Overweight and Obesity

Harvey Hsu M.D.July 9, 2007

Introduction

Obesity is a multifactorial chronic diseaseInvolves social, behavioral, cultural, physiological, metabolic and genetic factors.Second leading cause of preventable death in the United StatesMore evident in some minority groups, those with lower incomes, and less education

Overweight and Obese

Substantially raises risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, and some cancers.Social stigmatization and discrimination

Body Mass Index (BMI)

BMI = weight (kg)/ height (m2) or 704.5 x lb/in2

Overweight is defined as a BMI of 25 to 29.9 kg/m2

Obesity is a BMI of 30 kg/m2

Normal is a BMI 24.9 kg/m2 to 18.5 kg/m2

Underweight is <18.5 kg/m2

Obesity

Obesity class 1 BMI 30.0-34.9Obesity class 2 BMI 35.0- 39.9Obesity class 3 BMI >= 40Waist circumferenceMen > 102 cm ( > 40 in)Women > 88 cm ( > 35 in)

Body Mass Index

Lindsay Lohan is 5’6” and 112 lb BMI 18.1Jennifer Lopez is 5’6” and 118 lb BMI 19Amare Stoudemire is 6’10” and 245lb BMI 25.6George Bush is 6’0” and 190 lb BMI 25.8Arnold Schwarzenegger 6’2” and 257. BMI 33Competition wt 235 BMI 30.2

Body Mass Index

Walter Hudson (worlds fattest man) was 1400 lbs , height 5’ 11” ? BMI 198

Robert Wadlow (worlds tallest man) was 8’11” and 440 lb BMI 27.4

NHANES

65.7 percent of U.S. Adults are overweight or obese. (2001-2002) 33 percent are at a healthy weight Total 65.1 % overweigh or obese, 30.4% were obese, and 4.9% were extremely obese. (1999-2002)

NHANES

Hypertension

Age adjusted prevalence of high blood pressure increases progressively with higher levels of BMIEach kg of weight loss decreases systolic BP by 2.5mm and diastolic 1.7 mm/Hg

Dyslipidemia

Overweight and obesity are associated with increased cholesterol levels. Increased triglyceridesDecreased HDLIncreased LDL

Diabetes Mellitus

The increased risk of diabetes as weight increases has been shown by prospective studiesRelative risk of diabetes increases by approximately 25% for each additional unit of BMI over 22 kg/m2

Coronary Heart Disease

Observational studies have shown that overweight, obesity, and excess abdominal fat are directly related to cardiovascular risk factors, including high levels of total cholesterol, LDL-cholesterol, triglycerides, blood pressure, fibrinogen and insulin [86] , and low levels of HDL- cholesterol

Congestive heart failure

Overweight and obesity have been identified as important and independent risk factors for congestive heart failure (CHF) in a number of studies, including the Framingham Heart Study

Stroke

Overweight may be associated with ischemic strokeRecent prospective studies demonstrate that the risk of stroke shows a graded increase as BMI risesischemic stroke risk is 75 percent higher in women with BMI > 27, and 137 percent higher in women with a BMI > 32, compared with women having a BMI < 21

Gallstones

Risk of gallstones increases with adult weightRisk of either gallstones or cholecystectomy is as high as 20 per 1,000 women per year when BMI is above 40, compared with 3 per 1,000 among women with BMI < 24

Osteoarthritis

Association with increased weight and knee osteoarthritis is stronger in women.Every kilogram increase in weight increased the risk of developing osteoarthritis by 9 to 13%

Sleep Apnea

Obesity, particularly upper body obesity, is a risk factor for sleep apnea and has been shown to be related to its severityMost people with sleep apnea have a BMI>30Large neck girth is predictive

Cancer

Colon cancerBreast CancerEndometrial cancerGallbladder canceroverweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women

Relative to the normal weight category (BMI 18.5 to 25), obesity (BMI >30) was associated with 111 909 excess deaths (95% confidence interval [CI], 53 754-170 064) and underweight with 33 746 excess deaths (95% CI, 15 726-51 766). Overweightwas not associated with excess mortality (-86 094 deaths; 95% CI, -161 223to -10 966). JAMA. 2005;293:1861-1867 www.jama.com

Natural laws of Prehistoric Times

Eat when hungryEat food high in fatSleep near food supplyConserve energy

Treatment

DietExercisePharmacotherapySurgery

Diet

3500 kcal is equivalent to 1 pound1. Multiply your body weight times 13.

2. Add to that the number of calories you typically burn off during exercise each day.

3. Subtract 2% of that total for each decade after the age of 30.

4. The result is your daily caloric need.

Diet

Calculate total required caloriesHave patient record all mealsBehavior therapyVLCDs produce greater initial weight loss than LCDs. However, the long-term (> 1 year) weight loss is not different from that of the LCD

Exercise

One additional pound of fat burns 2 kcal/dayOne additional pound of muscle burns 75 kcal/dMaintains lean body mass and metabolismThe combination of a reduced calorie diet and increased physical activity produces greater weight loss than diet alone or physical activity alone

Pharmacotherapy

Dexfenfluramine/fenfluraminePhentermineSibutramine (Meridia)Orlistat (Xenical)

Dexfenfluramine/fenfluramine

Serotonin reuptake inhibitor/serotonin releaserAdverse Effects:– Valvular heart disease – Primary pulmonary hypertension– Neurotoxicity

Phentermine

A sympathomimetic amineCNS stimulationElevation of blood pressure

Sibutramine (Meridia)

Norepinephrine, dopamine, and serotinin reuptake inhibitorAdverse Effect- increase in heart rate and blood pressure, BP 1-3 mm/Hg HR 4-5 b/minUse in BMI>30Or in BMI >27 with risk factors

Orlistat (Xenical)

Inhibits pancreatic lipase, decreases fat absorptionAdverse effects– Decrease in absorption of fat soluble viatmins– Soft stools and anal leakage– Possible link to breast cancer

Orlistat (alli)

Other

Ephedrine, caffeine, fluoxetine, wellbutrin have been used for weight loss but not FDA approved.Zonisamide (Topamax)Recombinant Variant of Ciliary Neurotrophic Factor (CNTF)SR141716 (Rimonabant)

Antiobesity drugs in pipeline

Rimonabant(Acomplia) Cannabinoid receptor antagonistAxokine – Nerve growth factor agonistAC137/Pramlintide –Delays gastric emptyingAOD9604 – Increases lipolysis, decreases lipogenesis, and raises resting energy expenditureADP356 – Selective 5-HT2C receptor antagonistGT 389-255 – Gastrointestinal lipase inhibitor conjugated to fat-binding polymer

Zonisamide (Topamax)

16 week randomized, double-blind, placebo-controlled trial with optional single-blind extension for 16 more weeksAt 16 weeks: 5.9kg (6.0%) vs 0.4kg (1.0%)At 36 weeks: 9.2kg (9.4%) vs 1.5kg (1.8%)

Recombinant Variant of Ciliary Neurotrophic Factor (CNTF)

• 12 week double-blind, randomized, parallel group, dose-ranging, multicenter clinical trial

• Placebo: 0.1kg • rhvCNTF 0.3 mcg/kg: -1.5kg • rhvCNTF 1.0 mcg/kg: -4.1kg • rhvCNTF 2.0 mcg/kg: -3.4kg

Acomplia (rimonabant)

62.5 percent of patients treated for the full two years with the higher dose of Acomplia lost more than 5 percent of their body weight compared to 36.7 percent of those on the low dose of Acomplia and 33.2 percent of patients in the control group.

32.8 percent of patients treated for the full two years with the higher dose of Acomplia lost more than 10 percent of their body weight compared to 20 percent of patients on the low dose of Acomplia and 16.4 percent of patients in the control group

Axotine

Placebo

AXOKINE

0.5 mcg/kg      1.0 mcg/kg

Intent-to-Treat Analysis **

2.5 lbsn=52

5.2 lbsn=52* p= .08

6.5 lbsn=53* p< 0.01

Completer Analysis ***2.6 lbsn=48 (92%)

5.6 lbsn=47 (90%)* p= .07

7.0 lbsn= 47 (89%)* p< 0.01

Surgery

Gastrointestinal surgery (gastric restriction [vertical gastric banding] or gastric bypass [Roux-en Y]) can result in substantial weight loss, and therefore is an available weight loss option for well-informed and motivated patients with a BMI >40 or 35, who have comorbid conditions and acceptable operative risks

Gastric Bypass Laparoscopic Adjustable Gastric Band

Gastric Bypass Vertical Banded Gastroplasty

Gastric Bypass Roux-en-Y

                                                                  

                                                                       

Gastric Bypass Surgery Complications: 14-Year Followup

Surgical Complications Number of Patients % of PatientsVitamin B12 deficiency 239 39.9Readmit for various reasons 229 38.2Incisional hernia 143 23.9Depression 142 23.7Staple line failure 90 15.0Gastritis 79 13.2Cholecystitis 68 11.4Anastomotic problems 59 9.8Dehydration, malnutrition 35 5.8Dilated pouch 19 3.2

Data derived from source (Pories et al.) and modified based on personal communication.Source: Pories WJ, Swanson MS, MacDonald KG Jr, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222:339-350; discussion 350-352.

Gastric Bypass Surgery Weight Loss

Bariatric Surgery, A Systematic Review and Meta-analysis JAMA October 13, 2004

Gastric Bypass Surgery Benefits

Bariatric Surgery, A Systematic Review and Meta-analysis JAMA October 13, 2004

Diabetes: resolution in 76.8%, improvement 86%Cholesterol: total chol -33LDL -29 Triglycerides -79.65Hypertension: 61.7% resolved, improvement 78.5%Obstructive Sleep Apnea: 85.7% resolved

Low Carbohydrate Diets

NEJM - the group on the low-carbohydrate diet had lost significantly more weight than the group on the conventional diet at 3 months (P=0.001) and 6 months (P=0.02), but the difference in weight loss was not statistically significant at 12 months (P=0.26)

Low Carbohydrate Diets

Journal of Clinical Endocrinology and Metabolism, april 2003a very low carbohydrate diet is more effective than a low fat diet for short-term weight loss and, over 6 months, is not associated with deleterious effects on important cardiovascular risk factors in healthy women

TABLE 4 -- Means (and SE) of blood pressure and plasma lipid concentrations of women before and after 3 and 6 months of dieting

Very low carbohydrate diet group (n = 22) Low fat diet group (n = 20)

Baseline 3 months 6 months Baseline 3 months 6 months

Blood pressure (mm Hg) 116/79 (3.23/2.69)

112/72 (2.36/2.06)

114/74 (2.82/2.23)

115/75 (2.47/1.99)

116/75 (2.01/1.79)

113/74 (2.41/1.62)

Total cholesterol (mg/dl) 206.32 (6.63) 185.68 (5.64) 205.46 (6.79) 184.45 (6.07) 176.25 (5.87) 182.85 (6.21)

Triglycerides (mg/dl) 148.73 a (13.41) 92.41 (8.74) 113.86 (15.25) 109.25 (9.49) 101.80 (6.71) 111.00 (12.37)

LDL (mg/dl) 124.86 (5.39) 113.00 (5.34) 124.00 (5.81) 113.80 (6.36) 104.90 (5.97) 107.80 (5.86)

HDL (mg/dl) 51.77 (2.82) 54.09 (2.77) 58.73 (2.57) 48.75 (2.23) 51.05 (3.49) 52.85 (2.58)

To convert to SI units, multiply total cholesterol, LDL-cholesterol, HDL-cholesterol (mg/dl) × 0.0259 = mmol/liter; multiply triglycerides (mg/dl) × 0.1129 = mmol/liter.

Low Carbohydrate Diets

Annals 2004 (Yancy et al)- the group on the low-carbohydrate diet had lost significantly more weight than the group on the conventional diet at 24 weeks (mean change, -12.9 vs –6.7)Triglycerides low carb vs conventional (-74.2 mg/dl vs –27.9 P =0.004HDL (5.5 vs –1.6 (P<0.001)LDL (1.6 vs –7.4 P=0.2)

Low Carbohydrate Diets

Annals 2004 (Stern et al)- Weight loss between low carb group and conventional diet was similar after one year (-5.18.7 kg compared with –3.18.4kg P=0.20) Triglyerides conventional diet vs low carb (4vs -5.8P=0.044)HDL (-5 vs -1 P=028)LDL ( -4 vs 7 P=0.191)HgbA1c in diabetics(-0.1 vs –0.7 P=.102

Low Carbohydrate Diets

JAMA (Gardner et al)- The A TO Z Weight Loss Study, Atkins, Zone, Ornish, LEARNAt 12 months the Atkins diet had the most weight loss, while the other 3 were similar.Weight change relative to baseline at 12 monthsZone -1.6kgAtkins –4.7kgLEARN –2.6kgOrnish –2.2kg

Summary

Obesity is a chronic diseaseHave realistic expectationsModest weight loss (5-10%) has significant health benefits.