1. Obesity: Past, Present and Future A Multi-Disciplinary Approach to Obesity Indianapolis, Indiana October, 18 2012 George A. Bray, MD Pennington Center Baton Rouge, LA

2. Obesity Has a Long History  The Distant Past  The Intermediate Past  Today

3. Key Messages  Our diet has changed dramatically from the Distant Past  Humans have gradually conquered the environment over the Intermediate Past  Today we have less physical activity; obesity that is subsidized by the farm policies of the government; which at the same time subsidizes research to prevent and treat it.

4. Outline  Paleolithic Obesity  Neolithic Agriculture & Obesity  Greek Medicine-Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

5. Human Evolution as a 24 Hour Clock EraTime IntervalClock Interval Paleolithic2.5 mya – 10 kya23h 54 min

6. The Last 30 Minutes Today 50,000 40,000 30,000 10,000 20,000 Iron Age Bronze Age Neolithic (New Stone Age) Paleolithic (Old Stone Age)

7. Venus 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

8. Have You Ever Had a Llama 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

9. Wild Game and Domestic Meat Average Content (per 100 g) Wild Game *Domestic Meat ** Energy (kcal)133.1385.5 Protein (g)21.915.8 Fat (g)4.329.0 Cholesterol (mg)6775 * 43 species ** 4 varieties Eaton SB, Shostak M, Konner M. The Paleolithic Prescription. New York: Harper & Row 1988

10. Outline  Paleolithic Obesity  Neolithic Agriculture & Obesity  Greek Medicine - Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

11. Human Evolution as a 24 Hour Clock EraTime IntervalClock Interval Paleolithic2.5 mya – 10 kya23h 54 min Agricultural10kya to present 6 min

12. 70% of Modern Foods Come From The Agricultural Revolution CategoryExamples% of calories Dairy ProductsMilk, cheese, butter10.5% Refined SugarsSucrose, High fructose Corn Syrup, Syrups 18.6% Cereal GrainsWhole grains and Refined Grains 23.9% Refined Vegetable Oils Salad Oils, Cooking Oils, Shortening, Margarine 17.6% AlcoholWine, beer, distilled beverages 1.4% Total Calories from these sources 72.1% Cordain L, et al. Am J Clin Nutr. 2005;341-354.

13. Conclusions from Paleolithic and Neolithic Periods  Obesity appeared early in human history  It can develop on any diet  Women more often represented as fat  Associated with upper social classes  Related to abundance of food and less exercise  It is increasing in prevalence  It can be described in modern terms as a chronic, stigmatized, neurochemical disease

14. Obesity Has a Long History  The Distant Past  The Intermediate Past  Today

15. Outline  Paleolithic Obesity  Neolithic Agriculture & Obesity  Greek Medicine - Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

16. The Last 1.5 Minutes Today 2,500 2,000 1,500 500 1,000 Roman Medicine Greek Medicine Columbus & America Renaissance Middle Ages Industrial Revolution Printing Press Hippocrates

17. Four Humors & Four Elements Whose Disorder Produced Disease Yellow Bile Phlegmatic Blood Black Bile (Fire) (Earth) Melancholy (Water) Sanguine (Air) Dry Cold Wet Moist Choleric

18. Hippocrates Was the Father of 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

19. Hippocrates Approach to Diet and Treating Obesity  [o]bese people and those desiring to lose weight should perform hard work before food. Meals should be taken after exertion and while still panting from fatigue and with no other refreshment before meals except only wine, diluted and slightly cold.

20. Outline  Paleolithic Obeisty  Neolithic Agriculture & Obesity  Greek Medicine – Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

21. The Last 20 Seconds 1776-1795- French & American Revolutions American Revolutions 1500-1700 Age of exploration 1492 Columbus Discovers America 1456 Printing press 2000 1500 1600 1700 1900 1800 Regimine Sanitatis World War II 1939-45 World War I 1914-1918 Historical Events Afghanistan & Iraq

22. Outline  Paleolithic Obesity  Neolithic Agriculture & Obesity  Greek Medicine – Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

23. Human Evolution as a 24 Hour Clock EraTime IntervalClock Interval Paleolithic2.5 mya – 10 kya23h 54 min Agricultural10kya to present 6 min Industrial300 yr 10 sec

24. The Last 16 Seconds 1776-1795- French & American Revolutions American Revolutions 1500-1700 Age of exploration 1492 Columbus Discovers America 1456 Printing press 2000 1500 1600 1700 1900 1800 Santorio World War II 1939-45 World War I 1914-1918 Historical Events Afghanistan & Iraq

25. Santorio “Father of Metabolism” Sitting on His Scale with His Food Santorio, Father of Metabolism, used this scale to measure the effects on his weight of food intake and losses of body fluid. He introduced insensible losses of fluid. Correcting this was the basis for treating disease. Santorio, Ars Medica 1614 Frontespiece from his book

26. Outline  Paleolithic Obesity  Neolithic Agriculture & Obesity  Greek Medicine – Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

27. The Last 8 Seconds 2000 1750 1800 1850 1950 1900 Vietnam War World War II World War I Civil War 1861-65 American Constitution Revolutionary War (1776-81 Historical Events Afghanistan & Iraq

28. Diets Have a Long History 1863 to 1929 AuthorYearCaloriesProtein Banting18631100 (1600)172 Bouchard1890125083 Oertel18951180-1600170 Ebstein19041300102 v. Noorden1910-20130090-120 Dujardin-Beaumertz19241457116 Evans & Strang192936058 Grafe E, et al. Metabolic Diseases and their Treatment 1934; p 168.

29. From There to 99.99% Here: Summary  Obesity has been present since the Paleolithic times in all cultures & on all diets  The agricultural revolution changed 75% of our diet as did the industrial revolution to follow  The Four Humors were the basis for treating obesity from the time of Hippocrates into the 19 th century  Modern “obesity” begins about 1850 as do modern diets

30. Obesity Has a Long History  The Distant Past  The Intermediate Past  Today

31. Outline  Paleolithic Obesity  Neolithic Agriculture & Obesity  Greek Medicine – Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

32. Human Evolution as a 24 Hour Clock EraTime IntervalClock Interval Paleolithic2.5 mya – 10 kya23h 54 min Agricultural10kya to present 5 min Industrial300 yr 10 sec 20 th Century100 yr 3 sec

33. The Last 3 Seconds Leptin Doubly-labeled Water Obesity Epidemic Lifestyle therapy Gastric Bypass Metabolic chambers Central Adiposity World War II World War I Cushing’s Syndrome Babinski-Frohlich 2000 1900 1920 1940 1980 1960 History & Obesity

34. Activity TEF Basal metabolic rate IntakeExpenditure INDIVIDUAL INFLUENCES Genetic/Epigenetic Stable Wt Gain Wt Loss Fat Carb Protein EN VIR ONM ENT AL & SO CIE TAL INF LUEN CES

35. Activity TEF Basal metabolic rate IntakeExpenditure INDIVIDUAL INFLUENCES Genetic/Epigenetic Stable Wt Gain Wt Loss Fat Carb Protein EN VIR ONM ENT AL & SO CIE TAL INF LUEN CES

36. Heritability of Body Weight Bjoreson M Acta Paediatr Suppl. 1962 May;132:1-76 Twins: Fraternal Identical

37. Genetics of Childhood Obesity  5092 twin pairs from the Twins Early Development Study aged 8.3-11.6 y  Heights, weights and waist circumference were higher than 1990.  Heritability was 77% for BMI and 76% for waist circumference  Genetic influence on waist circumference was largely in common with BMI (60%), but there was an independent 40%. Wardle J et al Am J Clin Nutr 2008;398-404

38. 13 Weighted number or Risk Alleles Number of Individuals Average BMI (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

39. Activity TEF Basal metabolic rate IntakeExpenditure INDIVIDUAL INFLUENCES Genetic/Epigenetic Stable Wt Gain Wt Loss Fat Carb Protein EN VIR ONM ENT AL & SO CIE TAL INF LUEN CES

40. Body weight is a regulated system Pi-Sunyer et al JAMA 2006;761-775

41. Brain Central signals Stimulate NPY AGRP Cannabinoids Orexin-A Dynorphin Inhibit  -MSH CRH/UCN GLP-I CART NE 5-HT External factors Emotions Food characteristics Lifestyle behaviors Environmental cues Peripheral signalsPeripheral organs Food intake Glucose CCK, GLP-1, Apo A-IV Vagal afferents Insulin Leptin Cortisol – – + Gastrointestinal tract Adipose tissue Adrenal glands Ghrelin + Food Intake Regulation Is Complex Energy out

42. Activity TEF Basal metabolic rate Intake Expenditure INDIVIDUAL INFLUENCES Genetic/Epigenetic Stable Wt Gain Wt Loss Fat Carb Protein EN VIR ONM ENT AL & SO CIE TAL INF LUEN CES

43. Energy Intake 1910-2000: More Food After 1970 Corrected for Waste Total Consumption – Uncorrected for waste Putnam JJ Food Rev 2002;25:2-15

44. Classic Coke 8 fluid oz 100 kcal 1950 Extreme Gulp 52 fluid oz 2002 630 kcal Increased Portion Size Is One Problem 12 oz Coke = 150 kcal

45. Fruit Drink & Soft Drink Consumption 1977-2001 % of Total Calories Nielsen SJ Am J Prev Med 2004;27:205-210

46. Activity TEF Basal metabolic rate Intake Expenditure INDIVIDUAL INFLUENCES Genetic/Epigenetic Stable Wt Gain Wt Loss Fat Carb Protein EN VIR ONM ENT AL & SO CIE TAL INF LUEN CES

47. Decline in Physical Activity During Adolescence in Girls Study Year Age 9/10 11/12 13/14 15/16 17/18 16/17 18/19 Kimm et al NEJM 2002;347:709-715

48. Sedentary Activity Increased from 1960 to 2010 Church TS et al PLoS One. 2011;6(5):e19657.

49. Activity TEF Basal metabolic rate IntakeExpenditure INDIVIDUAL INFLUENCES Genetic/Epigenetic Stable Wt Gain Wt Loss Fat Carb Protein EN VIR ONM ENT AL & SO CIE TAL INF LUEN CES

50. Factors Affecting Energy Balance  Food Intake  Energy Expenditure  Sleep Deprivation  Ambient Temperature  Maternal age  Medications  Breast Feeding  Maternal Smoking

51. Prevalence of Obesity by Smoking Status of Mother – Children Age 5-6 Toschke et al Am J Epidemiol 2003;158:1068-1074

52. Breast Feeding and Obesity Von Kries et al BMJ 1999;319:147

53. Sekine et al Child Care Health Dev 2002;28:163-170 Overweight BMI > 25 kg/m 2 N = 8274 children Sleep Debt and Body Weight: The Toyama Study

54. Medications and Weight Gain  Anti-psychotics, particularly the second generation produce significant weight gain (4 kg in 10 wks for olanzepine and clozepine)  SSRI are less consistent  Beta-blockers produce 1.2 kg increase  Data on oral contraceptives are less consistent

55. Activity TEF Basal metabolic rate IntakeExpenditure INDIVIDUAL INFLUENCES Genetic/Epigenetic Stable Wt Gain Wt Loss Fat Carb Protein EN VIR ONM ENT AL & SO CIE TAL INF LUEN CES

56. The Network for Spread of Obesity: The Framingham Study [close] Slide Christakis NA & Fiowler JH NEJM 2007;350:370-379

57. Obesity Is Contagious  Obesity spread among the 12,067 people in this network  One’s chances of obesity (BMI<30kg/m 2 ) 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 obese 37% if a spouse became obese Christakis & Fowler NEJM 2007;357:370-9

58. Outline  Paleolithic Obesity  Neolithic Agriculture & Obesity  Greek Medicine – Hippocrates  Middle Ages/Renaissance & Obesity  Obesity in the 17 th and 18 th Century  Obesity in the 19 th Century  Obesity is HERE

59. Obesity Has Many Complications Phlebitis venous stasis

60. DiseasePrevalence Diabetes (Type 2)15.3% Impaired Glucose Tolerance25.8% Sleep Disordered Breathing19.6% Hypertension35.4% Dyslipidemia35.6% Degenerative Joint Disease50.3% Depression17.4% Gastroesophageal reflux43.3% Buchwald H, et al JAMA 2004;292:1724-1737 Prevalence of Chronic Diseases in Patients Undergoing Bariatric Surgery

61. Small Weight Losses Are Beneficial: The Diabetes Prevention Program 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

62. Redrawn from: Hamman RF et al. Diabetes Care. 2006;29(9):2102–2107. How Much Weight Loss Is Needed to Prevent Type 2 Diabetes? Change in Weight From Baseline (kg) 0-10-5+5 Incidence Rate per 100 Person-Years 10 20 15 5 0

63. Redrawn from: Hamman RF et al. Diabetes Care. 2006;29(9):2102–2107. Criteria for Successful Weight Loss: The Diabetes Prevention Program Change in Weight From Baseline (kg) 0-10-5+5 Incidence Rate per 100 Person-Years 10 20 15 5 0 GoodExcellent

64. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

65. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

66. Weight Change with Anti-Diabetic Drugs Weight GainWeight Neutral Weight Loss InsulinDPP-4 InhibitorsMetformin SulfonylureasAcarbosePramlintide GlitinidesMiglitolExenatide ThiazolidinedionesBromocriptineLiraglutide

67. DPP Research Group. Lancet. 2009;374(9702):1677–1686. Metformin and Lifestyle Reduce Weight Over Time in DPP

68. Pramlintide: An Amylin Analog  An analog of amylin that overcomes the tendency of human amylin to: –Aggregate, form insoluble particles –Adhere to surfaces  Pharmacokinetic and pharmacodynamic properties similar to human amylin Human amylinPramlintide (analog of amylin) Amide S S A Y T N S G V N T TT T N A A A L I K S S C C Q R L N N N F G F L V H P P P Y T N S G V N T TT T N A A A L I K S S C C Q R L N N N F G F L V H 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

69. BID Regimen TID Regimen Time (Months) Mean (SE) Percent Change in Body Weight (%) Placebo 120 mcg 240 mcg 360 mcg 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 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,

70. Combination of Pramlintide and Phentermine on Body Weight Aronne L et al Obesity 2010;18:1739-1746

71. Glucagon-Like Peptide 1  GLP-1 is the 7-36 amino acid sequence of glucagon  It is an incretin that is released from the L- cells of the intestine and enhances insulin release in the presence of glucose  It reduces glucagon release from the α- cells  It slows gastric emptying  It reduces food intake

72. Exenatide Chen YE, et al. J Biol Chem.1997;272:4108-4115; Knudsen LB, et al. J Med Chem. 2000;43:1664-1669. Liraglutide 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 ConservedSubstituted Additional relative to human GLP-1 (7-37)

73. 0102030405060708090 Mean  Weight (kg) Exenatide Reduces Body Weight in Placebo Controlled & Open-Label Trial Time (wk) Baseline Weight 98 kg 100 kg Placebo BID 5 µg Exenatide BID 10 µg Exenatide BID -5 -4 -3 -2 0 1 82-wk completers; N = 393; Mean ± SE; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc. Open-Label Extension Placebo-Controlled

74. Liraglutide Produces Dose-Related Weight Loss Astrup A et al Lancet 2009;374:1606-1616

75. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

76. Weight Change with Some Neurobehavioral Drugs Weight GainWeight Neutral Weight Loss TricyclicsHaloperidolBupropion LithiumAripiprazoleVenlafaxine EscitalopramParoxetineDesvenlafaxine MAO InhibitorsMitrazepineTopiramate Olanzapine/ClozapineLamotrigine RitalinZonisamide ResperidoneZiprazidone Valproate Carbamazepine

77. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

78. Time in Weeks Continuous Phentermine Alternate Phentermine & Placebo Placebo 5 10 Weight loss (kg) Weight loss (lbs) 0 Phentermine: A Norepinephrine Reuptake Inhibitor Munro JF et al BMJ 1968;1:352-4

79. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

80. Weight Loss Over Two Years with Orlistat: Integrated Database -10 -9 -8 -7 -6 -5 -4 -3 -2 0 -404812162024283236404448525660646872768084889296100104 Week % Weight Loss Placebo 120 mg 60 mg Hauptman Data on file Hoffmann-La Roche

81. A Meta-analysis of Weight Loss with Orlistat Adapted with permission from Padwal R, et al. Int J Obes Relat Metab Disord. 2003;27:1437-1446. Kelley, 2002* Broom, 2002 Hauptman, 2000 Finer, 2000 Davidson, 1999 Sjöström, 1998 Hollander, 1998* Rossner, 2000 Bakris, 2002 Miles, 2002* Total (95% CI) Lindgarde, 2000 WMD (Random)95% CI Study or Subcategory *All subjects had type 2 diabetes. WMD = weighted mean difference. Favors Treatment Favors Control -10-50105

82. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

83. Topiramate + Phentermine  Phentermine stimulates NE ( norepinephrine) release from hypothalamic neurons  It is approved for obesity but only short term  Topiramate approved for epilepsy and migraine  It also produces weight loss  Once-a-day, oral formulation of phentermine and controlled-release developed to reduce adverse side effects

84. Weight Loss During Treatment with Phentermine/Topiramate ITT Gadde K. et al Lancet 2011;377:1341-1352

85. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

86. Lorcaserin – Selective Approach to the Serotonin Receptor  Serotonin reduces food intake  Brain 5-HT2C receptors mediate this effect  5-HT2B receptors are associated with valvulopathy  5-HT2C receptor knock-out leads to obesity  Lorcaserin 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 with valvulopathy Smith SR, et al. NEJM. 2010;363:245-256.

87. Weight Loss in CompletersTreated with Lorcaserin Placebo N = 684 Cross-over N = 275 Continuous N = 564 Smith SR et al NEJM 2010; 363:245-256

88. Obesity Is HERE - Drug Therapy Approved Drugs That Produce Weight Loss In Diabetic Patients In Neurobehavioral Disorders In Obesity   Sympathomimetics   Orlistat   Topiramate/Phentermine   Lorcaserin – Serotonin agonist D rugs in Limbo   Bupropion/Naltrexone

89. Bupropion and Naltrexone  Bupropion is a norepinephrine reuptake inhibitor that is approved for smoking cessation and depression  Naltrexone used to counteract opioid drugs

90. Weight Loss in Completers Treated With Naltrexone-Bupropion Placebo N = 507 NB 16 N = 467 NB 32 N = 467 Bupropion 360 mg/d Drop-outs ̴ 50% Greenway FL, et al. Lancet. 2010;376:595-605.

91. Unintended Consequences During Treatment of Obesity YearDrugConsequence 1892ThyroidHyperthyroidism 1932DintrophenolCataracts/Neuropathy 1937AmphetamineAddiction 1968 Rainbow Pills Deaths-Arrhythmias 1971Aminorex Pulmonary Hypertension 1985 Gelatin-based VLCD CV Deaths 1997Phen/FenfluramineValvulopathy 1998PhenylpropanolamineStrokes 2003 Ma Huang Heart attacks/stroke 2007EcopipamDepression

92. Surgery for Obesity in the U.S. Steinbrook NEJM 2004;350:1075-1079; MarketData 17 April 2007

93. GASTRIC BANDING VERTICAL BANDED GASTROPLASTY Skin Subcutaneous Pouch PANCREATICO-DUODENAL BYPASS JEJUNO-ILEAL BYPASS GASTRIC BYPASS Bariatric Operations

94. 10-Year Weight Loss in SOS Sjostrom et al NEJM 2004:351:2683 Control Gastric By-Pass V-Band Gastroplasty Banding

95. O’Brien et al Ann Int Med 2006;144:625-633 Weight Loss in Patients with BMI Between 30 and 35

96. 2- Year Effect of Lap-Band or Lifestyle on weight Loss and Diabetes Remission BMI Range -30-40 kg/m2 Age 20-60; Diagnosis of Diabetes within 2 years Dixon JB et al JAMA 2008;299:316-323

97. Two and Ten Year Incidence of Diseases in the SOS Control Surgery 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

98. Obesity Is Here – The Last 0.01%: Summary  Obesity results from an imbalance in energy intake and expenditure in genetically susceptible people  Obesity spreads from person to person among close contacts  Obesity has a major predictor of diabetes  Modest weight loss is beneficial and can be achieved by many strategies, including lifestyle changes, diet, exercise, pharmacotherapy surgery  Adherence is the major criterion for successful weight loss  Unintended consequences of treatment for obesity continue to be a therapeutic problem  Many drugs have been tried, but the risk of side- effects has side-lined many.

99. Treatment for Obesity The human body is composed of head and limbs and torso kept slim by gents at great expense by ladies even more so. Ogden Nash