessor of Clinical MedicineFeinberg School of Medicine
Northwestern UniversityChicago, Illinois
Disclosures
Served as a consultant for Abbott, Merck,Schering-Plough, and Unilever (honorariumdonated to AHA); no further consultingactivities after May 1st 2008
Received honoraria for educational, notpromotional activities from Abbott, Merck,Pfizer, and Unilever (content always mine)
Metabolic Syndrome
Introduction
Definitions
Underlying Risk Factors and Pathophysiology
Metabolic Risk Factors ASCVD, Type 2DM
Clinical Diagnosis
Clinical Management
The Metabolic Syndrome
“We used to hunt for food,
now it hunts us”
-Dr. Van Italie
Twin Epidemics:Parallels in Prevalence
~61% of US Adults Are Overweight or Obese1
0
10
20
30
40
50
60
70
80
20-29 30-39 40-49 50-59 60-69 ≥70
Age, yr
Prevalence, %
WomenMen
Women Men
Overweight/Obesity2
Metabolic Syndrome3
1. Available at: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/obese/obse99.htm2. Available at: http://www.cdc.gov/nchs/about/major/nhanes/overweight.pdf3. Ford ES, et al. JAMA. 2002;287:356-359.
Accumulating Risk FactorsOver the Life cycle
Abdominalobesity
BorderlineRisk
Factors
Multiple
Metabolic
Risk Factors
Lifestyle Change --Decreased calories --Better Diet --Regular Activity
Avoiding weight gain; losing excess weight
Author’s adaption of Figure in Grundy, S. JACC 2006
Outcomes
- Diabetes- CHD
2
Prevalence of Metabolic Syndrome
0% 10% 20% 30% 40% 50%
20-29
60-69
Men
Women
Mex-Am
Prevalence
US Census data shows that the Metabolic Syndrome iscommon: age adjusted prevalence is 23.7%
NHANES III: Age-Adjusted Prevalence of3 Risk Factors for the Metabolic Syndrome*
*Criteria based on ATP III; diabetics wereincluded in diagnosis; overall unadjustedprevalence was 21.8%.
Per
cent 24.8
16.4
28.3
22.825.7
35.6
0
5
10
15
20
25
30
35
40
White
25.7% difference
African American Mexican-American
MenWomen
56.7%difference
Ford ES, et al. JAMA. 2002;287:356-359.
Metabolic Syndrome
Introduction
Definitions
Underlying Risk Factors and Pathophysiology
Metabolic Risk Factors ASCVD, Type 2DM
Clinical Diagnosis
Clinical Management
Clustering of Risk Factors in Framingham(Wilson et al 1999) Rela%ve Risk of 3 or more Risk Factors:
5 lb weight change can cause significant changein risk factor sum
0
1
2
3
4
5
6
Male Female
Relative Risk
Male
Female
What’s a Syndrome? A set of characteristics that are seen together
more frequently than by chance alone.
A set of symptoms or conditions that occurtogether and suggest the presence of acertain disease or an increased chance ofdeveloping the disease
A collection of symptoms that characterize a specificdisease --- No
Metabolic Syndrome: Constella%on of interrelated risk factors ofmetabolic origin
‐atherogenic dyslipidemia‐elevated blood pressure‐elevated blood glucose‐pro‐inflammatory state‐pro‐coagulable state
Not a discrete en%ty with a single cause Not a subs%tute for global risk assessment
Circulation 2005;112:2735-2752.
3
Criteria for Metabolic Syndrome:3 of 5 constitute a diagnosis (ATP III)
Elevated waist: >102 cm (>40 in) in mencircumference > 88 cm (>35 in) in women
Elevated TG: >150 mg/dL or on Rx Reduced HDL‐c 85 diastolic or on an%‐hypertensive treatment
Elevated fasOng >100 mg/dL or on drug Rxglucose
Subcutaneous Fat
Abdominal MuscleLayer
Intra-abdominalFat
Visceral Adiposity:The Critical Adipose Depot
Wrong!!! Measure on the Side of thePatient and at the level of the Iliac Crest
Modifications (Empiric) Elevated waist: >102 cm (>40 in) in men
circumference > 88 cm (>35 in) in women1) Some US adults on non-Asian origin (white,black, Hispanic) with marginally increased waistcircumference:
--37-39 inches in men -- 31-34 inches in women
may have a strong genetic contribution toinsulinresistance and should benefit from TLC
2) South Asians:--35 inches in men--31 inches in women
Visceral Fat and Insulin SensitivityVisceral Fat and Insulin Sensitivity
20 22 24 26 28 30 32 340
2
4
6
8
10
R = -0.056P < 0.05
Fat Area (cm2)
Insulin Sensitivity Index
Fujimoto WY. Obes Res. 1994; 2:364.
Atherogenic Dyslipidemia
Elevated TriglyceridesElevated small dense LDL
particlesReduced HDL-c
LiverLiverLDL I, II
LPL LPLIDL
SmallerLDL
HL
CETPTG
LPLRemnants
Berneis KK and Krauss RM. J Lipid Res. 2002;43:1363-1379.
Metabolic Origins of LDL ParticleSubclasses
PlasmaTG
200
TGTGSmallerSmallerVLDLVLDL
TG TGLargerLarger VLDL VLDL
LDL III, IV
LPL/HL
Pattern B
Pattern A
Small dense LDL
4
Atherogenic Particles
High TG, low HDL-csmall dense LDL-c
Non-HDL-C
Atherogenic Dyslipidemia:
TG-rich lipoproteins
VLDL VLDLR IDL LDL Small,denseLDL
Slide source: lipidsonline
Metabolic Syndrome
Only about 50% of hypertension related toinsulin resistance
Key point is that in overweight hypertensives,weight loss can help improve blood pressure
CHD Mortality Rates by Degreeof Glucose Tolerance ParisProspective Study
0
1
2
3
4
5
Normal IGT Type 2 DM glucose tolerance
Horm Metab Res 15 (Suppl): 41-46, 1985
Inci
denc
e ra
te/1
,000
Metabolic Syndrome
Definitions: Why a Syndrome?
Underlying Risk Factors and theMetabolic Syndrome; Pathophysiology
Metabolic Risk Factors, ASCVD and Type 2DM
Clinical Diagnosis
Clinical Management
Metabolic Syndrome: Major underlying risk factors are:
Obesity Risk identified by waist circumference
Insulin resistance Can have genetic components
Exacerbating factors Physical inactivity Advancing age Endocrine dysfunction Genetic aberrations affecting risk factors
Grundy et al. JACC 2006; 47:1093-100.
Eckel, Grundy, Zimmet, Lancet 2005
5
Relationship between BMI and Insulinresistance in volunteer population
McLaughlin T,Metabolism,
2004; 53:495-499.
Obesity and Insulin Sensitivity
McLaughlin T, Metabolism, 2004; 53: 495-499.
In the most insulin sensitive tertile (Tertile I)
--30% either overweight (25%) or obese (5%).
In the most insulin-resistant tertile (Tertile III)
--36% were obese
NAFLD
Nonalcoholic fatty liver disease is verycommon one estimate is that 30 million obese adults in the
United States have fatty liver Most often, it occurs in those who are
obese diabetes elevated lipids
Progressive Liver damage Simple fatty liver (steatosis).
Simple fatty liver is the accumulation of fat in theliver cells.
Non-damaging No scarring or inflammation. People are asymptomatic.
Progressive liver damage
Nonalcoholic steatohepatitis (NASH). Most common form of nonalcoholic fatty liver
disease An inflammation of the liver due to the
accumulation of fat. NASH may lead to cirrhosis — scarring of the liver
Metabolic Syndrome
Case Study
Definitions
Underlying Risk Factors and Pathophysiology
Metabolic Risk Factors ASCVD, Type 2DM
Clinical Diagnosis
Clinical Management
6
ARMITAGE, J. et al. Heart 2000;84:357-360
Increasing LDL-c gives increasing risk;certain subsets at especially high risk
10 yrCHDrates %
8.0
1.0
Diabetic
Non-diabetic
5.0 (194) Total cholesterol
6.0 (236)
Logscale Met
Syndrome
Increasing BP gives increasing risk;certain subsets at especially high risk
Obesity and Risk of MI in27,000 subjects
Lancet, November 2005
BMI Waist/hip ratios
Obesity and Risk of MI in27,000 subjects
Lancet, 2005
0 1 2 3 4 50
2
4
6
8
C-reactive protein (mg/L)
# of Characteristics of theMetabolic Syndrome
Ridker PM, et al. Circulation. 2003;107:391-397.
CRP and Metabolic Syndrome
ATP III Definition ofMetabolic Syndrome
Three of five:• Abdom. Obesity• Elevated TG• Low HDL-c• Elevated BP• Elevated fasting
glucose
Metabolic Syndrome and Eventfree CV survival Metabolic Syndrome
Overview
Underlying Risk Factors and the MetabolicSyndrome
Metabolic Risk Factors, ASCVD & Type 2DM
Clinical Diagnosis
Clinical Management
7
Criteria for Clinical Dx MetabolicSyndrome: Elevated waist: >102 cm (>40 in) in men
circumference > 88 cm (>35 in) in women Elevated TG: >150 mg/dL or on Rx Reduced HDL-c < 40 mg/dL in men
< 50 mg/dL in women or on Rx Elevated BP: >130 systolic
or > 85 diastolic or on anti-hypertensive treatment
Elevated fasting >100 mg/dL or on drug Rx
Other Definitions of MetabolicSyndrome World Health Organization
Includes measure of insulin resistance indefinition
Type 2 DM or IFG or IGT and two risk factors BP, HDL, TG, BMI and/or W/H ratio, urinary
microalbumin
IDF Same risk factors as ATP III Difference is that waist circumference is
mandatory part of definition (adjusted for ethnicgroup)
Two others needed for diagnosis
Three definitions of MetabolicSyndrome and CHD Risk
Odds ratios are modest IDF…..1.32 (1.03-1.7) WHO.. 1.45 (1-2.1) ATP III 1.38 (1-1.93)
Adjustment for smoking, inactivity and life-course socioeconomic position resulted inattenuation of these associationsLawlet et al 2006
Metabolic Syndrome
Overview
Underlying Risk Factors and the MetabolicSyndrome
Metabolic Risk Factors, ASCVD & Type 2DM
Clinical Diagnosis
Clinical Management
Diet Reduced saturated fats and dietary cholesterol Enhanced LDL lowering:
plant stanols/sterols increased viscous fiber(more unsaturated fats, less carbs in those with
metabolic syndrome) Regular physical activity Weight loss Healthy foods – fruits, vegetables, fish, nuts
Therapeutic Lifestyle Change(Total Lifestyle Change)
*P
8
Aerobic Exercise ImprovesInsulin Sensitivity
*P
9
Omega 3 or N-3 Fatty Acids -Named for Placement 1st Double Bond (see N-6and N-9)
N-3 Polyunsaturated Fatty Acids Affect Platelet Function, triglycerides, HDL Raise LDL-c in Combined Hyperlipidemia Lower rates of Sudden Death
Marine: EPA C20:5 (w-3) and DHA C22:6 Plant: Linolenic Acid (C18:3;w-3)
Omega-3 Fatty Acids
0
5
10
15
Death CardiacMortality
Non Fatal MI
Cancer
Event Rate (%)
- 56%P=.03
- 65%P=.01
- 70%P
10
Cumulative Incidence of Diabetes in DPP
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.
00 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.0
YearYear
4040
3030
2020
1010
Cumulative Incidence Cumulative Incidence ––DiabetesDiabetes
00
LifestyleLifestyle
MetforminMetformin
PlaceboPlacebo(%)(%)
(%)(%)
(%)(%)
(%)(%)
TLC and Metabolic Syndrome
Increased Waist (> 35 cm) Trim extra calories – 200 per day reduces
postprandial TG and hence fasting TG values HDL< 50 mg/dL in a woman
Liberalize fat intake (canola, nuts, avocados) Increase physical activities
Fasting TG > 150 mg/dL Improve food choices to favor
complex carbohydrates and grains low-fat dairy foods instead of simple carbohydrates and
meats
Low-risk Women in Nurses’Health Study (3% of cohort)
Not current smokers BMI under 25 Engaged in moderate-vigorous activity for at least 30
minutes on average (could be brisk walking) Averaged ½ drink of alcoholic beverage/day In highest 40% of cohort for consumption of diet
high in cereal fiber high in marine n-3 fatty acids high in folate high in ratio of polyunsaturated to saturated fat low in trans and glycemic load
Stampfer et al NEJM 2000.
Metabolic Syndrome in Young AdultsAmsterdam Growth and Health Longitudinal Study: 450boys and girls; 13 36 years;
3 major determinants Fatness Fitness Lifestyle
Arch. Intern. Med. 2005; 165(1): 428.
Eat less, EatSmartMove moredaily!
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