Health Risks and Comorbid Conditions

Outline

• Overview of the Metabolic Syndrome

• Risks of Obesity and the Metabolic Syndrome

• Specific Health Risks

• Answers to Questions & Summary

Question # 1

Which of the following is not part of the Metabolic Syndrome?

1. High HDL-cholesterol (> 50 mg/dL)

2. High blood pressure (> 130/85)

3. High Triglyceride (> 150 mg/dL)

4. Impaired fasting glucose (100-126 mg/dL)

5. Increased waist circumference [> 88cm (F) 102cm (M)]

Development of the Concept

• 1904 - Life insurance data

• 1947 - Vague introduces adipomuscular ratio

• 1967 - Crepaldi insulin resistance and disease

• 1970 - Feldman Epidemiological relation

• 1982 - Ratio of waist to hip circumference related to morbidity and mortality in 2 separate laboratories

• 1988 - Reaven describes Syndrome X

Abdominal Obesity

Abdominal Adiposity

Courtesy of Steven Smith, M.D.

Visceral Subcutaneous

Body Fat Distribution and Glucose Tolerance

Kissebah JCEM 1982;54:254-260.

Time (min)

Insu

lin

(μ

U/m

L

0 30 60 90 120 150 1800

50

100

150

200

250

Upper Body Lower Body Control

Time (min)

Glu

cose

(m

g/d

L)

0 30 60 90 120 150 1800

50

100

150

200

250

Visceral Obesity and Risk of Dyslipidemia

Despres JP, et al. Arteriosclerosis. 1990;10:497-511.

Obese: Level of deep abdominal fat

VariableNonobese

(n = 25)Low

(n = 10)High

(n = 10)

% Body fat 28.0 ± 5.6 47.0 ± 6.4 49.8 ± 3.2

Deep abdominal fat area (cm2) 50.3 ± 16.8 107.0 ± 33.4 186.7 ± 36.8

TG (mmol/L) 0.79 ± 0.35 1.47 ± 0.79 2.57 ± 2.41

CHOL (mmol/L) 4.59 ± 0.88 5.18 ± 0.93 5.65 ± 1.23

LDL CHOL (mmol/L) 3.00 ± 0.87 3.56 ± 0.92 3.81 ± 1.10

HDL CHOL (mmol/L) 1.36 ± 0.24 1.25 ± 0.18 0.96 ± 0.12

Fasting insulin (pmol/L) 39.0 ± 12.4 91.5 ± 59.9 150.3 ± 57.3

Glucose area ([mmol/L/180 min] x 103)

10.7 ± 0.19 1.14 ± 0.22 1.40 ± 0.19

Insulin area ([pmol/L/180] x 103) 46.6 ± 19.4 82.1 ± 48.3 121.0 ± 39.5

Metabolic Syndrome: NCEP ATP III

JAMA 2001;285:2486-2497.

Risk Factor Cut-PointsCentral Adiposity

M (waist) > 40 in > 102 cm F > 35 in > 88 cmTriglycerides ≥ 150 mg/dL ≥ 7.1 mmol/LHDL-C M < 40 mg/dL < 0.9 mmol/L F < 50 mg/dL < 1.0 mmol/LBlood Pressure ≥ 130/≥ 85 mm Hg

Fasting Glucose ≥ 110 (100) mg/dL ≥ 6.1 mmol/L

Age-Adjusted Prevalence of the Metabolic Syndrome

Ford. JAMA 2002;287:356-9.

Among 8814 Adults Age > 20

Characteristics of the Metabolic Syndrome

• Abdominal obesity• Glucose intolerance• High triglycerides• Low HDL-cholesterol• High blood pressure• Insulin resistance

• Microalbuminuria• Small dense LDL• Inflammatory markers• Thrombotic factors• Endothelial

dysfunction• Hyperuricemia

Full members Wannabes

Central Fat and Lifestyle Health Risk

1st quintile

5th quintile

0 1 2 3 4 5 6 7 8 9 10 11 12

1.0

0.95

1.0

0.95

Years of follow-up

Waist to hip ratio

Pro

babi

lity

of r

emai

ning

fr

ee o

f myo

card

ial

infa

rctio

nP

roba

bilit

y of

su

rviv

al

Lapidus. BMJ 1984;289:1257-61.

Outline




• Answers to questions & Summary

Excess fat stores

GenesEnvironment

Activity Food Intake

Diseases due to increased fat cellsize & visceral fat

Stigma

Sleep apnea

OsteoarthritisDiabetes

GB Disease

NAFLD CVD

Cancer

Diseases due to increased fat

mass

Pathogenesis of Health Problems Associated with Obesity

AngiotensinogenAngiotensinogen

Fat CellFat Cell

Free Fatty Acids Free Fatty Acids

LactateLactate

LeptinLeptin

Adipsin (ASP) (complement (3a;D)Adipsin (ASP) (complement (3a;D)Lipoprotein

Lipase (LPL)LipoproteinLipase (LPL)

IL-6IL-6

Cholesterolester Transfer Protein (CETP)

Cholesterolester Transfer Protein (CETP)

Prostacyclin Prostacyclin

Plasminogen Activator Inhibitor (PAI-1)Plasminogen Activator Inhibitor (PAI-1)

TNF-TNF-

Phospholipid Transfer Protein (PLTP)

Phospholipid Transfer Protein (PLTP)

AdiponectinAdiponectin

ProstaglandinProstaglandin

Monobutyrin Monobutyrin

Galectin-12Galectin-12

The Fat Cell is an Endocrine Cell

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis

Coronary heart disease Diabetes Dyslipidemia Hypertension

Gynecologic abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Osteoarthritis

Skin

Gall bladder disease

Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate

Phlebitisvenous stasis

Gout

Medical Complications of ObesityIdiopathic intracranial hypertension

Stroke

Cataracts

Severe pancreatitisSevere pancreatitis

Outline



– Mortality

– Morbidity


• Answers to questions & Summary

Question # 2

Which of the following is NOT an estimate of excess deaths from obesity?

1. 450,000

2. 365,000

3. 325,000

4. 275,000

5. 112,000

0

0.5

1

1.5

2

2.5

3

< 1

8.5

18.5

- 2

0.4

20.5

- 2

1.9

22.0

- 2

3.4

23.5

- 2

4.9

25.0

- 2

6.4

26.5

- 2

7.9

28.0

- 2

9.9

30.0

- 3

1.9

32.0

- 3

4.9

35.0

- 3

9.9

> 4

0.0

Body Mass Index Interval

Rela

tive

Ris

k o

f D

eath

White Men

White Women

BMI and Mortality by Ethnic Group The American Cancer Society Study

Calle NEJM 1999;341:1097.

Relative Risk of Death by BMI Levels from the NHANES I, II, & III Surveys

BMI Level Relative Risk by Age Category

25-59 60-69 ≥ 70

< 18.5 1.38 2.30 1.69

18.5 to < 25 1.00 1.00 1.00

25 to < 30 0.83 0.95 0.91

30 to < 35 1.20 1.13 1.03

≥ 35 1.83 1.63 1.17

Flegal et al JAMA. 2005;1861.

Range of Estimates of Mortality Associated with Overweight

Author YearEstimated excess

deaths

Foege & McGinnis 1993 300,000

Fontaine et al 1999275,000 to

325,000

Mokdad et al 2004 365,000

Flegal et al NHANES I

2005 112,000

Overweight*(BMI 25 - 29.9)

Obese*(BMI > 30)

Female (non-smoker, 40 years of age) 3.29 y 7.08 y

Male (non-smoker, 40 year of age) 3.05 y 5.82 y

Obesity Decreases Life Expectancy:The Framingham Study

Peeters Ann Int Med 2003;138:24-32.

* Compared to a BMI 18.5-24.9 kg/m2

Question # 3

Which disease has the highest risk in association with obesity?

1. Breast cancer

2. Diabetes

3. Cardiovascular disease

4. Osteoarthritis

5. Kidney stones

Outline


• Risks from Obesity and Metabolic Syndrome– Increased mortality

– Increased morbidity



Relationship Between BMI and Comorbidities Is Positive,

Even in the “Normal” Range

Willett WC, et al. N Engl J Med. 1999;341:427-434.

Body Mass Index(kg/m2)

Rel

ativ

e R

isk

Women Men

4

6

5

3

2

1

0

< 21 22 23 24 25 26 27 28 29 30

Body Mass Index(kg/m2)

4

6

5

3

2

1

0

< 21 22 23 24 25 26 27 28 29 30

Rel

ativ

e R

isk

Type 2 diabetes

Cholelithiasis

Hypertension

Coronary heart disease

Prevalence (%) by BMI Categories

< 21.9 22 to 23.9

24 to 24.9

25 to 27.9

28 to 29.9

30 to 34.9

35 to 39.9

> 40

High BP 18.7 21.8 25.3 31.6 39.2 46.6 55.8 62

High Chol

33.5 38.4 40.9 44.1 46.1 46.7 44.1 38.9

Diabetes 1.9 2.2 2.7 3.7 5.6 8.7 12.8 15.2

Arthritis 31 33.8 36.3 38.6 42.3 45.1 48.7 54.9

Coakley et al IJO 1998;22:958.

BMI and Chronic Disease Prevalence in the Nurses Health Study

Proportion of Disease Prevalence Attributable to Obesity

Type 2 Diabetes 57%

Gall bladder disease 30%

Hypertension 17%

Cardiovascular disease 17%

Osteoarthritis 14%

Breast Cancer 11%

Uterine Cancer 11%

Colon Cancer 11%

Age- and Sex-Adjusted Prevalence of Risk Factors for BMI > 30 kg/m2

Variable

NHES

1960-62

NHANES

1971-75

NHANES

1976-80

NHANES

1988-94

NHANES

1999-00

High cholesterol (>6.2 mM)

38.9 33.1 31.5 23.0 17.9

High BP

>140/>90

41.6 46.5 35.6 22.3 23.7

Diagnosed Diabetes

2.9 5.9 6.3 9.0 10.1

Gregg et al JAMA 2005;293:1868.

Outline


• Specific Health Risks– Increased risk of diabetes

– Increased risk of heart disease

– Increased risk of hypertension

– Increased risk of cancer

– Other increased risks


Relationship Between BMI and Risk of Type 2 Diabetes Mellitus

Chan J et al. Diabetes Care 1994;17:961.Colditz G et al. Ann Intern Med 1995;122:481.

Age

-Adj

uste

d R

elat

ive

Ris

k

Body Mass Index (kg/m2)

< 23 24 - 24.9

25 - 26.9

27 -28.9

33 -34.9

0

25

50

75

100

1.02.9 4.3 5.0

8.1 15.8

27.6

40.3

54.0

93.2

< 22 23 - 23.9

29 -30.9

31 -32.9

35 +

1.0 1.52.2

4.46.7

11.6

21.3

42.1

1.0

Men

Women

Waist Circumference Relative Risk of Type 2 DM

< 28 inches 1.0

28 - 29 1.2

30 - 31 2.8

32 - 33 4.0

34 - 35 4.8

36 - 37 5.5

> 38 6.2

*Controlled for age, family history of diabetes, exercise, smoking, saturated fat intake, calcium, potassium, magnesium, and glycemic index.

Nurses’ Health Study: Waist Circumference Directly Related to Risk for Type 2 Diabetes

Carey et al. Am J Epidemiol. 1997;145:614.

Prevalence

Caucasian/African-American (N = 1057) 17%

Caucasian/Hispanic(N = 560) 18%

Hispanic (N = 31) 45%

African-American(N = 97) 47%

Prevalence of Type 2 Diabetes Among Diabetic Children in 4 Studies

Fagot-Campagna et al. J Pediatr 2000;136:664.

Group Relative Risk

Non-diabetic throughout 1.0

MI/stroke before diabetes 2.8

MI/stroke after diabetes 3.7

Diabetes at baseline 5.0

Nurses Health Study: Diabetes & MI/Stroke

Hu Diab Care 2002;25:1129.

Outline








BMI Multivariate Relative Risk< 21 1.0

21 to < 23 1.2

23 to < 25 1.3*

25 to < 29 1.8*

> 29 3.3*

BMI and Risk of Coronary Heart Disease in the Nurses Health Study

Manson et al NEJM 1995;333:677-85.

* = p < 0.05

0

0.5

1

1.5

2

2.5

Folsom et al. Arch Intern Med 2000;160:2117.

Body Mass Index Tertile3 2

3

11

2

Re

lativ

e R

isk

Waist

-Hip R

atio

Tertile

Abdominal Fat Distribution Increases the Risk of Coronary Heart Disease

The Iowa Women’s Health Study

0

1

2

3

4

5

6

7

< 19.1 19.1 -20.3

20.4 -21.5

21.6 -23.2

> 23.3

-5 or more-4.9 to +4.9

+5 to 10.9+11 to 19.9

+20 or more

WeightChange, kg

Body Mass Index (kg/m2) at 18 Years of Age

RelativeRisk

BMI Weight Gain and Cardiovascular Risk

Willett et al JAMA. 1995;273:461-5.

Body Weight and Weight Gain During Adult Life and Risk of CHD

Weight Change Category Relative Risk of CHD

Loss of 4% 1.89

Stable 1.00

Gain 4 - 10% 1.48

Gain 10 - 15% 1.65

Gain 15 - 25% 1.48

Gain 25 - 35% 1.95

Gain more than 35% 2.62

Rosengren et al Europ H J 1999;20:269-277.

The Interheart Study: Risk of MI

FactorOdds Ratio

Population Attributable Risk

Abdominal Obesity (WHR)+ 2.24 33.7

Diabetes+ 3.08 12.3

Hypertension+ 2.48 23.4

ApoB/ApoA1+ 3.87 54.2

Smoking* 2.27 36.4

Psychosocial+ 2.51 28.8

* Adj for Age, Sex & Geography+ Adj Age, Sex & Smoking

Yusuf et al Lancet 2004;364-352.

Incidence per 1000 person years

Group Men Women

Normal Weight 5.1 9.7

Overweight 8.6 10.7

Obese 9.9 14.3

Obesity and the Risk of New Onset Atrial Fibrillation

Wang et al JAMA 2004;292:2471-77.

Incidence (%)

Group Men Women

Normal Weight 5.0 3.5

Overweight 6.0 3.8

Obese 10.0 6.8

10-Year Cumulative Incidence of Heart Failure in the Framingham Study

Kenchaiah et al NEJM 2002;347:305-313.

Outline








Prevalence of Elevated Blood Pressure by BMI Category

BMI Ranges Men Women

< 25 18.2 16.6

25 - 26 22.5 21.9

27 - 29 25.2 24.0

> 30 38.4 32.2

NHLBI Evidence Report 1988.

Outline








Mortality from Cancer in American Men and Women

Calle NEJM 2003;348:1625.

Men Women

• Liver• Pancreas• Stomach/Esophagus• Colon/Rectum• Gallbladder• Multiple Myeloma• Kidney• Non-Hodgkin’s• Prostate

• Uterus• Kidney• Cervix• Pancreas/Esophagus• Gallbladder• Breast• Non-Hodgkin’s• Liver• Ovary• Colon/Rectum

Outline• Overview of the Metabolic Syndrome

• Overview of Risks






• Answers to Questions and Summary

Other Increased Risks

• Kidney stones• Complications of pregnancy• Sleep disorders• Osteoarthritis• Stigmatization

Relative Risk

BMI Categories Men Women

< 21 0.73 1.15

21 - 22.9 1.00 1.00

23 - 24.9 0.94 1.26

25 - 27.4 1.20 1.34

27.5 - 29.9 1.24 1.75

> 30 1.33 1.90

Taylor et al JAMA 2005;293:455-462.

Body Mass Index and the Relative Risk of Symptomatic Kidney Stones

Pregnancy Complications in Obese and Overweight Nulliparous Women

BMI Categories

Complications < 2020 to 24.9

25 to 29.9 >30

Gestational Diabetes 1.0 1.3 2.4 5.2

Preeclampsia 1.0 1.3 2.0 3.3

Eclampsia 1.0 1.4 2.0 3.0

Caesarean 1.0 1.3 1.8 2.7

Baeten et al Am J Pub Health 2001;91:436-440.

Moderate Weight Change and Sleep Disordered Breathing

Weight Change (%)Apnea-Hypopnea Index

(Events/hour)

- 20 kg - 48

10 kg - 26

- 5 kg - 14

5 kg 15

10 kg 32

20 kg 70

Peppard et al JAMA 2000;284:3015-3021.

Adjusted Odds Ratio for Osteoarthritis by Tertiles of BMI

Tertiles of BMI Hand Hip Knee

1 1 1 1

2 5.4 3.4 3.8

3 8.3 1.4 9.3

Oliveria et al Epidemiology 1999;10:161.

BMI and Physical Functioning (SF-36)The Nurses Health Study

BMI Categories Relative Risk

< 21.9 0.94

22 - 23.9 1.00

24 - 24.9 1.05

25 - 27.9 1.23

28 - 29.9 1.49

30 - 34.9 1.66

35 - 39.9 2.08

> 40 3.08

Coakley et al IJO 1998;22:958-963.

Outline





Question # 1

Which of the following is not part of the Metabolic Syndrome?

1. High HDL-cholesterol (> 50 mg/dL)

2. High blood pressure (> 130/85)

3. High Triglyceride (> 150 mg/dL)

4. Impaired fasting glucose (100-126 mg/dL)

5. Increased waist circumference [> 88cm (F) 102cm (M)]

Question # 2

Which of the following is NOT an estimate of excess deaths from obesity?

1. 450,000

2. 365,000

3. 325,000

4. 275,000

5. 112,000

Question # 3

Which disease has the highest risk in association with obesity?

1. Breast cancer

2. Diabetes

3. Cardiovascular disease

4. Osteoarthritis

5. Kidney stones

Summary

• The metabolic syndrome defined as central adiposity, hypertension, impaired fasting glucose and dyslipidemia is a major risk factor for heart disease and diabetes

• Obesity shortens life and increases the number of excess deaths

• Diabetes, heart disease, osteoarthritis, cancer, kidney stones, complications of pregnancy, sleep apnea and impaired physical functioning are all associated with obesity

Health Risks and Comorbid Conditions

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