obesity: past, present and future a multi-disciplinary approach to obesity indianapolis, indiana...
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Obesity: Past, Present and Future
A Multi-Disciplinary Approach to ObesityIndianapolis, IndianaOctober, 18 2012
George A. Bray, MDGeorge A. Bray, MD
Pennington CenterPennington Center
Baton Rouge, LABaton Rouge, LA
Obesity Has a Long HistoryObesity Has a Long History
The Distant PastThe Distant Past The Intermediate PastThe Intermediate Past TodayToday
Key MessagesKey Messages
Our diet has changed dramatically from Our diet has changed dramatically from the Distant Pastthe Distant Past
Humans have gradually conquered the Humans have gradually conquered the environment over the Intermediate Pastenvironment over the Intermediate Past
Today we have less physical activity; Today we have less physical activity; obesity that is subsidized by the farm obesity that is subsidized by the farm policies of the government; which at the policies of the government; which at the same time subsidizes research to prevent same time subsidizes research to prevent and treat it.and treat it.
OutlineOutline
Paleolithic ObesityPaleolithic Obesity Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine-HippocratesGreek Medicine-Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
Human Evolution as a 24 Hour Human Evolution as a 24 Hour ClockClock
Era Time Interval Clock Interval
Paleolithic 2.5 mya – 10 kya
23h 54 min
The Last 30 MinutesThe Last 30 Minutes
Today
50,000
40,000
30,000
10,000
20,000
Iron AgeBronze AgeNeolithic(New Stone Age)
Paleolithic(Old Stone Age)
Venus of Hohle FelsVenus of Hohle Fels
The Venus of Hohle Fels was found in 2008 in a cave in the Swabian region of Germany. It is made from a Mammoth ivory tusk. Radiocarbon dating places its origin 35,000 years ago. It has large breasts abundant abdomen and exaggerated female genitalia. It weighs 33 grams and is 6.0 cm tall
Conrad, NJ Nature 2009;459:248
Have You Ever Had a Llama Have You Ever Had a Llama Steak?Steak?
A young Llama in the higher ANDES mountains at about 12,000 feet. They are grass-fed and their steaks do not have the “melt in your mouth” we are used to from the corn-fed cattle that are fattened up before sending them to market
Wild Game and Domestic MeatWild Game and Domestic Meat
Average Content (per 100 g)
Wild Game * Domestic Meat **
Energy (kcal) 133.1 385.5
Protein (g) 21.9 15.8
Fat (g) 4.3 29.0
Cholesterol (mg) 67 75
* 43 species
** 4 varieties
Eaton SB, Shostak M, Konner M. The Paleolithic Prescription. New York: Harper & Row 1988
OutlineOutline
Paleolithic ObesityPaleolithic Obesity Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine - HippocratesGreek Medicine - Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
Human Evolution as a 24 Hour Human Evolution as a 24 Hour ClockClock
Era Time Interval Clock Interval
Paleolithic 2.5 mya – 10 kya
23h 54 min
Agricultural 10kya to present
6 min
70% of Modern Foods Come From 70% of Modern Foods Come From The Agricultural RevolutionThe Agricultural Revolution
Category Examples % of caloriesDairy Products Milk, cheese, butter 10.5%
Refined Sugars Sucrose, High fructose Corn Syrup, Syrups
18.6%
Cereal Grains Whole grains and Refined Grains
23.9%
Refined Vegetable Oils
Salad Oils, Cooking Oils, Shortening, Margarine
17.6%
Alcohol Wine, beer, distilled beverages
1.4%
Total Calories from these sources
72.1%
Cordain L, et al. Am J Clin Nutr. 2005;341-354.
Conclusions from PaleolithicConclusions from Paleolithicand Neolithic Periodsand Neolithic Periods
Obesity appeared early in human historyObesity appeared early in human history It can develop on any dietIt can develop on any diet Women more often represented as fatWomen more often represented as fat Associated with upper social classesAssociated with upper social classes Related to abundance of food and less Related to abundance of food and less
exerciseexercise It is increasing in prevalenceIt is increasing in prevalence It can be described in modern terms as a It can be described in modern terms as a
chronic, stigmatized, neurochemical diseasechronic, stigmatized, neurochemical disease
Obesity Has a Long HistoryObesity Has a Long History
The Distant PastThe Distant Past The Intermediate PastThe Intermediate Past TodayToday
OutlineOutline
Paleolithic ObesityPaleolithic Obesity Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine - HippocratesGreek Medicine - Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
The Last 1.5 MinutesThe Last 1.5 Minutes
Today
2,500
2,000
1,500
500
1,000
Roman Medicine
Greek Medicine
Columbus & AmericaRenaissance Middle Ages
Industrial RevolutionPrinting Press
Hippocrates
Four Humors & Four Elements Four Humors & Four Elements Whose Disorder Produced DiseaseWhose Disorder Produced Disease
Yellow Bile
Phlegmatic
BloodBlack Bile
(Fire)
(Earth)
Melancholy
(Water)
Sanguine(Air)
Dry
Cold Wet
Moist
Choleric
Hippocrates Was the Father Hippocrates Was the Father of Medicineof Medicine
Hippocrates (460-370 BC) is called the “Father of Medicine.” Born on the Island of Cos. His major achievements were: •To separate medicine from philosophy,•To give a scientific base for clinical care.•To give physicians a high moral inspiration.
National Library of Medicine
Hippocrates Approach to Diet Hippocrates Approach to Diet and Treating Obesityand Treating Obesity
[o]bese people and those desiring to lose [o]bese people and those desiring to lose weight should perform hard work before weight should perform hard work before food. Meals should be taken after exertion food. Meals should be taken after exertion and while still panting from fatigue and and while still panting from fatigue and with no other refreshment before meals with no other refreshment before meals except only wine, diluted and slightly cold.except only wine, diluted and slightly cold.
OutlineOutline
Paleolithic ObeistyPaleolithic Obeisty Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine – Hippocrates Greek Medicine – Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
The Last 20 SecondsThe Last 20 Seconds
1776-1795- French &1776-1795- French & American RevolutionsAmerican Revolutions
1500-1700 Age of exploration1500-1700 Age of exploration
1492 Columbus Discovers America1492 Columbus Discovers America1456 Printing press1456 Printing press
2000
1500
1600
1700
1900
1800
Regimine Sanitatis
World War II 1939-45World War I 1914-1918
Historical Events Afghanistan & Iraq
OutlineOutline
Paleolithic ObesityPaleolithic Obesity Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine – Hippocrates Greek Medicine – Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
Human Evolution as a 24 Hour Human Evolution as a 24 Hour ClockClock
Era Time Interval Clock Interval
Paleolithic 2.5 mya – 10 kya
23h 54 min
Agricultural 10kya to present
6 min
Industrial 300 yr 10 sec
The Last 16 SecondsThe Last 16 Seconds
1776-1795- French &1776-1795- French & American RevolutionsAmerican Revolutions
1500-1700 Age of exploration1500-1700 Age of exploration
1492 Columbus Discovers America1492 Columbus Discovers America1456 Printing press1456 Printing press
2000
1500
1600
1700
1900
1800
Santorio
World War II 1939-45World War I 1914-1918
Historical Events Afghanistan & Iraq
Santorio “Father of Metabolism” Santorio “Father of Metabolism” Sitting on His Scale with His FoodSitting on His Scale with His Food
Santorio, Father of Metabolism, used thisscale to measure theeffects on his weightof food intake andlosses of body fluid.He introduced insensiblelosses of fluid. Correcting this was the basis for treating disease.
Santorio, Ars Medica 1614Frontespiece from his book
OutlineOutline
Paleolithic ObesityPaleolithic Obesity Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine – Hippocrates Greek Medicine – Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
The Last 8 SecondsThe Last 8 Seconds
2000
1750
1800
1850
1950
1900
Vietnam WarWorld War IIWorld War I
Civil War 1861-65
American ConstitutionRevolutionary War (1776-81
Historical Events Afghanistan & Iraq
Diets Have a Long History Diets Have a Long History 1863 to 19291863 to 1929
Author Year Calories Protein
Banting 1863 1100 (1600) 172
Bouchard 1890 1250 83
Oertel 1895 1180-1600 170
Ebstein 1904 1300 102
v. Noorden 1910-20 1300 90-120
Dujardin-Beaumertz 1924 1457 116
Evans & Strang 1929 360 58
Grafe E, et al. Metabolic Diseases and their Treatment 1934; p 168.
From There to 99.99% Here: From There to 99.99% Here: SummarySummary
Obesity has been present since the Paleolithic Obesity has been present since the Paleolithic times in all cultures & on all dietstimes in all cultures & on all diets
The agricultural revolution changed 75% of our The agricultural revolution changed 75% of our diet as did the industrial revolution to followdiet as did the industrial revolution to follow
The Four Humors were the basis for treating The Four Humors were the basis for treating obesity from the time of Hippocrates into the obesity from the time of Hippocrates into the 1919thth century century
Modern “obesity” begins about 1850 as do Modern “obesity” begins about 1850 as do modern dietsmodern diets
Obesity Has a Long HistoryObesity Has a Long History
The Distant PastThe Distant Past The Intermediate PastThe Intermediate Past TodayToday
OutlineOutline
Paleolithic ObesityPaleolithic Obesity Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine – Hippocrates Greek Medicine – Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
Human Evolution as a 24 Hour Human Evolution as a 24 Hour ClockClock
Era Time Interval Clock Interval
Paleolithic 2.5 mya – 10 kya
23h 54 min
Agricultural 10kya to present
5 min
Industrial 300 yr 10 sec
20th Century
100 yr 3 sec
The Last 3 SecondsThe Last 3 Seconds
LeptinLeptinDoubly-labeled WaterDoubly-labeled WaterObesity EpidemicObesity EpidemicLifestyle therapyLifestyle therapyGastric BypassGastric BypassMetabolic chambersMetabolic chambersCentral AdiposityCentral AdiposityWorld War IIWorld War II
World War IWorld War ICushing’s SyndromeCushing’s SyndromeBabinski-FrohlichBabinski-Frohlich
2000
1900
1920
1940
1980
1960
History & Obesity
Activity
TEF
Basalmetabolic
rate
Intake Expenditure
INDIVIDUAL INFLUENCES Genetic/Epigenetic
Stable
Wt Gain Wt Loss
Fat
Carb
Protein
ENVIRONMENTAL & SOCIETAL INFLUENCES
Activity
TEF
Basalmetabolic
rate
Intake Expenditure
INDIVIDUAL INFLUENCES Genetic/Epigenetic
Stable
Wt Gain Wt Loss
Fat
Carb
Protein
ENVIRONMENTAL & SOCIETAL INFLUENCES
Heritability of Body Weight
Bjoreson M Acta Paediatr Suppl. 1962 May;132:1-76
Twins:
Fraternal
Identical
Genetics of Childhood ObesityGenetics of Childhood Obesity
5092 twin pairs from the Twins Early 5092 twin pairs from the Twins Early Development Study aged 8.3-11.6 y Development Study aged 8.3-11.6 y
Heights, weights and waist circumference were Heights, weights and waist circumference were higher than 1990.higher than 1990.
Heritability was 77% for BMI and 76% for waist Heritability was 77% for BMI and 76% for waist circumferencecircumference
Genetic influence on waist circumference was Genetic influence on waist circumference was largely in common with BMI (60%), but there largely in common with BMI (60%), but there was an independent 40%. was an independent 40%.
Wardle J et al Am J Clin Nutr 2008;398-404
<3 4 5 6 7 8 9 10 11 12 >13Weighted number or Risk Alleles
Nu
mb
er o
f In
div
idu
als A
verage B
MI (kg
/m2)
24.5
27.5
27.0
26.5
26.0
25.5
25.0
3000
2000
1000
0
Willer et al Nat Med 2009;41:25-34
BMI Increases as Number of Alleles Increase
Activity
TEF
Basalmetabolic
rate
Intake Expenditure
INDIVIDUAL INFLUENCES Genetic/Epigenetic
Stable
Wt Gain Wt Loss
Fat
Carb
Protein
ENVIRONMENTAL & SOCIETAL INFLUENCES
Body weight is a regulated system
0 12 24 36 48 60 72 84 96 108-10
-8
-6
-4
-2
0
Placebo
Rimonabant 5 mg
Rimonabant 20 mg
Placebo
Weeks of Treatment
Wei
gh
t L
oss
(kg
)
Pi-Sunyer et al JAMA 2006;761-775
Brain
Central signalsStimulate
NPYAGRP
CannabinoidsOrexin-A
Dynorphin
Inhibit-MSH
CRH/UCNGLP-ICART
NE5-HT
External factors
EmotionsFood characteristicsLifestyle behaviorsEnvironmental cues
Peripheral signals Peripheral organs
Food intake
Glucose
CCK, GLP-1, Apo A-IVVagal afferents
Insulin
Leptin
Cortisol
–
–
+
Gastrointestinal tract
Adipose tissue
Adrenal glands
Ghrelin+
Food Intake Regulation Is Complex
Energyout
Activity
TEF
Basalmetabolic
rate
Intake Expenditure
INDIVIDUAL INFLUENCES Genetic/Epigenetic
Stable
Wt Gain Wt Loss
Fat
Carb
Protein
ENVIRONMENTAL & SOCIETAL INFLUENCES
Energy Intake 1910-2000: Energy Intake 1910-2000: More Food After 1970More Food After 1970
1900 1920 1940 1960 1980 20002000
2200
2400
2600
2800
3000
3200
3400
3600
3800
4000
Year
En
erg
y (k
cal/
d)
Corrected for Waste
Total Consumption – Uncorrected for waste
Putnam JJ Food Rev 2002;25:2-15
Classic CokeClassic Coke8 fluid oz8 fluid oz
100 kcal1950
Extreme Gulp52 fluid oz
2002
630 kcal
Increased Portion Size Is One Increased Portion Size Is One ProblemProblem
12 oz Coke = 150 kcal
Fruit Drink & Soft Drink Consumption Fruit Drink & Soft Drink Consumption 1977-20011977-2001
0
2
4
6
8
10
Fruit Drinks Soft Drinks Total
1977-781989-911994-961999-01
% o
f T
ota
l Cal
ori
es
Nielsen SJ Am J Prev Med 2004;27:205-210
Activity
TEF
Basalmetabolic
rate
Intake Expenditure
INDIVIDUAL INFLUENCES Genetic/Epigenetic
Stable
Wt Gain Wt Loss
Fat
Carb
Protein
ENVIRONMENTAL & SOCIETAL INFLUENCES
Decline in Physical Activity Decline in Physical Activity During Adolescence in GirlsDuring Adolescence in Girls
0 1 2 3 4 5 6 7 8 9 10 110
10
20
30
40
50WhiteBlack
ME
T t
imes
/wk
Study YearAge 9/10 11/12 13/14 15/16 17/18 16/17 18/19
Kimm et al NEJM 2002;347:709-715
Sedentary Activity Increased from 1960 to 2010
Church TS et al PLoS One. 2011;6(5):e19657.
Activity
TEF
Basalmetabolic
rate
Intake Expenditure
INDIVIDUAL INFLUENCES Genetic/Epigenetic
Stable
Wt Gain Wt Loss
Fat
Carb
Protein
ENVIRONMENTAL & SOCIETAL INFLUENCES
Factors Affecting Energy Factors Affecting Energy BalanceBalance
Food IntakeFood Intake Energy ExpenditureEnergy Expenditure Sleep DeprivationSleep Deprivation Ambient TemperatureAmbient Temperature Maternal ageMaternal age MedicationsMedications Breast FeedingBreast Feeding Maternal SmokingMaternal Smoking
Prevalence of Obesity by Smoking Prevalence of Obesity by Smoking Status of Mother – Children Age 5-6Status of Mother – Children Age 5-6
0
10
20Never SmokedEarly PregnancyThru Pregnancy
Overweight Obese
Pre
vale
nce
(%
95%
CI)
Toschke et al Am J Epidemiol 2003;158:1068-1074
Breast Feeding and ObesityBreast Feeding and Obesity
Duration of breast feeding
Prevalence of obesity At age 6
None 4.5%
3 months 3.8%
3-5 months 2.3%
6-12 months 1.7%
> 12 months 0.8%
Von Kries et al BMJ 1999;319:147
Sekine et al Child Care Health Dev 2002;28:163-170
Overweight BMI > 25 kg/m2
N = 8274 children
0
1
2
3
4
5
6
<8 8-9 9-10 >10
Hours of Sleep
Od
ds
Rat
io a
ge
6-7
ySleep Debt and Body Weight: Sleep Debt and Body Weight:
The Toyama StudyThe Toyama Study
Medications and Weight GainMedications and Weight Gain
Anti-psychotics, particularly the second Anti-psychotics, particularly the second generation produce significant weight gain (4 generation produce significant weight gain (4 kg in 10 wks for olanzepine and clozepine)kg in 10 wks for olanzepine and clozepine)
SSRI are less consistentSSRI are less consistent Beta-blockers produce 1.2 kg increaseBeta-blockers produce 1.2 kg increase Data on oral contraceptives are less Data on oral contraceptives are less
consistentconsistent
Activity
TEF
Basalmetabolic
rate
Intake Expenditure
INDIVIDUAL INFLUENCES Genetic/Epigenetic
Stable
Wt Gain Wt Loss
Fat
Carb
Protein
ENVIRONMENTAL & SOCIETAL INFLUENCES
The Network for Spread of The Network for Spread of Obesity: The Framingham StudyObesity: The Framingham Study
[close]•Slide
Christakis NA & Fiowler JH NEJM 2007;350:370-379
Obesity Is Contagious
Obesity spread among the 12,067 people in Obesity spread among the 12,067 people in this network this network
One’s chances of obesity (BMI<30kg/mOne’s chances of obesity (BMI<30kg/m22) ) increased by:increased by: 57% if a friend became obese; 57% if a friend became obese; 40% if an adult sibling became obese;40% if an adult sibling became obese; 37% if a spouse became obese37% if a spouse became obese
Christakis & Fowler NEJM 2007;357:370-9
OutlineOutline
Paleolithic ObesityPaleolithic Obesity Neolithic Agriculture & Obesity Neolithic Agriculture & Obesity Greek Medicine – Hippocrates Greek Medicine – Hippocrates Middle Ages/Renaissance & ObesityMiddle Ages/Renaissance & Obesity Obesity in the 17Obesity in the 17thth and 18 and 18thth Century Century Obesity in the 19Obesity in the 19thth Century Century Obesity is HEREObesity is HERE
Obesity Has Many Complications
Phlebitisvenous stasis
Coronary heart disease
Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome
Gall bladder disease
Gynecologic abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome
Gout
Stroke
Diabetes
Osteoarthritis
Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate
Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension
Dyslipidemia
Cataracts
Skin
Idiopathic intracranial hypertension
Severe pancreatitis
Disease Prevalence
Diabetes (Type 2) 15.3%
Impaired Glucose Tolerance 25.8%
Sleep Disordered Breathing 19.6%
Hypertension 35.4%
Dyslipidemia 35.6%
Degenerative Joint Disease 50.3%
Depression 17.4%
Gastroesophageal reflux 43.3%
Buchwald H, et al JAMA 2004;292:1724-1737
Prevalence of Chronic Diseases in Prevalence of Chronic Diseases in Patients Undergoing Bariatric SurgeryPatients Undergoing Bariatric Surgery
Small Weight Losses Are Beneficial:
The Diabetes Prevention Program
-8
-7-6
-5
-4-3
-2
-10
1
Wei
gh
t C
han
ge
in D
PP
(K
g)
0 6 12 18 24 30 36 42 48
Months in study
Lifestyle
+
Placebo
Reduces Risk of Diabetes by 58%
DPP N Engl J Med 2002;346(6): 393-403
Redrawn from: Hamman RF et al. Diabetes Care. 2006;29(9):2102–2107.
How Much Weight Loss Is Needed How Much Weight Loss Is Needed to Prevent Type 2 Diabetes?to Prevent Type 2 Diabetes?
Change in Weight From Baseline (kg)
0-10 -5 +5
Inci
den
ce
Rat
e
pe
r 1
00
Pe
rso
n-Y
ea
rs
10
20
15
5
0
Redrawn from: Hamman RF et al. Diabetes Care. 2006;29(9):2102–2107.
Criteria for Successful Weight Loss: Criteria for Successful Weight Loss: The Diabetes Prevention ProgramThe Diabetes Prevention Program
Change in Weight From Baseline (kg)
0-10 -5 +5
Inci
den
ce
Rat
e
pe
r 1
00
Pe
rso
n-Y
ea
rs
10
20
15
5
0
GoodExcellent
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
Weight Change with Anti-Diabetic Weight Change with Anti-Diabetic DrugsDrugs
Weight Gain Weight Neutral
Weight Loss
Insulin DPP-4 Inhibitors Metformin
Sulfonylureas Acarbose Pramlintide
Glitinides Miglitol Exenatide
Thiazolidinediones Bromocriptine Liraglutide
DPP Research Group. Lancet. 2009;374(9702):1677–1686.
Metformin and Lifestyle Reduce Weight Over Time in DPP
–8
–6
–4
–2
0
2
Cha
nge
in W
eigh
t (kg
)
0 1 2 3 4 5 6 7 8 9 10
Years Since DPP Randomization
Placebo
Metformin
Lifestyle
Pramlintide: An Amylin AnalogPramlintide: An Amylin Analog
An analog of amylin that overcomes the tendency of human amylin to:An analog of amylin that overcomes the tendency of human amylin to:
– Aggregate, form insoluble particles Aggregate, form insoluble particles – Adhere to surfacesAdhere to surfaces
Pharmacokinetic and pharmacodynamic properties similar to Pharmacokinetic and pharmacodynamic properties similar to human amylinhuman amylin
Human amylin Pramlintide (analog of amylin)
Amide
S S AYTNSG
V NT
T T T
N
A A A
LI
K SS
CC Q
RL N
NNFG
FL
VH
Amide
PP PYTNSG
VNT
T T T
N
A A A
LI
K SS
CC Q
RL N
NNFG
FLVH
Adapted from Young A, et al. Drug Dev Res 1996; 37:231-248
Adapted from Westermark P, et al. Proc Natl Acad Sci 1990; 87:
5036-5040
0 2 4 6 8 10 12-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
BID Regimen TID Regimen
Time (Months)
Me
an
(S
E)
Pe
rcen
t C
ha
ng
e
in B
od
y W
eig
ht
(%)
Placebo
120 mcg
240 mcg
360 mcg
0 2 4 6 8 10 12-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
ITT Pop (N=59-34/group)
ITT Pop (N=18-27/group)
ITT Pop (N=18-38/group)
Extension (wt maint.)
ITT Pop (N=62-37/group)
Time (Months)
Extension (wt. Maint.)Phase 2b Phase 2b
Randomized 24 Week Trial of Pramlintide with 52-Week Extension
% CHANGE IN WEIGHT (ITT Populations, Observed Data)
Smith SR et al Diabetes Care 2008;31:1816–1823,
0 10 20 30-15
-10
-5
0
Placebo
Pramlintide
Pram + Phen
Weeks of Treatment
Wei
gh
t L
oss
(kg
)
Combination of Pramlintide and Phentermine on Body Weight
Aronne L et al Obesity 2010;18:1739-1746
Glucagon-Like Peptide 1
GLP-1 is the 7-36 amino acid sequence of GLP-1 is the 7-36 amino acid sequence of glucagonglucagon
It is an incretin that is released from the L-It is an incretin that is released from the L-cells of the intestine and enhances insulin cells of the intestine and enhances insulin release in the presence of glucoserelease in the presence of glucose
It reduces glucagon release from the It reduces glucagon release from the αα-cells-cells It slows gastric emptyingIt slows gastric emptying It reduces food intakeIt reduces food intake
ExenatideExenatide
Chen YE, et al. J Biol Chem.1997;272:4108-4115; Knudsen LB, et al. J Med Chem. 2000;43:1664-1669.
LiraglutideLiraglutide
• Based on human GLP-1 (7-37)• 97% homologous with GLP-1• Resistant to DPP-4• Full agonist at the GLP-1 receptor• Noncovalent binding to albumin, self-
association, slow release from injection site gives prolonged survival time
• t½ 12 hr after sc injection
▪ From saliva of the Gila Monster▪ 53% homologous with GLP-1
▪ Insensitive to DPP-4▪ Full agonist at the GLP-1 receptor
▪ Metabolically stable • t½ 4-5 hr after sc injection
Conserved Substituted Additional relative to human GLP-1 (7-37)
0 10 20 30 40 50 60 70 80 90
Mea
n
Wei
gh
t (k
g)
Exenatide Reduces Body Weight in Placebo Controlled & Open-Label Trial
Time (wk)
Baseline Weight
98 kg100 kg100 kg
Placebo BID5 µg Exenatide BID10 µg Exenatide BID
-5
-4
-3
-2
-1
0
1
82-wk completers; N = 393; Mean ± SE; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc.
Open-Label ExtensionPlacebo-Controlled
Liraglutide Produces Dose-Related Weight Loss
-5 0 5 10 15 20-10
-8
-6
-4
-2
0Placebo1.2 mg/d1.8 mg/d2.4 mg/d3.0 mg/dOrlistat
Ran
dom
izat
ion
Scr
eeni
ng
Weeks from Randomization
Wei
gh
t L
oss
(kg
)
Astrup A et al Lancet 2009;374:1606-1616
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
Weight Change with Some Neurobehavioral Drugs
Weight Gain Weight Neutral
Weight Loss
Tricyclics Haloperidol Bupropion
Lithium Aripiprazole Venlafaxine
Escitalopram Paroxetine Desvenlafaxine
MAO Inhibitors Mitrazepine Topiramate
Olanzapine/Clozapine Lamotrigine
Ritalin Zonisamide
Resperidone Ziprazidone
Valproate
Carbamazepine
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
0
4
8
12
16
20
24
28
32
0 4 8 12 16 20 24 28 32 36
Time in Weeks
Continuous Phentermine
Alternate Phentermine & Placebo
Placebo
5
10
We
igh
t lo
ss
(k
g)
We
igh
t lo
ss
(lb
s)
0
Phentermine: A Norepinephrine Reuptake Inhibitor
Munro JF et al BMJ 1968;1:352-4
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
Weight Loss Over Two Years with Orlistat:
Integrated Database
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104
Week
% W
eig
ht
Lo
ss
Placebo
120 mg
60 mg
Hauptman Data on file Hoffmann-La Roche
A Meta-analysis of Weight Loss with A Meta-analysis of Weight Loss with Orlistat Orlistat
Adapted with permission from Padwal R, et al. Int J Obes Relat Metab Disord. 2003;27:1437-1446.
Kelley, 2002*Broom, 2002
Hauptman, 2000Finer, 2000Davidson, 1999Sjöström, 1998Hollander, 1998*
Rossner, 2000Bakris, 2002
Miles, 2002*
Total (95% CI)
Lindgarde, 2000
WMD (Random)95% CIStudy or Subcategory
*All subjects had type 2 diabetes.
WMD = weighted mean difference.FavorsTreatment
FavorsControl
-10 -5 0 105
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
Topiramate + Phentermine
Phentermine stimulates NE ( norepinephrine) Phentermine stimulates NE ( norepinephrine)
release from hypothalamic neuronsrelease from hypothalamic neurons
It is approved for obesity but only short termIt is approved for obesity but only short term
Topiramate approved for epilepsy and migraineTopiramate approved for epilepsy and migraine
It also produces weight lossIt also produces weight loss
Once-a-day, oral formulation of phentermine and Once-a-day, oral formulation of phentermine and
controlled-release developed to reduce adverse controlled-release developed to reduce adverse
side effectsside effects
Weeks of Treaatment
Wei
gh
t L
oss
(%
)
0 8 16 24 32 40 48 56-16
-14
-12
-10
-8
-6
-4
-2
0Placebo
Phen 7.5 + Top 46 mg
Phen 15.0 + Top 92.0 mg
Weight Loss During Treatment with Phentermine/Topiramate
ITT
Gadde K. et al Lancet 2011;377:1341-1352
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
Lorcaserin – Selective Approach to the Serotonin Receptor
Serotonin reduces food intakeSerotonin reduces food intake Brain 5-HT2C receptors mediate this effectBrain 5-HT2C receptors mediate this effect 5-HT2B receptors are associated with 5-HT2B receptors are associated with
valvulopathyvalvulopathy 5-HT2C receptor knock-out leads to obesity5-HT2C receptor knock-out leads to obesity Lorcaserin selectively targets the 5-HT2C receptorLorcaserin selectively targets the 5-HT2C receptor
~100-fold selectivity over 5-HT2B receptor~100-fold selectivity over 5-HT2B receptor ~15-fold selectivity over 5-HT2A receptor~15-fold selectivity over 5-HT2A receptor
Lorcaserin has not been found to be associated Lorcaserin has not been found to be associated with valvulopathywith valvulopathy
Smith SR, et al. NEJM. 2010;363:245-256.
0 8 16 24 32 40 48 56 64 72 80 88 96 104-12
-10
-8
-6
-4
-2
0
Placebo
Continuous
Cross-Over
Weeks of Treatment
Wei
gh
t L
oss
(kg
)Weight Loss in CompletersTreated
with Lorcaserin
Placebo N = 684Cross-over N = 275Continuous N = 564
Smith SR et al NEJM 2010; 363:245-256
Obesity Is HERE - Drug TherapyApproved Drugs That Produce Weight Loss
In Diabetic PatientsIn Neurobehavioral Disorders
In Obesity Sympathomimetics Orlistat Topiramate/Phentermine Lorcaserin – Serotonin agonistDrugs in Limbo Bupropion/Naltrexone
Bupropion and Naltrexone
Bupropion is a norepinephrine reuptake Bupropion is a norepinephrine reuptake inhibitor that is approved for smoking inhibitor that is approved for smoking cessation and depressioncessation and depression
Naltrexone used to counteract opioid Naltrexone used to counteract opioid drugsdrugs
0 8 16 24 32 40 48 56-10
-8
-6
-4
-2
0
Placebo
NB 16
NB 32
Weeks of Treatment
Wei
gh
t L
oss
(%
)
Weight Loss in Completers TreatedWith Naltrexone-Bupropion
Placebo N = 507NB 16 N = 467NB 32 N = 467
Bupropion 360 mg/dDrop-outs [ 50%
Greenway FL, et al. Lancet. 2010;376:595-605.
Unintended Consequences During Treatment of Obesity
YearYear DrugDrug ConsequenceConsequence
18921892 ThyroidThyroid HyperthyroidismHyperthyroidism
19321932 DintrophenolDintrophenol Cataracts/NeuropathyCataracts/Neuropathy
19371937 AmphetamineAmphetamine AddictionAddiction
19681968 Rainbow PillsRainbow Pills Deaths-ArrhythmiasDeaths-Arrhythmias
19711971 AminorexAminorex Pulmonary HypertensionPulmonary Hypertension
19851985 Gelatin-based VLCDGelatin-based VLCD CV DeathsCV Deaths
19971997 Phen/FenfluraminePhen/Fenfluramine ValvulopathyValvulopathy
19981998 PhenylpropanolaminePhenylpropanolamine StrokesStrokes
20032003 Ma HuangMa Huang Heart attacks/strokeHeart attacks/stroke
20072007 EcopipamEcopipam DepressionDepression
Surgery for Obesity in the U.S.
Steinbrook NEJM 2004;350:1075-1079; MarketData 17 April 2007
1991 1993 1995 1997 1999 2001 2003 2005 20070
20000
40000
60000
80000
100000
120000
140000
160000
180000
Year
No
Su
rger
ies
in U
.S.
GASTRIC BANDING
VERTICAL BANDEDGASTROPLASTY
SkinSubcutaneous Pouch
PANCREATICO-DUODENALBYPASS
JEJUNO-ILEALBYPASS
GASTRICBYPASS
Bariatric Operations
10-Year Weight Loss in SOS
0 2 4 6 8 10-50
-40
-30
-20
-10
0
10
Years of Follow-up
Wei
gh
t L
oss
(%
)
Sjostrom et al NEJM 2004:351:2683
Control
Gastric By-Pass
V-Band Gastroplasty
Banding
0 6 12 18 24-30
-25
-20
-15
-10
-5
0
Surgical
Non-surgical
Time in Months
% W
eig
ht
Lo
ss
O’Brien et al Ann Int Med 2006;144:625-633
Weight Loss in Patients with BMI Between 30 and 35
2- Year Effect of Lap-Band or Lifestyle on weight Loss and Diabetes Remission
Surgery Lifestyle-30
-20
-10
0
Weight Loss
2-yr
Wei
ght
Loss
(kg)
Surgery Lifestyle0
25
50
75
Diabetes RemissionPe
rcen
tR
emis
sion
inD
iabe
tes
BMI Range -30-40 kg/m2Age 20-60; Diagnosis of Diabetes within 2 years
Dixon JB et al JAMA 2008;299:316-323
Two and Ten Year Incidence of Diseases in the SOS
0
5
10
15
20
25
30
High TG Low HDL High Uric Acid
Inci
den
ce (
%)
ControlSurgery
2-Year 10-year 2-year 10-year 2-year 10-year
High-TG Low HDL High Uric Acid Sjostrom et al NEJM 2004:351:2683
Obesity Is Here – The Last 0.01%:Summary
Obesity results from an imbalance in energy intake Obesity results from an imbalance in energy intake and expenditure in genetically susceptible peopleand expenditure in genetically susceptible people
Obesity spreads from person to person among close Obesity spreads from person to person among close contactscontacts
Obesity has a major predictor of diabetesObesity has a major predictor of diabetes Modest weight loss is beneficial and can be Modest weight loss is beneficial and can be
achieved by many strategies, including lifestyle achieved by many strategies, including lifestyle changes, diet, exercise, pharmacotherapy surgerychanges, diet, exercise, pharmacotherapy surgery
Adherence is the major criterion for successful Adherence is the major criterion for successful weight lossweight loss
Unintended consequences of treatment for obesity Unintended consequences of treatment for obesity continue to be a therapeutic problemcontinue to be a therapeutic problem
Many drugs have been tried, but the risk of side-Many drugs have been tried, but the risk of side-effects has side-lined many.effects has side-lined many.
Treatment for Obesity
The human body is composedThe human body is composed
of head and limbs and torsoof head and limbs and torso
kept slim by gents at great expensekept slim by gents at great expense
by ladies even more so.by ladies even more so.
Ogden NashOgden Nash
