“Obesity and Chronic Diseases”

Colorado Center for Health WellnessNational Press Foundation

April 29, 2013

Robert H. Eckel, M.D.Professor of Medicine

Professor of Physiology and BiophysicsCharles A. Boettcher II Chair in Atherosclerosis

University of Colorado Anschutz Medical Campus

robert.eckel@ucdenver.edu

Medical Complications of Obesity

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndromepulmonary embolismPulmonary hypertension

Gall bladder disease

Gonadal abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndromeerectile dysfunction

Gout

Stroke

Diabetes

Osteoarthritis

Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate, thyroid

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Pancreatitis

Cognitive impairment

CHF, arrhythmias

Eckel RH, NEJM 358:1941, 2008

Eckel RH, NEJM 358:1941, 2008

Obesity and Cancer: Meta-analysis – 221 Datasets from 1966-2007

Renehan AG et al, Lancet 371:569, 2008

RR of Cancer in Men with a 5 Kg/m2

Increase in BMI

Renehan AG et al, Lancet 371:569, 2008

- 282,137 incident cases

RR of Cancer in Women with a 5 Kg/m2

Increase in BMI

Renehan AG et al, Lancet 371:569, 2008

- 126,804 incident cases

Obesity and a Strong RR (>1.2) of Cancer

• Men – Esophagus - adenoCa 1.52– Thyroid 1.33– Colon 1.24– Renal 1.24

• Women– Endometrial 1.59– Gallbladder 1.59– Esophageal - adenoCa 1.51– Renal 1.34

Renehan AG et al, Lancet 371:569, 2008

T47D Cancer Cells Stained with Oil Red O for Neutral Lipid

FDG PET Scans of Metastatic Prostate Cancer before and 24 Hours after Fatty

Acid Oxidation is Blocked

Basal FDG-PET Scan Etomoxir 24 hours

Obesity and Cancer Screening

http://www.cancer.gov

Hypertension and Obesity: NHANES III (1988-1994)

Brown CD et al, Obes Res 8:605, 2000

The Link Between Insulin Resistance and Endothelial Dysfunction

Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634.Caballero AE. Obesity Res. 2003;11:1278-1289.

Lipolytically Active Abdominal Adipose Tissue IL-1, IL-6, TNF

VasodilationShear StressInflammationAtherosclerosisThrombosisCRPPAI-1

Vascular Endothelium

©

Mechanisms Relating Obesity to Hypertension

Narkiewicz K et al Obes Rev 7:155, 2006

Ischemic Heart Disease Mortality vs Usual BP by Age

.

Prospective Studies Collaboration. Lancet. 360:1903, 2002

Systolic Blood Pressure Diastolic Blood Pressure

Usual diastolic BP (mm Hg)

50-59

60-69

70-79

80-89

Age (yr) at risk

40-49

80 90 100 11070

IHD mortality(floating absolute risk and 95% CI)

Usual systolic BP (mm Hg)

50-59

60-69

70-79

80-89

40-49

256

128

64

32

16

8

4

2

1

0120 140 160 180

Age (yr) at risk

BMI and Diabetes: A Large Effect!

BMI, body mass index. Willett WC et al. NEJM 341:427,1999

BMI (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 <21 22 23 24 25 26 27 28 29 30

Type 2 diabetes

Cholelithiasis

BMI (kg/m2)

Rel

ativ

e R

isk

4

6

5

3

2

1

0

Hypertension

Coronary heart disease23

Risk for Development of T2DM

0102030405060708090

100

Effect of BMI in Women

Attained BMI

<22 22- 23- 24- 25- 27- 29- 31- 33- >35 23 24 25 27 29 31 33 35

NHS. Ann Int Med 122:481, 1995

Age-adjustedRR(%) ofDevelopingT2DM over 14 yr in women aged 30-55 in 1976

Overweight 34%

Obese 31%2007

Natural History of T2DM:A Critical Understanding

75

Insulin resistance

RelativeFunction

(%) 5025

0

Years of Diabetes-15 -10 -5 0 5 10 15 20 25

ß-cell

IGT

Diabetes

100125

Glucose (mg/dL)

350

250

100

-15 -10 -5 0 5 10 15 20 25

Fasting glucose

Post-meal glucose

300

200150

Weyer C et al. J Clin Invest 104: 787, 1999

500

400

300

200

100

00 1 2 3 4 5

Insu

lin S

ecre

tio

n (U

/mL

)

Insulin Action (mg/kg EMBS per minute)

Normal Glucose Tolerance

Insulin Resistance

-C

ell

Fai

lure

ImpairedGlucose

ToleranceType 2

Diabetes

Pathogenesis: ß-Cell Compensationand Decompensation and T2DM

DPP:Mean Weight Change from Baseline

-8

-7-6

-5

-4-3

-2

-10

1

Wei

gh

t C

han

ge

(Kg

)

0 6 12 18 24 30 36 42 48Months

Lifestyle

Metformin

+Placebo

N= 3051 2865 1500 3857.2%

4.2%

NEJM 2002;346: 393

0 1 2 3 4

0

10

20

30

40

Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

All participants-2.8 years

Years from randomization

Cu

mu

lati

ve i

nci

den

ce (

%)

31% 58%

NEJM 346: 393, 2002

DPP: Diabetes Prevention

-10 -8 -6 -4 -2 0 2 4 6

6

11

16

metformin

placebo

Diabetes Risk by Weight Change in the DPP

Change from baseline weight (kg)

Dia

bet

es i

nci

den

ce /

100

per

s-yr

Diabetes 56:1153, 2007

Weight loss explained 64% of the risk reduction from metformin (a weight loss drug?)

Genetic Risk vs. Lifestyle in T2DM?Genetic Risk vs. Lifestyle in T2DM?(TCF7L2 SNP)

Genetic Risk vs. Lifestyle in T2DM?Genetic Risk vs. Lifestyle in T2DM?(TCF7L2 SNP)

Lifestyle intervention “trumps” genetic risk

Florez J et al, DPP Research Group, NEJM 355:241, 2006

Weight Loss in T2DM and Less CVD:Did Look AHEAD Answer All the

Questions?

• Primary Objective – To assess the long-term (11.5 yr) effects of an intensive weight

loss program over 4 years in overweight and obese subjects with type 2 diabetes.– n ~ 5000 men and women– age: 45-74 yr – BMI > 25 kg/m2– Primary outcome – time to a major CVD event– Secondary outcomes - many

Controlled Clin Trials 24:610, 2003

8%

Look AHEAD Research Group, 2011

Intensive Lifestyle Intervention (ILI)

Diabetes Support & Education (DSE)

0

10

20

30

40

50

60

70

80

90

100

> 0 % ≥ 10 % ≥ 5 % ≥ 7 %

74%

55%

46%

25%

35%

18%10%

23%

% o

f Par

ticip

ants

≥ 5 % ≥ 0%

18%

26%

45%

≥ 15 %

4%9%

Weight Gain Weight Loss

Percentage of Participants in ILI and DSE Groups Who Met Different Weight Loss

Criteria at Year 4

4-Year Weight Loss Outcomes

-6

-5

-4

-3

-2

-1

0

Overweight

Class I

Class II

Severe

Ch

ang

e in

bo

dy

we

igh

t (%

)

*

* Overweight significantly different from all other groups (p<0.001)

Look AHEAD Research Group, 2011

Revised NCEP ATP III LDL-C Goals

Circulation 2004; 110: 227

Moderately High

190* 0–1 RF’s

160*

2+ RF (10-20%/10 yr)

100* CHD or Risk Equivalent

(>20%/10 yr)

High(Very High)

ConsiderDrug Rx

CHD Risk Category

LDL-C Goal

<100(<70)

<130

<160

2+ RF (<10%/10 yr)

Moderate

Low

<130

130*

* Consider drug options if below goal, but above goal for next higher risk level

Metabolic Syndrome: Residual Risk

• April 2008– Known CHD

• On a statin

– LDL-C 67 mg/dl– TG 300 mg/dl– HDL-C 32 mg/dL– ETT – normal

• June 2008– AMI at work

• Resuscitation failed

• Could this have been avoided?Grady D. A Search for Answers in Russert’s Death. The New York

Times. June 17, 2008. Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.

The New Definition of The Metabolic Syndrome (3 or more)

Approved by NHLBI, AHA, IDF, IAS, World Heart Federation

• Abdominal circumference (1 of 5)– men > 94 cm– women > 84 cm

• adjusted locally around the world• Triglycerides > 150 mg/dl• HDL cholesterol

– men < 40 mg/dl– women < 50 mg/dl

• Blood pressure > 130/85• Glucose > 100 mg/dl

Eckel RH et al, Lancet, 375:181, 2010

39

Metabolic Syndrome is Designed for Lifestyle Intervention

• An intervention that improves the quality of the diet, increases physical activity and produces weight reduction often – waist circumference (+ visceral fat)– triglycerides– HDL cholesterol– blood pressure– glucose– inflammatory markers

Fatty Liver (Foie Gras)

Normal goose liver

Goose liver after 3 months of overfeeding and inactivity

Definition: NAFLD & NASH

• NAFLD = Non-Alcoholic Fatty Liver Disease– Spectrum includes

• Steatosis• Steatohepatitis• Fibrosis and cirrhosis

• NASH = Non-Alcoholic Steatohepatitis – Histological diagnosis

• Necro-inflammation• Fibrosis• Cirrhosis

– Histology similar to alcoholic hepatitis

Pathogenesis of NAFLD

-Neuschwander-Tetri, Hepatology, 2002

Pathogenesis of NAFLD

-Neuschwander-Tetri, Hepatology, 2002

“first hit”

Pathogenesis of NAFLD

-Neuschwander-Tetri, Hepatology, 2002

“second hit”

Prevalence of NAFLD

20-30% US adults60% of obese adults

Steatosis

-Neuschwander-Tetri, Hepatology, 2002-McCullough AJ. NAFLD: AASLD Symposium, Nov 9 2001

2-3% US adults20-25% of obese adults

NASH

-Neuschwander-Tetri, Hepatology, 2002-McCullough AJ. NAFLD: AASLD Symposium, Nov 9 2001

Prevalence of NAFLD

Cirrhosis and NAFLD

2-3% of obese adults

-Neuschwander-Tetri, Hepatology, 2002-McCullough AJ. NAFLD: AASLD Symposium, Nov 9 2001

Who should bescreened for NAFLD?

Patients at Higher Risk for NASH

• Obese (BMI > 30 kg/m2)– BMI > 25 < 30 kg/m2

• Diabetes mellitus (Type 2)

• HOMA > 1.64 (More insulin resistant)

• Family History

• Age > 50 yr

• Males > females

• Hispanic > White > Black

• Metabolic syndrome

Important Caveat

Standard blood tests for liver disease, may be completely

normal in many patients with NAFLD:

Even patients with NASH or advanced fibrosis due to

NASH!!!!

Abrams G, et al. Hepatology 2004;40:475

Obstructive Sleep Apnea-Hypopnea Syndrome

• Snoring• Severe sleepiness• Restless sleep• Night sweats• Morning dry mouth/sore throat• Nocturia• Morning headaches• Erectile dysfunction• Morning confusion• Personality change

Approach to the Obese Patient with Suspected OSAH

De Souza AGP et al, Obes Rev 10:1467, 2008

ANC = Adjusted Neck Circ

CVD Mortality and Obesity: Cancer Prevention Study II

0.6

1.0

1.4

1.8

2.2

2.6

3.0 Men (n=84,376)Women (n=217,857)

<18.5 22 25 30 35Body Mass Index (BMI)

Relative Risk of Death

Non-smokers Without known heart disease

Calle EE et al. NEJM 341:1097,1999

28

Metabolic Pathophysiology of Obesity and CVD

• Hypertension

• Dyslipidemia

• Inflammation

• Diabetes

77

4655

106

8997

128

110

83

Abdominal Obesity and Coronary Heart Disease in Women: The Nurses’ Health Study

LowMiddleHigh

High (81.8 - <139.7)

Middle (73.7 - <81.8)

Low (38.1 - <73.7)

(25.2 - <48.8) (22.2 - <25.2) (12.2 - <22.2)

Waist GirthTertiles (cm)

Inci

den

ce

rat

e p

er 1

00,

000

p

ers

on

-yea

rs

Body Mass Index Tertiles (kg/m2)

Follow-up of 8 years

140

120

100

80

60

40

20

0

Adapted from Rexrode KM et al. JAMA 280: 1843, 1998

CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin

Resistance, Hypertension)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Mea

n V

alu

e o

f L

og

CR

P

0 1 2 3 4

Number of Metabolic Disorders

Festa et al. Circulation 102:42, 2000

Hazard Ratio for the Risk of Diabetes Over 17 Years in Healthy Young Adults, According

to BMI in Adolescence and in Adulthood

Tirosh A et al. N EJM 364:1315, 2011

37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps

Hazard Ratio for the Risk of Coronary Heart Disease Over 17 Years in Healthy Young Adults, According

to BMI in Adolescence and in Adulthood

Tirosh A et al. N EJM 364:1315, 2011

37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps

Cardiac Abnormalities in Obesity• Coronary heart disease• Diastolic dysfunction• Left ventricular hypertrophy +/- failure

– eccentric– concentric

– adipositas cordis (cardiomyopathy of obesity)

• Right ventricular hypertrophy– Pulmonary hypertension

• obstructive sleep apnea• central hypoventilation• thromboembolic disease

– Deep venous thrombosis

• Autonomic dysfunction

• Arrhythmias, prolonged QTc, sudden death

Summary and Conclusions:Obesity and Co-Morbid Conditions Needing

Assessment

• Cancer risk

• Hypertension

• Diabetes

• Dyslipidemia

• Non-alcoholic fatty liver disease

• Obstructive sleep apnea-hypopnea

• Cardiovascular disease risk

• Symptom-based further evaluation prn

Thank You!