Obesity and Chronic Diseases

Colorado Center for Health Wellness National Press Foundation April 29, 2013
Robert H. Eckel, M.D. Professor of Medicine Professor of Physiology and Biophysics Charles A. Boettcher II Chair in Atherosclerosis University of Colorado Anschutz Medical Campus

robert.eckel@ucdenver.edu

Medical Complications of Obesity

Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome pulmonary embolism Pulmonary hypertension Idiopathic intracranial hypertension Stroke Cognitive impairment Cataracts Coronary heart disease CHF, arrhythmias Diabetes Hypertension Dyslipidemia Pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate, thyroid

Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis

Gall bladder disease Gonadal abnormalities abnormal menses infertility polycystic ovarian syndrome erectile dysfunction Osteoarthritis

Skin
Gout

Phlebitis venous stasis

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

- 282,137 incident cases

Renehan AG et al, Lancet 371:569, 2008

RR of Cancer in Women with a 5 Kg/m2 Increase in BMI

- 126,804 incident cases

Renehan AG et al, Lancet 371:569, 2008

Obesity and a Strong RR (>1.2) of Cancer

Men
Esophagus - adenoCa Thyroid Colon Renal 1.52 1.33 1.24 1.24
1.59 1.59 1.51 1.34

Women
Endometrial Gallbladder Esophageal - adenoCa Renal

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

Lipolytically Active Abdominal Adipose Tissue

IL-1, IL-6, TNFa

Vascular Endothelium

Vasodilation Shear Stress Inflammation Atherosclerosis Thrombosis CRP PAI-1

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

Mechanisms Relating Obesity to Hypertension

Narkiewicz K et al Obes Rev 7:155, 2006

Ischemic Heart Disease Mortality vs Usual BP by Age

Systolic Blood Pressure
256 128 Age (yr) at risk 80-89 70-79

Diastolic Blood Pressure

Age (yr) at risk 80-89

70-79
60-69 50-59 40-49

64
IHD mortality (floating absolute risk and 95% CI) 32 16 8 4

60-69
50-59

40-49

2
1 0

120 140 160 180 Usual systolic BP (mm Hg)

.

70 80 90 100 110 Usual diastolic BP (mm Hg)

Prospective Studies Collaboration. Lancet. 360:1903, 2002

BMI and Diabetes: A Large Effect!

Women
6
5

Men
6
5

4
3 2 1 0 <21 22 23 24 25 26 27 28 29 30

4
3 2 1 0 <21 22 23 24 25 26 27 28 29 30

BMI (kg/m2)
Type 2 diabetes Cholelithiasis

BMI (kg/m2)
Hypertension Coronary heart 23 disease

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

Risk for Development of T2DM

Effect of BMI in Women
100 90 80 Age-adjusted 70 RR(%) of 60 Developing 50 T2DM over 14 40 yr in women aged 30-55 in 30 20 1976 10 0

2007
Overweight 34%

Obese 31%

<22 22- 23- 24- 2523 24 25 27

27- 29- 31- 33- >35 29 31 33 35

Attained BMI
NHS. Ann Int Med 122:481,

Natural History of T2DM: A Critical Understanding

Glucose (mg/dL)

350 300 250 200 150 100 -15 125 100 75 50 25 0

Diabetes

Post-meal glucose Fasting glucose

IGT

-10

-5

10

15

20

25

Insulin resistance

Relative Function (%)

-cell

-15

-10

-5

10

15

20

25

Years of Diabetes

Pathogenesis: -Cell Compensation and Decompensation and T2DM

500

Insulin Secretion (mU/mL)

b-Cell Failure

400

300

Normal Glucose Tolerance Impaired Glucose Tolerance Type 2 Diabetes

0 1 2 3 4 5

200

100

Insulin Action (mg/kg EMBS per minute)

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

DPP:Mean Weight Change from Baseline

+1 0 -1 -2 -3 -4 -5 -6 -7 -8
Weight Change (Kg)

Placebo
Metformin Lifestyle 4.2%

7.2% N= 3051

2865

1500

385

12 18

24

30

36

42

48

NEJM 2002;346: 393

Months

DPP: Diabetes Prevention

All participants-2.8 years
Cumulative incidence (%)
40 Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac ) Metformin (n=1073, p<0.001 vs. Plac) Placebo (n=1082)

30

31% 58%

20

10

0 0
NEJM 346: 393, 2002

Years from randomization

Diabetes incidence / 100 pers-yr

Diabetes Risk by Weight Change in the DPP

16
Weight loss explained 64% of the risk reduction from metformin (a weight loss drug?)
placebo

11
metformin

6
-10 -8 -6 -4 -2 0 2 Change from baseline weight (kg) 4 6

Diabetes 56:1153, 2007

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

Percentage of Participants in ILI and DSE Groups Who Met Different Weight Loss Criteria at Year 4
100 90 80 % of Participants 70 60 50 40
45% 55% 46% 35% 26% 18% 8% 25% 18% 23% 10% 9% 4% 74%

Intensive Lifestyle Intervention (ILI) Diabetes Support & Education (DSE)

30
20 10 0 5% 0% >0% 5%

7%

10 %

15 %

Weight Gain

Weight Loss Look AHEAD Research Group, 2011

4-Year Weight Loss Outcomes

Change in body weight (%)
0 -1 -2 -3 -4 -5 -6 Overweight Class I Class II Severe

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

Look AHEAD Research Group, 2011

Revised NCEP ATP III LDL-C Goals

CHD Risk Category
High (Very High) Moderately High Moderate Low
CHD or Risk Equivalent
(>20%/10 yr)

LDL-C Goal
<100
(<70)

Consider Drug Rx
100*

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

<130 <130 <160

130*
160* 190*

2+ RF
(<10%/10 yr)

01 RFs

Circulation 2004; 110: 227

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

Metabolic Syndrome:
April 2008
Known CHD
On a statin

Residual Risk

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 Grady D. A Search for Answers in Russerts Death. The New York avoided?
Times. June 17, 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)

Goose liver after 3 months of overfeeding and inactivity

Normal goose liver

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

first hit

-Neuschwander-Tetri, Hepatology, 2002

Pathogenesis of NAFLD

second hit

-Neuschwander-Tetri, Hepatology, 2002

Prevalence of NAFLD

Steatosis

20-30% US adults 60% of obese adults

-Neuschwander-Tetri, Hepatology,

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

Prevalence of NAFLD

NASH 2-3% US adults 20-25% of obese adults

-Neuschwander-Tetri, Hepatology,

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

Cirrhosis and NAFLD

-Neuschwander-Tetri,

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

2-3% of obese adults

Who should be screened 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

ANC = Adjusted Neck Circ

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

CVD Mortality and Obesity:

Cancer Prevention Study II
Relative Risk of Death 3.0 2.6 2.2 1.8 1.4 Men (n=84,376) Women (n=217,857) Non-smokers Without known heart disease

1.0
0.6 <18.5 22 25 28 30 Body Mass Index (BMI) 35

Calle EE et al. NEJM 341:1097,1999

Metabolic Pathophysiology of Obesity and CVD

Hypertension Dyslipidemia Inflammation Diabetes

Abdominal Obesity and Coronary Heart Disease in Women: The Nurses Health Study
Incidence rate per 100,000 person-years
128 110
140 120

Follow-up of 8 years
83

106 89 77 46 55

97

100
80 60 40

Waist Girth Tertiles (cm)

High (81.8 - <139.7) Middle (73.7 - <81.8) Low (38.1 - <73.7)

20
0 High (25.2 - <48.8) Middle (22.2 - <25.2) Low (12.2 - <22.2)

Body Mass Index Tertiles (kg/m2)

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

CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin Resistance, Hypertension)
Mean Value of Log CRP

1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 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
37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps

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

Hazard Ratio for the Risk of Coronary Heart Disease Over 17 Years in Healthy Young Adults, According to BMI in Adolescence and in Adulthood
37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps

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

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!