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!