Molecular and Clinical Nutrition Course

1
Molecular and Clinical Nutrition Course

• Obesity
• Frank Greenway, M.D.
• September 25, 2006

2
Overview

• What is obesity
• The extent of the problem
• Treatment
• Diet
• Behavior
• Medication
• Surgery

3
What is Obesity?

• Excess of body fat difficult to measure
• Clinical BMI in Kg/m2
• DEXA, densitometry and dilution methods
• Visceral fat insulin resistance
• Clinical Waist circumference
• Research CT or MRI scanning
• Ectopic fat associated with insulin resistance
  muscle, liver

4
Obesity is Common Costly

• The prevalence of obesity in the United States
  has increased from 14 in 1980 to 30 in 2000.
• The prevalence of diabetes follows the prevalence
  of obesity by 10-20 years
• Obesity, diabetes and cancer each cost the United
  States health care system 1 billion per year.

5
The Cost of Obesity Compared to other Chronic
Diseases

• 
  
• Billions
• Obesity 1 75.0
• Type 2 Diabetes 2 73.7
• Coronary heart disease 3 52.4
• Hypertension 4 28.2
• Arthritis 5 23.9
• Breast Cancer 6 7.1

1 Finkelstein EA, Obes Res 200412 4. Hodgson
TA et al. Med Care 200139599 2 ADA Diabetes
Care, 200326917 5 Yelin
Callahan. Arthritis Rheum 1995381351 3 Hodgeson
TA et al. Medical Care 199937994. 6Brown ML,
et al. Medical Care 200240(suppl) IV-104
6
Metabolic Syndrome

• Cardiovascular risk factors that occur together
  and relate to insulin resistance
• Definition controversial but involves enlarged
  waist, low HDL, high triglycerides, elevated
  fasting glucose and elevated blood pressure
• Not clear if risk greater than components
• 5-10 age 20-30 and 40 age 60-70

7
Prevalence of Obesity
30
25
Women
20
Percent
15
Men
10
5
0
1960
1970
1980
1990
2000
Year
CDC/NCHS
8
Prevalence of Obesity
USA
Australia
Population percentage with BMI 30 kg/m2
England
50
Mauritius
45
40
35
30
Brazil
25
20
15
10
2030
5
2025
2020
0
2015
2010
2005
2000
1995
1990
1985
1980
1975
1970
1965
1960
E249
IOTF/WHO, 1998
9
Prevalence of Diabetes Follows Obesity by 10 years
CDC website
10
Obesity A Chronic Disease

• Before NIH conference in 1985 obesity was
  considered to be just bad habits.
• Change in perception in 1994 by the demonstration
  of leptin deficiency in rats.
• Obesity is an excess of fat - hard to measure
• Body Mass Index (BMI) approximates body fat and
  obesity is a BMI over 30 kg/m2
• Obesity is stigmatized in our society and this is
  particularly true for women and children.

11
Relation between mortality and BMI
Data from Lew EA Mortality and weight insured
lives and the American Cancer Society studies.
Ann Intern Med 1031024-1029, 1985.
12
Mortality Body Mass Index
13
Mortality Diastolic Blood Pressure
14
Obesity Defined by Body Mass Index (BMI)
BMI Weight (kg)/Height (m2)
Behavioral Risk Factor Surveillance System, CDC
15
BMI Risk Categories

• 25-30 overweight
• 30-35 obese I
• 35-40 obese II
• 40
• If waist 35 in women or 40 in men or obesity
  related disease like diabetes present

• Diet and lifestyle
• Add medications
• Add medications
• Surgery
• Drop back one category

16
What Causes Obsity?

• Genetic causes do exist
• People with no leptin are fat and become normal
  when the leptin is replaced.
• Leptin gave obesity credibility as a disease
• Our genes did not change in the last 50 years,
  but obesity is rapidly increasing over that time
• There must be enviornmental factors.

17
Family Pedigree of Patients with a Mutated Leptin
Gene Ozata et al, JCEM 84 3686- , 1999
18
Patients Before Treatment
19
Body Weight Over the 3 First Months of Treatment
Male
Female
Female
20
After Ten Months of Treatment
21
Calcium and Risk of High Body Weight
Relative Risk for Highest Quartile of Body Fat
Quartiles of Calcium Intake
Zemel MB, et al. FASEB J. 2000.
22
Sugar and HFCS Consumption
125
100
Cane Sugar
75
Per capita (lb/yr)
50
High-Fructose
Corn Syrup
25
0
1965
1970
1975
1980
1985
1990
1995
2000
Year
USDA-ERS
23
Milk and Regular Soft Drink
Consumption
50
Soft Drinks
40
Per Capita Consumption
(gallons/y)
30
20
Milk
10
1970
1975
1980
1985
1990
1995
2000
Year
USDA
24
The Obesity Virus

• Adenovirus AD-36 was discovered about 1980 when
  the prevalence of obesity rose.
• Identical twins discordant for antibodies to the
  virus the positive twin is fatter
• Prevalence of antibodies to the virus is 20 in
  the obese and 5 in the lean.
• Even thin people positive for antibodies are
  fatter than those that are negative.

25
Diet

• Calorie intake must be less than caloric
  expenditure Calories DO count.
• Diet composition protein-fat-carbohydrate
• Calorie Controlled portions.
• The larger the meals the more trouble people have
  in estimating calories.
• Obese people eat larger meals.

26
Low Carbohydrate, High Fat, High Protein Diets

• High fat, low carbohydrate and high protein diets
  were popular in the 1970s with claims that
  calories do not count on these diets.
• Studies done on a metabolic ward showed that
  equal calories give equal fat loss.
• These diets were discouraged because their use
  was thought to increase cardiovascular risk,
  especially in regard to lipids.

27
Weight Loss Atkins Diet
28
Lipids and Cardiovascular Risk Improved
29
Safety of High Protein ad lib Fat

• 6-month trial (n65) more weight (8.8 vs. 5.1
  kg) loss, fat loss (7.6 vs. 4.3 kg), and
  triglyceride reduction.
• Increased GFR, kidney size and BUN but no change
  in albuminuria felt adaptive.
• No change in bone mineral content or homocysteine.

30
Low Fat Diets

• After a loss of 13 kg subjects on a low fat diet
  kept off more weight over 2 years than a balanced
  diet.
• 10 reduction in dietary fat produces a 4-5 kg
  weight loss in a person with a BMI of 30 kg/m2

31
Conclusions

• Over 6 months low carbohydrate, high fat, and
  high protein diets increase weight loss, give
  improvements in lipids and have no apparent risks
  on the kidneys, bone or homocysteine.
• High fat diets in the absence of a caloric
  deficit have been demonstrated to predispose to
  cardiovascular disease.
• High CHO diets are best for maintenance

32
Dietary Treatment with Calorie-Controlled
Portions

• 1200 kcal/d diet with 2 meals and 2 snacks
  replaced with calorie-controlled portions gave 5
  times more weight loss than an exchange diet over
  3 months.
• One meal and 1 snack replaced by calorie-
  controlled portions after the 3 month program
  gave a 9 weight loss at 1yr and an 11 at 2yr

33
3-Month 1200 kcal/d DietExchange vs. Calorie
Control
34
Slim Fast 1 Meal and 1 Snack Replacement
35
Olestra

• Olestra is made by esterifying sucrose with fatty
  acids
• Its characteristics depend on the length and
  saturation of the fatty acids
• It has the mouth feel and cooking characteristics
  of triglyceride
• It is not digested by intestinal lipase and thus
  can covertly replace fat in the diet

36
Ole Trial Change in Body Fat
0
-1
Fat-Reduced
-2
Control
-3
-4
Fat Loss from Baseline (kg)
-5
Fat-substituted
-6
-7
-8
0
3
6
9
Bray et al AJCN 2002
Months of Treatment
37
Exercise

• For purposes of maintaining a healthy weight,
  activity and exercise are the same.
• For the purposes of athletic competition no pain
  no gain may make sense.
• Calories are work
• Work is mass times distance (W M x D)
• One burns 2/3 of ones weight in calories for
  every mile walked or run. Running just takes
  less time

38
Activity (Exercise)

• If you weigh 150 pounds you will burn 100
  calories for each mile you walk or run.
• At 3 miles per hour, an hour a day of walking
  will burn 2,100 calories per week.
• It has been estimated that one needs to burn
  2,000 to 2,500 calories per week to maintain a
  weight loss.

39
Effect of walking on HDL Cholesterol
40
Exercise
41
Behavior Modification

• An education approach
• Use smaller plates, put food in opaque
  containers, set fork down between bites etc.
• An analytic approach
• Why do you eat after work? If you come home,
  turn on the TV, see food ads and then eat, try
  coming home and going for a walk. If it helps
  reduce eating, make it a habit.

42
Jenny Craig
43
Dietary Herbal Supplements

• In 1994 the Dietary Supplement Health and
  Edcucation Act (DSHEA) was passed declaring herbs
  are classified as food.
• The sponsor must prove a drug safe to the FDA to
  receive approval
• The FDA must prove a food is unsafe to remove it
  from the market.
• Dietary herbal supplements are popular, quality
  is unregulated, and studies sparce

44
Caffeine and Ephedrine as a Drug

• Caffeine 200 mg and ephedrine 20 mg three times a
  day were an approved prescription drug in Denmark
  for obesity treatment
• It had 80 of the market share even when
  dexfenfluramine was available.
• It has a history of safety and efficacy
• Up to twice this dose was used to treat asthma in
  US adults and children (1970s)

45
Caffeine Prevents Ephedrine Resistance
Ephedrine Norpinephrine
Catechins
Aspirin
Beta Receptor
Fat Loss
CAMP
PDE
Caffeine Aminophylline
46
Ephedrine and Caffeine are Synergistic at 20
mg/200 mg
47
Caffeine Ephedrine (200 mg/20 mg tid)
48
Adverse Events in Caffeine and Ephedrine Study
49
Loss/Kg Weight Loss Women Caff/Ephed Vs
Anorectics
50
Three-Month Study with Herbal Caffeine and Ephedra
51
Treating Obesity as a Chronic Disease with Drugs

• Drugs work only when taken
• Average weight in most studies is 100 kg
• The placebo group needs some treatment
• Weight loss usually plateaus at 6 months
• Europe A 10 weight loss
• USA 5 more loss than placebo
• Weight loss vs. weight maintenance.

52
Safety Issues

• Obesity treatment has a poor safety record
• Obesity is still viewed by many as a moral issue
  - gluttony and lack of will-power
• Obesity is stigmatized
• Desperate victims raise abuse concerns
• Therefore, obesity medications are held to a
  higher standard.

53
Obesity Drug Disasters

• 1893 Thyroid hormone hyperthyroidism
• 1933 Dinitrophenol cataracts, temp.
• 1937 Amphetamine - addiction
• 1967 Rainbow pills (digitalis, diuretics and
  amphetamine) cardiac arrhythmia, death
• 1971 Aminorex pulmonary hypertension
• 1997 Fenfluramine cardiac valvulopathy
• 2000 Phenylpropanolamine stroke
• 2004 Ephedra MI, stroke, psychiatric sx

54
Fenfluramine 1-Year Rx 1-Year Follow-up
55
No Behavior Modification
56
With Behavior Modification
57
Orlistat 120 mg/tid - Europe
58
Sibutramine - USA
59
Weight Maintenance Orlistat
60
Weight Maintenance Sibutramine
61
Drugs Approved for Obesity Before 1985

• Habits can be learned or extinguished over a
  period of up to 12 weeks.
• Obesity medications before 1985 were tested and
  approved for up to 12 weeks.
• Amphetamine-related Phentermine (IV),
  Diethylpropion (IV), Benzphetamine (III) and
  Phendimetrazine (III)
• Efficacy Drugs doubled weight loss/week

62
Phentermine and DiethylpropionDifference from
Placebo
63
Phentermine Continuous and Intermittent Treatment
Munro JF et al. Br Med J 1968 Feb
101(5588)352-4
64
Orlistat 120 mg tidDifference from Placebo
65
Drop in Cholesterol for Each Percent Weight Loss
66
Safety Orlistat

• An inhibitor of pancreatic lipase causing 1/3 of
  dietary fat to be lost in the stool
• Adverse events Diarrhea, Flatulence and
  Dyspepsia
• Reduction in total and LDL cholesterol and blood
  pressure
• Slight reduction in glucose and HgbA1c in
  diabetics and prevention of diabetes in IGT.

67
Over-The Counter Orlistat Alli
Rossner S et al. Obes Res 8(1)49-60, 2000.
68
Sibutramine 10-20 mg/d Difference from Placebo
69
Diastolic Blood PressureOrlitat Vs. Sibutramine
70
Safety Sibutramine

• Norepinephrine and serotonin reuptake inhibitor -
  terminates meal early
• Adverse events Dose-related dry mouth, insomnia
  and nausea
• Heart rate up 4 bpm and no consistent effect on
  blood pressure
• Slight improvement in glucose and HgbA1c in
  diabetics

71
Weight Loss with Combination Therapy
72
Phase II Qnexa Trial
Website
73
RimonabantA Cannabanoid-1 Antagonist

• CB-1 receptors in brain (wide distribution), gi
  tract, immune cells and adipose tissue
• CB-1 agonists activate mesolimbic dopaminergic
  reward system
• Rimonabant is 100x CB-1 receptor specific, and
  inhibits sweet intake (marmosets) and fat intake
  (mice)
• Adiponectin secretion and metabolism
  (pair-feeding) stimulated by rimonabant

74
Rimonabant, the First CB1 BlockerA Multi-impact
Medication

Rimonabant
Central
Peripheral
Brain
Adipocyte
CB1
CB1
? Food intake

• Adiponectin
• ? Insulin resistance
• ? Triglycerides
• ? Glucose tolerance
• ? HDL cholesterol

Weight loss
75
Weight Loss Rimonabant
76
Risk FactorsImprove More than Weight Loss

• HDL 56 weight independent
• Triglycerides 47 weight independent
• Insulin 50 weight independent
• Pulse and blood pressure improved unlike
  sibutramine

77
Metabolic Syndrome Prevalence Effect of
Rimonabant at 1 year (ITT analysis)
PVan Gaal et al. Lancet 20053651389-97
78
Rimonabant Adverse Events
79
Rimonabant Approvable

• Rimonabant weight loss is similar to sibutramine,
  but gives 2X the benefit of weight loss on
  triglycerides and HDL without benefit on blood
  pressure.
• Reduces metabolic syndrome by 50
• Received an approvable letter from FDA
• Rejected for smoking cessation.
• Depression and anxiety may be a concern

80
Weight Loss at 1 year
81
IMS Health, National Prescription Audit Plus7,
Years 1997 2003, Extracted March 2004, NPA
Plus Therapeutic Category Report, Years December
1966 -1996, Hard Copy Books
82
Cosmetic Concerns Drive Obesity Drug Sales

• 80 of the obesity drug prescriptions are written
  for women.
• Men have greater cardiovascular risk from obesity
  than women.
• Fat women are stigmatized more than fat men in
  our society.
• People say they want to lose weight for health
  reasons, but this is secondary.

83
IMS Health, National Disease and Therapeutic
Index, Years 1998-2003, Extracted September 2004
84
Obesity Drugs are Poorly Reimbursed by 3rd Party
Payors

• Most payors consider obesity a life-style
  disease and do not cover those expenses
• When payors do pay for obesity medication, it is
  often due to physicians writing letters
  explaining the medical complications that will
  improve with weight loss.
• Even when approved expenses or duration are often
  capped.

85
Weight Loss Drugs Add to Behavior Mod Meal
Replacement
Wadden TA et al. Arch Int Med. 161218-27, 2001
86
Sibutramine w/wo Behavior Modification vs
Behavior Alone
Wadden TA et al. NEJM 353(20)2111-20, 2005
87
Indications for Bariatric Surgery

• Body Mass Index (BMI) over 40 kg/m2 or a BMI of
  35 kg/m2 with obesity-related medical problems
  like diabetes that should improve with weight
  loss.
• It is recommended that candidates be failures to
  more conservative treatment, but conservative
  treatments are generally ineffective for people
  this obese.

88
Procedure Types

• Restrictive procedures like vertically banded
  gastroplasty or lap band give less weight loss.
• Restrictive and malabsorbtive procedures like the
  gastric bypass improve diabetes
  disproportionately to the weight loss they give.
  Due to hormonal changes from the bypass with
  increased GLP-1.

89
Weight LossBariatric Surgery and Medication
90
Complications ofBariatric Surgery
91
Advantages to Bariatric Surgery
92
Bariatric Surgerys Benefits On NIDDM
1Braddley 79, 1Sylvan 95, 2Hickey 98, 3Pories 95,
4Cowan 98, 5Pories 92, 6Long 94, 7McDonald 97,
8Yashkov 97, 9 Haciyanli 01 , 10Sjostrom 00,
11Scopinaro 98, 12Klein 02, 13Marceau 98,
14DeMaria 01, 15Dept. Of Health 00, 16Karason 00,
17DeMaria 01
93
Improving Complications

• Although the weight loss with restrictive
  bariatric surgery improves hypertension at 2
  years post-op, the blood pressure returns to
  normal by 8 years post-op despite a more than a
  20 weight loss.
• Improvement in HTN is sustained with bypasses
• A 12 weight loss prevents new cases of diabetes.

94
Roux-en-Y Gastric Bypass
Esophagus
Stomach
Duodenum
Roux Limb
Jejunum
Common Limb
95
Conclusions

• Bariatric surgery is indicated at a BMI of 40
  kg/m2 or 35 kg/m2 with complications.
• Gastric bypass, which can be done
  laparoscopically, is preferred in the US.
  Diabetes is improved, HTN improvement sustained,
  weight loss is greater and sustained, weight loss
  failures are fewer and revisionary surgery is
  less common.

96
Summary

• Obesity has long been viewed as just bad habits
  and a result of gluttony and sloth
• Evidence is mounting that weight is a
  physiologically controlled variable and obesity
  is a chronic disease
• Obesity associated diseases have good rxs, 5
  weight loss impacts risk factors and 12 needed
  to prevent diabetes.
• Combination rxs are giving better wt. loss.