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A. Definitions and Epidemiology

  1. In USA, increasing number of adults and children are above optimal body mass index (BMI)
    1. In 2003-4, 32% of adults in US were obese; increased in men but not women since 1999 [3]
    2. In 2003-4, 17% of US children and adolescents were overweight; increased since 1999 [3]
    3. Sixth most important risk factor for disease worldwide [2]
    4. Prevalance of obesity (BMI >30kg/m2) is ~20% in USA in 2000 and is increasing [6]
    5. Compared with whites, obesity onset was generally faster in blacks and hispanics
    6. About 28% of men and 44% of women are attempting to lose weight in USA [7]
    7. All persons should be screened for obesity and counseling initiated as appropriate [57,58]
    8. Increasing problem in children and adolescents and must be addressed [4]
  2. Classification of Obesity
    1. BMI is a measure of weight normalized for body surface area (height dependent)
    2. BMI (conversion included) = [weight(pounds)x703]÷ [height(inches) squared]
    3. Healthy (normal) body mass index (BMI) is 19-25 kg/square meter
    4. Optimal BMI in whites is 23-25 based on life tables [9]
    5. Optimal BMI for blacks is 23-30 based on life tables [9]
    6. Overweight is BMI 25-30
    7. Mild Obesity is BMI 30-32
    8. Moderate Obesity is BMI 32-35
    9. Severe (morbid or medically complicated) Obesity is BMI>35
  3. Morbidity from Obesity
    1. Mainly due to medical complications in three areas:
    2. Diabetes mellitus (DM) type 2 (DM2)
    3. Hypertension (HTN)
    4. Myocardial Infarction (MI) [5] and congestive heart failure (CHF) [10]
    5. Osteoarthritis
    6. Increased risk of various cancers [94] and cancer death [78]
    7. Other complications described below
  4. Mortality and Obesity [9,11]
    1. Increasing obesity correlates with increasing mortality
    2. Overweight have ~3 years and obese ~7 years reduction in lifespan [11]
    3. Smoking combines with overweight / obesity to reduce lifespan up to 13 years [11]
    4. Obesity likely contribute to about 280,000 deaths per year in USA [13]
    5. Obesity in adolescent women increases risk for premature death [88]
    6. Obesity-related excess mortality declines with age
    7. Morbid obesity carries a 6-12 fold increased risk of death
    8. Increased body weight and lack of physical activity are equal contributors to mortality [22]
  5. Other Considerations
    1. Weight gains of >10 pounds (4.5kg) after age 21 should be avoided
    2. Ratio of waste to hip circumference should not exceed 1.0 (men and women; see below)
  6. Metabolic Syndrome [15,70]
    1. Defined as having at least 3 of the following 5 criteria:
    2. Abdominal Obesity: waist circumference >102cm men, >88cm women
    3. Hypertriglyceridemia: triglycerides >149 mg/dL (>1.68 mmol/L)
    4. Low HDL: <40mg/dL (1.04 mmol/L) men, <50mg/dL (1.29 mmol/L) women
    5. High blood pressure: >130/85 mm Hg
    6. High fasting glucose: >109 mg/dL (>6.1 mmol/L)
    7. Insulin resistance is not required for syndrome
    8. Overall prevalence of metabolic syndrome is 22% and is age dependent in USA
    9. Chronic intervention is critical to prevent progression to frank DM
    10. Prediabetes occurs in obese youth with similar characteristics as metabolic syndrome [54]

B. Adipocyte Metabolism

  1. Energy Metabolism
    1. At rest, >50% of body heat is generated from inefficient conversion of food to ATP
    2. Most of the heat is produced in visceral organs and distributed around the body by blood
    3. When ATP and heat needs have been met, additional food energy converted to fat
  2. Brown Adipose Tissue
    1. Associated with viscera
    2. High mitochondrial content with uncoupled oxidative phosphorylation
    3. Thermoregulatory role - main function is conversion of energy to heat
  3. White Adipose Tissue
    1. Subcutaneous fat
    2. Main function is fat storage
    3. Distribution of white fat in body may determine risk for cardiovascular (CV) disease (CVD)
  4. Regulation of Fatty Acid Storage
    1. Insulin
    2. ß-adrenergic regulated processes
    3. Leptins
    4. Glucocorticoids
    5. Thyroid hormone
    6. Gastrointestinal (GI) fat absorption may be important in determining serum lipid levels
  5. Distribution of Body Fat
    1. Body fat may be distributed mainly in Central areas or Peripheral areas
    2. The predominant form of obesity has been used to characterize patients
    3. Early data suggested central obesity is the main risk factor for CVD
    4. This type of obesity is characterized by an "android" or "apple" shape
    5. Ratio of waist (umbilicus) to hip (pubic symphysis) is often used as a measure
    6. A waist to hip ratio of >0.85 is a CV risk factor in central form obesity
    7. This ratio also correlates (r=0.4) with elevated serum triglyceride and low HDL
    8. Peripheral (non-central) obesity may have lower CV risk than central obesity

C. Endocrinology of Weight Control [16]

  1. Body weight is dependent on balance between energy intake and energy expenditure
    1. Energy intake in form of food and drink
    2. Energy expenditure has resting and activity components
    3. Resting component is energy required to metabolize foods and generate heat
    4. Activity includes voluntary physical activity and non-exercise activity
  2. Key endocrine systems involved in weight regulation
    1. HPA Axis
    2. Leptin system including leptin-regulated hormones (see below)
    3. Gherlin
    4. Neuropeptide Y (NP-Y) and PYY
    5. Fatty Acid Synthetase
    6. Insulin
    7. Autonomic Nervous System
    8. Dopamine D2 Receptors (modulates motivation and rewards)
  3. HPA Axis
    1. Corticotropin releasing hormone (CRH) and glucocorticoids are key hormones here
    2. In starvation, CRH levels are reduced or unchanged
    3. In times of stress, CRH and glucocorticoid levels increase
    4. During starvation, leptin and insulin levels fall, and glucocorticoid levels rise
    5. These changes also stimulate the production of neuropeptide Y (NP-Y)
    6. Most catabolic hormone levels increase in starvation (serotonin, urocortin, MSH, others)
  4. Plasma Gherlin [17]
    1. Orexigenic hormone secreted by stomach and duodenum
    2. Increased levels stimulate increased eating in animals in humans [80]
    3. Nutrient intake and gastric bypass reduce levels of ghrelin
    4. Inhibition of ghrelin may lead to reduced food intake
    5. PYY released after meal significantly reduce ghrelin levels (see below) [72]
  5. Leptin (Lep) System (see below) [19]
    1. Lep communicates nutritional status to the brain, activates neurons in hypothalamus
    2. Plasma and central nervous system (CNS) Lep levels correlate with body fat stores
    3. The ob gene encodes Lep; the db gene encodes the Lep receptor (Lep-R)
    4. Lep signals block NPY and AGRP (orexigens) and stimulate CART and POMC (anorexigens)
    5. Diet induced weight loss causes Lep levels to fall as body fat stores decline
    6. When dieting stops, Lep levels remain low, stimulating eating and weight gain
    7. Lep system's set point can apparently be altered by "baseline" (chronic) body fat level
    8. Lep also negatively impacts bone density, inhibiting osteogenesis [19]
  6. Fatty Acid Synthetase (FAS) [16]
    1. FAS is a 2500 amino acid protein expressed in brain, lungs and liver
    2. Inhibition of FAS in animals reduces food intake up to 90% in 24 hours
    3. FAS inhibition leads to reduced neuropeptide Y (NP-Y) levels
    4. Elevated NP-Y associated with increased food intake
  7. Other Hormones
    1. Glucocorticoids and some androgens increase fat deposition
    2. Glucocorticoids increase leptin levels
    3. Thyroid hormone required for fat breakdown
    4. Androgens and estrogens may play a role in deposition of fat
  8. Prader-Willi syndrome is genetic disease with excessive food intake leading to obeisty [55]

D. Molecular Endocrinology of Energy Metabolism

  1. Key Molecules
    1. Lep Lep receptor (Lep-R)
    2. Glucagon-like peptide 1 (GLP-1)
    3. Melanin-concentrating hormone (MCH)
    4. Melanocortin-4 receptor (MC4-R)
  2. Lep [19,20]
    1. Lep, coded by ob, is a 167 amino acid protein on human chromosone 7p31
    2. Main physiologic role is signal energy availability to brain in energy-deficient states
    3. Lep levels are increased in obese persons
    4. Lep causes fat breakdown, is primarily responsible for starvation-induced changes
    5. Most obese patients have high levels of Lep, but do not to respond to these levels
    6. Lep (or Lep-R) deficient patients have hyperphagia and morbid obesity
    7. Treatment of Lep deficient patients with recombinant Lep leads to weight loss, appetite reduction, improvement in gonadotropin (FSH, LH) levels [21]
    8. Overweight persons treated with Lep have minimal decrease in weight
  3. Lep-R [51]
    1. Member of the cytokine receptor family, expressed at high levels in hypothalamus
    2. Lep-R activation in CNS inhibits NP-Y, stimulates MSH, GLP1, CFH, urocortin, MCH
    3. Peripheral Lep-R found on hepatocytes, adipocytes, pancreatic islets, other cells
    4. Lep-R deficiency found in 3% of early onset severe obesity, have elevated Lep levels, hyperphagia [51]
  4. Peripheral Lep Effects
    1. Inhibits intracellular lipid concentrations fatty-acid and triglyceride synthesis,
    2. Increases lipid oxidation
    3. Blocks acetyl-CoA carboxylase, rate limiting step in fatty-acid synthesis
    4. This leads to reduced malonlyl-CoA, a key regulator of fatty acid catabolism
    5. Low serum levels of Lep occur after weight loss, and stimulate HPA axis
    6. Also appears to stimulate hematopoiesis and macrophage function
  5. POMC
    1. Precursor peptide for alpha-melanocyte stimulating hormone (MSH) and ACTH
    2. MSH binds to the melanocortin 4 (MC4) receptor and stimulates appetite
    3. POMC and MC4 mutations have been found in some morbidly obese humans
    4. Mutations in MC4-R lead to morbid obesity and binge eating [82,83]
  6. PPAR Gamma 2 (PPARg2)
    1. Peroxisome proliferator activated receptor (PPAR) gamma 2
    2. PPARg2 is a transcription factor involved in adipocyte differentiation
    3. Mutations in gene for PPARg2 found in ~3% of obese patients overall
    4. All patients with PPARg2 mutations were severely obese (>37kg/m2 BMI)
    5. These kinds of mutations appear to accelerated differentiation of adipocytes
    6. Phosphorylation of serine 114 defective in mutant genes
  7. Resistin [25]
    1. Adipocyte gene down-regulated by rosiglitazone (insulin sensitizer)
    2. May link increased fat mass and insulin resistance
    3. Levels greatly increased in obese mice; reduced by glitazone treatment
    4. May be a mediator of insulin resistance in obese persons
    5. Specific inhibitors being developed
  8. NP-Y System [93]
    1. NPY is a 36 residues polypeptide with tyrosines (Y) at either end
    2. Synthesized in arcuate nucleus of hypothalamus
    3. Two receptors, Y1R (arcuate and paraventricular nuclei) and Y2R (arcuate nucleus)
    4. NPY binds Y1R and stimulates food intake, favors synthesis and storage of fat
    5. NP-Y can stimulate menses, and mediate hypothalamic responses to leptin deficiency
    6. NP-Y Increased in times of starvation
    7. Glucocorticoids stimulate NP-Y production
    8. Leptin and insulin repress NP-Y production
    9. PYY derived from L neuroendocrine cells in distal small and entire large intestines
    10. PYY released in proportion to calories injested and binds inhibitory Y2R in arcuate nucleus
    11. PYY injections into people reduce appetite and food consumption ~30% [72]
  9. Orexin
    1. Hormone made by lateral hypothalamus
    2. On binding its receptor, stimulates appetite
    3. May be useful in modulating cachexia (wasting) and eating behavior
  10. Insulin
    1. Insulin binding in brain reduces feed intake in animals
    2. Insulin blood levels correlate with body fat stores
    3. Insulin is absolutely require for storage of fat in the body
    4. Thus, Type I diabetics cannot store fat, and type II diabetics often become obese
    5. Insulin resistance is correlated with central obesity and CV risk

E. Causes of Human Obesity

  1. Overeating and Sedentary Lifestyle [76]
    1. In USA and other Western countries, this appears to be THE major problem
    2. Lack of appropriate exercise and activity levels is the most important contributor [76]
    3. A minority of cases of obesity appear to be truely due to endocrine abnormalities
    4. Molecular defects in energy metabolism control can exacerbate lifestyle contributions
    5. Reducing caloric intake and increasing physical activity will greatly reduce obesity
  2. "Fast Food" consumption increases weight gain and insulin resistance [65]
  3. Endocrine
    1. Major endocrine dysfunction as cause for obesity are uncommon
    2. Hypothyroidism
    3. Cushing's Syndrome
    4. Hyperandrogenism
    5. Polycystic Ovarian Syndrome (PCOS)
    6. Insulin Resistance including DM2
  4. Smoking cessation makes a minor contribution to obesity rates in USA

F. Complications Due To or Associated With Obesity [26]

  1. HTN
    1. Obesity is a strong risk factor for HTN
    2. Increases sympathetic tone, increasing vascular resistance
    3. Increased sympathetic tone also increases insulin resistance (see below)
    4. Weight loss reduces risk for HTN in women
    5. Weight loss reduces blood pressure in both men and women [29]
  2. Coronary Artery Disease (CAD)
    1. Increased body mass index is a major risk factor for CAD
    2. Waste to hip ratio better risk factor for MI than BMI [5]
    3. Increased waist to hip ratio is a ~3X risk factor for CAD independent of BMI
    4. Increased sodium intake correlates with increased cardiac disease and all-cause mortality in obese persons [31]
    5. Higher BMI is associated with increased C-reactive protein (CRP) levels [32]
    6. This suggests that systemic inflammation is accompanies increased BMI
    7. Systemic inflammation likely contributes to atherosclerosis
  3. CHF [10]
    1. Sustaining adipose tissue requires increased left ventricular (cardiac) output
    2. Both systolic and diastolic dysfunction are found in obese persons
    3. Micro- and macrovascular disease contribute to cardiac dysfunction
    4. Obesity is an independent risk factor ~2X for developing CHF [10]
    5. Pulmonary HTN probably contributes to right sided CHF
  4. Respiratory Disease
    1. Restrictive Lung Disease, often leading to pulmonary HTN
    2. Right Ventricular Hypertrophy
    3. Right sided CHF may progress to cor pulmonale
    4. Sleep Apnea (Pickwickian Syndrome)
  5. Insulin Resistance Syndromes (IRS) [56]
    1. Insulin resistance is present in ~90% of these patients
    2. Difficult to routinely administer glucose tolerance test to identify IRS
    3. IRS is likely present in obese patients with elevated plasma triglyceride and insulin concentrations and the ratio of plasma triglycerides to HDL
    4. Serum level of retinol-binding protein 4 (RBP4) correlates with insulin resistance [86]
    5. IRS associated with 2-5X increased risk for chronic renal failure [59]
    6. Frank DM2 may develop
  6. Hyperlipidemia
    1. Often with hypertriglyceridemia (low HDL) and DM
    2. A low (15% total) fat diet, ad libitum, promotes weight loss, reduces cholesterol (Chol)
  7. Obesity is a ~1.5X risk for atrial fibrillation [62]
  8. Osteoarthritis [2]
  9. Increased Cancer Risks [33,94]:
    1. Endometrial (1.6X increased risk)
    2. Breast
    3. Kidney (1.3X)
    4. Colorectal Cancer (1.24X in men)
    5. Esophageal and/or gastric cardia (1.5X) [34,94]
    6. Renal Cancer (>1.3X)
    7. Pancreatic cancer risk increased 1.7X (BMI >30 versus <25) [35]
    8. Gallbladder cancer in women (1.6X) [94]
    9. Increased risk of cancer-related death [78]
  10. Gastroesophageal Reflux Disease (GERD) [48,73]
    1. Most often severely symptomatic GERD
    2. Risk for GERD is 2.8X for BMI>30kg/m2 versus general population
    3. Risk for GERD is 3.3X for men and 6.3X for women with BMI>35kg/m2
    4. Obesity increases risk for erosive esophagitis and gastric cardia adenocarcinoma
    5. Unknown if weight loss improves symptoms, though this is likely
  11. Nonalcoholic Fatty Liver [37]
    1. Clear association with obesity (~60%) and type 2 DM
    2. Exacerbated by moderate to high alcohol consumption [38]
    3. Hypertriglyceridemia is a risk factor
    4. Elevated aminotransferase levels and slight elevations of alkaline phosphatase
    5. Increased risk of cirrhosis
  12. Other Probable Associations
    1. Gallstones
    2. Lower extremity edema (venous and lymphatic obstruction)
    3. Urinary Incontinance
  13. Obesity alone is probably not a risk factor for postoperative complications of general surgery; comorbid conditions are likely main contributors [79]

G. Treatment [1,12]

  1. Overview [26]
    1. Combination of different modalities is required
    2. Changing eating behavior COMBINED with exercise is critical [39]
    3. Long term exercise program is only method for maintaining weight loss
    4. Lifestyle modifications prevent frank diabetes in high risk patients [36]
    5. Pharmacologic therapy is adjunctive; used alone is ineffective
    6. Most pharmacologic agents for weight loss provide 2.5-4.5kg weight loss in 12 months [26]
    7. Goal is 0.5-1.0kg weight loss per week in first 6 months of initiation of therapy
    8. Surgery is probably best first line therapy for morbid obesity (BMI >35-40)
  2. Food Intake
    1. Modification of eating behavior is essential but probably not sufficient
    2. Dietary counseling of modest benefit that diminishes over time [90]
    3. Eating a low (15.1% total) fat, ad libitum diet reduces weight and Chol
    4. Reduction of caloric intake by 500-1000 kcal/day can lead to 05kg/week weight loss
    5. Higher fiber diets may protect against obesity by reducing insulin levels [40]
    6. In obese patients with IRS, increased dairy intake may reduce DM 2 and cardiac risk [41]
    7. Similar weight loss 2.1-4.7kg at 1 year with "Atkins", "Ornish", Weight Watchers, Zone diets at 1 year, though Atkins may be superior to others [49,66]
    8. Carbohydrate restricted ("Atkins") diet is superior to fat restricted diet for obesity, in the first 3-6 months of diet [14,27], continuing out to 6-12 months [49,60,61]
    9. Carbohydrate restricted diet has better lipid profile than low-fat diet [49,60,61]
    10. Low carbohydrate diet for 2 weeks in obese persons with Type 2 DM lead to improvement in insulin sensitivity, HbA1c and Chol [68]
    11. In general, carbohydrate restricted diet recommended over fat restricted diet
  3. Exercise [39]
    1. Effectively reduces weight regardless of genetic predispositions or eating habits [42]
    2. Improves CV fitness, reduces insulin resistance and abdominal fat
    3. Is only known method for maintaining weight loss
    4. Exercise improves metabolic parameters including Chol levels
    5. At least 20 minutes of excercise at least 3X per week is effective
    6. Long bouts of exercise are no more effective than short bouts for weight control [6]
    7. Combination of weight training and aerobics done 5-6 times per week is most effective
    8. Aerobic exercise should be performed at 60-70% max heart rate, >30 minutes/day
    9. Must be continued throughout comprehensive weight loss program
  4. Medical Therapy [26,53]
    1. Appetite Suppressants
    2. Block Nutrient Absorption
    3. Increase Energy Expenditure
  5. Appetite Suppressants [53]
    1. Some medications reduce appetite but treatment must be continued
    2. Appetite suppressant drugs are recommended for patients 20-30% overweight
    3. Orlistat, sibutramine and rimonabant show clear weight loss effects [7]
    4. Most are stimulants and increase effective serotonin and/or norepinephrine (NE) levels
    5. Combined medical therapy with lifestyle modifications provides best weight loss [28]
    6. Fenfluramine and dexfenfluramine have been removed from the market
    7. Phenylpropanolamine has been withdrawn from over-the-counter market due to >15 fold increased stroke risk in women but not in men [44]
    8. Topiramate (Topamax®) and Zonisamide (Zonegran®), anti-seizure agents, have shown some activity with unclear mechanisms [26]
    9. Ephedra and ephedrine, stimulant alkaloids, are also be used for weight loss [74,75]
    10. Ephedra causes psychiatric, autonomic and cardiac side effects [74,75]
  6. Monoamine Reuptake
    1. Sibutramine (Meridia®)
    2. Phentermine - NE reuptake inhibitor; reduced use due to questionable valve disease
    3. Diethylpropion (Tenuate®, Tepanil®) - 75mg/d sustained release; minimal efficacy [12]
  7. Sibutramine (Meridia®) [45,63]
    1. 5-HT and norepinephrine reuptake inhibitor, not scheduled
    2. Dose is 10-20mg po qd (typically 15mg/d)
    3. Weight reduction 5kg alone and 7.5kg with lifestyle modifications at 1 year [28]
    4. Also reduced plasma triglycerides, total chol, LDL
    5. With diet, significantly helped maintain weight loss over 12-24 months [46]
    6. Intermittant therapy (weeks 1-12, 19-30, 37-48) is essentially as effective as continuous 48 weeks of therapy for weight loss (3.3-3.8kg) [47]
    7. Behavior therapy (BT) + sibutramine more effective than BT alone in adolescent [77] and adult [28] obesity
    8. Generally mild side effects: dry mouth, constipation, insomnia, modest increases in blood pressure and heart rate, nervousness
    9. Approved in USA for BMI >30kg/m2 or >27kg/m2 with complications of obesity
    10. Dose dependent increases in blood pressure and heart rate
    11. Should be used in patients who have failed diet/exercise therapy alone [26,63]
    12. Reduced weight ~4.5kg in patients with DM2 and improved glycosylated hemoglobin [67]
    13. Reduced BMI in obese adolescents -2.9kg/m2 when added to behavior therapy [87]
  8. Orlistat (Xenical®) [50]
    1. Synthetic derivative of lipstatin (an inhibitor of lipases)
    2. Inhibits GI absorption of fats by blocking lipase action
    3. No effect on gastric acid or emptying, gallbladder motility
    4. No apparent effect on absorption or metabolism of other drugs
    5. Patients on hypocaloric diets lost 3-4kg additional weight with orlistat
    6. Reduced weight ~2.6kg in patients with DM2 and improved glycosylated hemoglobin [67]
    7. Reduced weight ~2.5kg in obese adolescents (120mg tid x 1 year) versus placebo [24]
    8. Serum total and LDL Chol dropped ~5 mg/dL more on orlistat than placebo
    9. Fasting glucose and insulin, as well as HbA1c, reduced on orlistat versus placebo
    10. GI bloating, flatulance, and other mild disturbances in ~30%
    11. These symptoms are due to fat malabsorption leading to steatorrhea
    12. Reduces absorption of fat soluble vitamins, particularly Vitamin D
    13. Patients treated with orlistat gain less weight than placebo when drug is stopped
    14. Dose is 120mg po tid
  9. Selective Serotonin Reuptake Inhibitors (SSRI)
    1. Fluoxetine (Prozac®) has relatively good appetite suppressing activity wtih ~4.5kg weight loss at 1 year, dose 60mg qd [26,67]
    2. Paroxetine (Paxil®) also has activity but overall associated with weight gain
    3. Serotonin and norepinephrine reuptake blocker sibutramine (see above) [45]
  10. Phentermine (Ionamin®, Lonamin®) [12]
    1. Schedule IV drug, sympathomimetic mechanism
    2. Noradrenergic reuptake inhibitor related to benzphetamine
    3. Previously used in combination with Fenfluramine
    4. Moderate reduction in weight associated with phentermine 15-30mg/d
    5. Increased risk of pumlonary hypertension (likely not a concern)
    6. Must monitor blood pressure
  11. Fenfluramine (Pondimin®) [38,39] and Dexfenfluramine (Redux®)
    1. Previously used alone or in combination with phentermine
    2. Agents alone and in combination cause valvular heart defects [52]
    3. Both withdrawn from the market
  12. Rimonabant [30,71,84]
    1. Selective cannabanoid 1 receptor antagonist
    2. Central and peripheral GI actions: Increases satiety and reduces food intake
    3. Acts on adipose tissue to improve metabolic syndrome parameters
    4. In obese patients (BMI 34-37kg/m2, 100kg baseline weight) 20mg po qd reduced weight by
  13. 7-6.7kg versus placebo at 1 year [89]
    1. Reduced waste circumference and with maintenance therapy, prevented weight re-gain
    2. Improvements in HDL-Chol, triglycerides, insulin resistance, glucose, metabolic syndrome
    3. In 18 month study, reduced total atheroma volume (but not percent atheroma volume) in coronary arteries of obese patients with metabolic syndrome [8]
    4. Generally well tolerated with nausea (11%), depressed/anxious mood, dizziness
    5. Depressive or anxious mood disorders lead to discontinuation 2.5-3.0X more commonly than placebo [93]
    6. Close monitoring for mood effects and suicidal ideation required [93]
    7. Approved in European Union for weight reduction
  14. Weight Loss with Medical Therapy [53]
    1. Sibutramine: 3.4 - 6.0 kg
    2. Phentermine: 3.6kg
    3. Orlistat: ~2.75kg
    4. Fluoxetine: 5-7kg
    5. Bupropion: 2.8kg
    6. Rimonabant: ~5.4kg
    7. Topiramate: 6.5% loss
  15. Bariatric Surgery (see below)

H. Surgical Therapy [18,43,64,69]

  1. Usually called "Bariatric" Surgery [69]
    1. More effective than nonsurgical treatments for weight loss and comorbidities
    2. Generally for patients with BMI > 40kg/m2 or more
    3. Surgery likely beneficial for BMI 35-40kg/m2 as well
    4. Weight loss 20-30kg in most cases, maintained up to 10 years
    5. High-volume surgical centers critical for reduced complications
    6. >100,000 operations in 2003 [81]
  2. Indications
    1. Body weight 2X ideal or morbid obesity
    2. Serious weight-related morbidity (see above)
    3. Failure of supervised weight reduction programs
  3. Bypassing Satiety Centers
    1. Gastroplasty or gastric stapling, inducing early satiety, may be used
    2. Laparoscopic adjustable gastric banding (see below)
    3. Gastric bypass with Roux-en-Y procedure (direct esophageal dumping to jejunum)
    4. Partial biliopancreatic bypass with 80% gastrectomy (gastroileal bypass)
    5. Gastric bypass is probably most effective for weight loss
  4. Many patients can lose 50% or more of their excess weight with these surgeries
  5. Laparoscopic Adjustable Banding [85]
    1. Subcutaneous port for infusion of saline, adjustment of band lumen
    2. Mean ~20% weight loss at 2 years, improvement in metablic syndrome
  6. Other Improvements [43,64]
    1. Diabetes resolves in >75%, improved or resolved in >85%
    2. Hyperlipidemia improved in at least 70% of patients
    3. Hypertension resolved in >60%
    4. Obstructive sleep apnea improved or resolved in >80%
    5. Hyperuricemia also reduced 35% at 10 years versus placebo
  7. Complications
    1. Malabsorption, particularly of vitamins
    2. Overall, ~5% of patients undergoing surgery have serious complications
    3. Mortality <1.1% for biliopancreatic bypass and lower for all other procedures
    4. Increased hospitalization 2X in year after Roux-en-Y bypass compared with year before [82]
    5. Increased early mortality in medicare beneficiaries undergoing bariatric surgery [83]
  8. Multidisciplinary approach with close followup can be extremely effective
  9. Excellent outcomes 10 years after bariatric surgery (versus non-surgical therapy) [64]
  10. Mortality Benefit in Severe Obesity [18]
    1. 25-30% reduction in mortality in severe obesity [91]
    2. Up to 40% reduction in mortality in severe obesity [92]
    3. Greatest reductions in cardiovascular disease, cancer, and diabetes [91,92]

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