obesity update internal medicine review columbia university august 12, 2010 judith korner, md, phd...
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Obesity updateObesity update
Internal Medicine Review
Columbia University
August 12, 2010
Judith Korner, MD, PhD
Assistant Professor, Department of Medicine
College of Physicians & Surgeons
Director, Weight Control Center
Columbia University Medical Center
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19961991
Obesity Trends* Among U.S. AdultsBRFSS, 1991, 1996, 2004
(*BMI 30, or about 30 lbs overweight for 5’4” person)
No Data <10% 10%–14% 15%–19% 20%–24% ≥25%
2004
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Pulmonary diseasePulmonary diseaseabnormal functionabnormal functionobstructive sleep apneaobstructive sleep apneahypoventilation syndromehypoventilation syndrome
Nonalcoholic fatty liver Nonalcoholic fatty liver diseasediseasesteatosissteatosissteatohepatitissteatohepatitiscirrhosiscirrhosis
Coronary heart diseaseCoronary heart disease
DiabetesDiabetes
DyslipidemiaDyslipidemia
HypertensionHypertension
Gynecologic abnormalitiesGynecologic abnormalitiesabnormal mensesabnormal mensesinfertilityinfertilitypolycystic ovarian syndromepolycystic ovarian syndrome
OsteoarthritisOsteoarthritis
SkinSkin
Gall bladder diseaseGall bladder disease
CancerCancerbreast, uterus, cervixbreast, uterus, cervixcolon, esophagus, pancreascolon, esophagus, pancreaskidney, prostatekidney, prostate
PhlebitisPhlebitisvenous stasisvenous stasis
GoutGout
Medical Complications of ObesityIdiopathic intracranial Idiopathic intracranial hypertensionhypertension
StrokeStroke
CataractsCataracts
Severe pancreatitisSevere pancreatitisGERDGERD
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0
25
50
75
100
Relationship Between BMI and Risk of Type 2 Relationship Between BMI and Risk of Type 2 DiabetesDiabetes
Chan J et al. Diabetes Care 1994;17:961.Colditz G et al. Ann Intern Med 1995;122:481.
Age
-Adj
uste
d R
elat
ive
Ris
k
Body Mass index (kg/m2)
MenMen
WomenWomen
<22 <23 23-
23.9
24-
24.9
25-
26.9
27-
28.9
29-
30.9
31-
32.9
33-
34.9
35+
1.0
2.91.0
4.31.0
5.01.5
8.12.2
15.8
4.4
27.6
40.3
54.0
93.2
6.711.6
21.3
42.1
Slide Source:www.obesityonline.org
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0
1
2
3
4
5
6
Relationship Between Weight Gain in Adulthood and Relationship Between Weight Gain in Adulthood and Risk of Type 2 Diabetes MellitusRisk of Type 2 Diabetes Mellitus
Re
lativ
e R
isk
Weight Change (kg)Willett et al. N Engl J Med 1999;341:427.
-10 -5 0 5 10 15 20
MenMen
WomenWomen
Slide Source:www.obesityonline.org
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0.6
1.0
1.4
1.8
2.2
2.6
3.0
Relationship Between BMI and Relationship Between BMI and Cardiovascular Disease MortalityCardiovascular Disease Mortality
Rel
ativ
e R
isk
of D
eath
Body Mass index
<18.5
MenMen
WomenWomen
Calle et al. N Engl J Med 1999;341:1097.
18.5–
20.4
20.5–
21.9
22.0–
23.4
23.5–
24.9
25.0–
26.4
26.5–
27.9
28.0–
29.9
30.0–
31.9
32.0–
34.9
35.0–
39.9
>40.0
Lean Overweight Obese
Slide Source:www.obesityonline.org
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Relationship Between BMI and Comorbidities Relationship Between BMI and Comorbidities is Positive, Even in the “Normal” Rangeis Positive, Even in the “Normal” Range
Willett WC, et al. N Engl J Med. 1999;341:427-434.
Body Mass IndexBody Mass Index(kg/m(kg/m22))
Relative Relative RiskRisk
WomenWomen MenMen
4
6
5
3
2
1
0<21 22 23 24 25 26 27 28 29 30
Body Mass IndexBody Mass Index(kg/m(kg/m22))
4
6
5
3
2
1
0<21 22 23 24 25 26 27 28 29 30
Type 2 diabetesType 2 diabetes
CholelithiasisCholelithiasis
HypertensionHypertension
Coronary heart diseaseCoronary heart disease
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Physical Exam
•Vitals (use appropriate size BP cuff )
•Height, Weight, Calculate BMI (kg/m2)
wt (lb) x 703 Overweight ≥ 25ht (in2) Obese ≥ 30
•Measure waist circumference
(>35 inches for women; >40 inches for men)
•Skin changes: acanthosis nigricans, pigmented striae
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9
How to Measure Waist Circumference
● Place a measuring tape, held parallel to the floor, around the patient’s abdomen at the level of the iliac crest
● The tape should fit snugly around the waist without compressing the skin
● Take the measurement at the end of a normal expiration
A waist circumference of ≥40 inches in men or ≥35 inches in women is diagnostic of abdominal obesity and suggests the presence of other cardiometabolic risk factors.
Adapted from Grundy SM, et al. Circulation. 2005;112:2735-2752.
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Laboratory Tests
•Biochemistry Profile
•Thyroid Profile
•Lipid Profile
•Fasting Insulin and Glucose
Consider insulin resistance if insulin > 10U/ml or glucose is >95 mg/dl
•EKG
•If clinical suspicion of Cushing’s - 24 hr UFC
•If clinical suspicion of PCOS - androgen profile
•If clinical suspicion of sleep apnea - sleep study
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Initiating a Discussion about Weight
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What’s in a Name?Patients’ Preferred Terms for Describing Obesity
• “Imagine you are visiting your doctor for a check up. The nurse has measured your weight and found that you are at least 50 pounds over your recommended weight.”
• “Please indicate how desirable or undesirable you would find each of the following terms if your doctor used it to describe your weight.”
Wadden Obesity Res 11, 2003
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Wadden, Obes Res 11:1140
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Initiating a Discussion
• “Ms. Jones, could we talk for a moment about your weight?”
• “Tell me your thoughts about your weight at this time. I know how hard you’ve worked in the past to control it. What are your goals now?”
as opposed to
• The “call-it-what-it-is” approach which fails to recognize the offensive, derogatory manner in which the terms fatness and obesity are used by the public.
Wadden Obesity Res 11, 2003
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Setting Realistic Goals
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Realistic Goals
• Moderate weight loss: 5-10% reduction in body weight over 6-12 months
• Weight loss of this magnitude significantly decreases the severity of obesity-associated risk factors
NIH/NHLBI, Obes Res 1998
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Forget about Barbie
• Barbie’s projected human measurements:
39-18-33
• Average white woman:
age 18-25: 38-32-41
age 36-45: 41-34-43
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Goal Weight Loss Defined by Subjects
% Reduction
•Dream 38%
•Happy 31%
•Acceptable 25%
•Disappointed 17%
•Average goal weight reduction was 32%
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Cornerstone of Weight Loss Treatment
• Behavior Therapy, Diet, Exercise
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Behavior Therapy• Self-monitoring includes recording dietary intake (food choices,
amounts, times), exercise and changes in body weight. • Stimulus control - identify and change cues that are associated with
eating too much and exercising too little. For example, limiting exposure to food or separating eating from other activities such as reading or watching television.
• Reinforcement encourages attainment of difficult to achieve goals. Reinforcement may come from a social support network or getting non-food rewards for reaching goals.
• Stress management helps coping with stressful events by developing outlets besides eating for reducing stress. Evaluating setbacks and determining how to do better next time can break the chain of negative thinking and self-punishment when lapses occur.
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Diet
• Whatever works, but is healthy. Don’t be afraid to try different approaches.– Low glycemic diets may reduce appetite (Ludwig DS)– Low calorie density foods enhance satiety with fewer calories (Rolls B)– Less palatable foods reduce calorie intake– Structure helps
• Liquid meal replacements• Prepackaged food
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VLCD: ≤800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior
Wadden Annals of Int Med 119:688 1993
Long-Term Weight Loss: Non-Pharmacologic Treatment
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Weight Loss Treatment
• Behavior Therapy, Diet, Exercise
• Pharmacotherpy:
BMI 30, or 27 and 2 co-morbidities
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Adapted from Ryan et al. Adapted from Ryan et al. Obesity Res.Obesity Res. 1995;3(suppl 4):553S-559S. 1995;3(suppl 4):553S-559S.
S = sibutramineS = sibutramine
= norepinephrine,= norepinephrine, = serotonin= serotonin
Mechanisms of Action: Sibutramine and Active Metabolites Block Serotonin, Norepinephrine, and
Dopamine Reuptake
Norepinephrine
Serotonin
MAOMAO
Catabolism
Catabolism
ReleaseRelease
MAOMAO
Catabolism
Catabolism
SSSS
SSSS
SSSS
SSSS
ReleaseRelease
REUPTAKEREUPTAKE
REUPTAKEREUPTAKE
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Sibutramine: EfficacyMean Weight Change in 1 Year Trial
**PP < 0.01 vs placebo. < 0.01 vs placebo.Bray et al, Obes Res 1996;4:263-270Bray et al, Obes Res 1996;4:263-270
Treatment MonthTreatment Month
00
MeanMeanWeightWeightChangeChange
(%)(%)
-8-8
10 mg qd (n = 79)10 mg qd (n = 79)
15 mg qd (n = 93)15 mg qd (n = 93)
-10-10
-6-6
-4-4
-2-2
00
11 22 33 44 55 66 77 88 99 1010 1111 1212
Placebo (n = 76)Placebo (n = 76)
**
**
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Mean (±SE) Weight Loss in the Four Groups, as Determined by an Intention-to-Treat Analysis (Panel A) and a Last-Observation-Carried-Forward Analysis (Panel B)
Wadden, T. et al. N Engl J Med 2005;353:2111-2120
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Proportion of patients who maintained 5% and 10% weight loss from baseline on sibutramine
67%
90%
57%
82%
44%
69%
56%59%
36%
56%
26%
52%
21%
46%
0
10
20
30
40
50
60
70
80
90
100
Placebo Sibutramine
5% Responders 10% Responders
6 12 18 24 MONTH 6 12 18 24James PT et al. Effect of sibutramine on weight maintenance after weight loss: arandomised trial. Lancet 2000; 356: 2119–25
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Sibutramine: Safety– Adverse events:
Headaches, constipation, fatigue, dry mouth most common
– Vital signs:
Potentially clinically significant blood pressure increases (1/12)
– Contraindicated in patients with uncontrolled hypertension, coronary heart disease, other vascular disease or co-administration with SSRIs or MAOIs.
– Pulmonary hypertension and valvular heart disease, associated with fenfluramines, not reuptake inhibitors
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OrlistatMechanism of Action
30% of fat not absorbed
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Weight Change Over 104 Weeks
**PP < 0.05 (vs placebo). < 0.05 (vs placebo).Sjöström L, et al. Sjöström L, et al. LancetLancet. 1998;352:167. 1998;352:167172.172.
1313
1010
WeekWeek
8.1%8.1%**
00 1515 3030 4545 6060 7575 9090 104104
00
EucaloricEucaloricHypocaloric Hypocaloric
DietDiet
4.5%4.5%55
Weight Loss (%)Weight Loss (%)
PlaceboPlacebo
OrlistatOrlistat
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Orlistat Safety
• The most common side effects include abdominal discomfort, oily spotting, flatuence with discharge, fecal urgency and incontinence.
• Absorption of fat-soluble vitamins and some medications (eg. cycolsporine) may be affected.
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Noradrenergic Agents• Schedule IV drugs have a low potential for abuse
• Phentermine (Adipex-P, Fastin): 18.75-37.5 mg/day
• Phentermine resin (Ionamin): 15-30 mg/day
• Diethylpropion (Tenuate, Tenuate Dospan):25 mg 3x/day or sustained release 75 mg/day
• Phenylpropanolamine (Dexatrim, Acutrim): withdrawn from market due to association with hemorrhagic stroke
Yanovski NEJM 346:591 2002
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Noradrenergic Agents (cont’d)
• Approved by the FDA for short-term use:
~ 3 months• Studies show between 2-10 kg weight loss over
placebo• Side effects: insomnia, dry mouth, constipation,
euphoria, palpitations, hypertension
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R. Steinbrook, NEJM 350, 2004
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Other Options for Weight Loss
• Metformin
• Review patient’s medications and consider alternatives
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Does lifestyle intervention or administration of metformin prevent or delay the development of diabetes?
Eligibility Criteria•3234 nondiabetic persons•Elevated fasting glucose (95-125 mg/dl) and•Elevated glucose 2h after 75g glucose load (140-199 mg/dl)•BMI ≥ 24 (≥ 22 in Asians)
NEJM 346:393 2002
Diabetes Prevention Program Research Group
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Average Wt LossPlacebo: 0.1 kg
Metformin: 2.1 kg
Lifestyle: 5.6 kg50% ≥7% at 24 wk38% ≥ 7% at most recent visit
Decrease in dailyenergy intakePlacebo: 249 kcalMetformin: 296 kcalLifestyle: 450 kcal
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Cum
ulat
ive
Inci
denc
eof
Dia
bete
s (%
)
Year
Placebo
Metformin
Lifestyle
Diabetes Prevention Program Research Group
Reduction in Incidence Compared with PlaceboMetformin: 31%LifeStyle: 58%
Number needed to treat for 3 y to prevent 1 case of DMMetformin: 13.9Lifestyle: 6.9 NEJM 346: 393 2002
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Impact of Anti-Diabetic Therapies on Weight
GAIN NEUTRAL LOSS
Sulfonylurea
Glinide
Metformin GLP-1 agonist
TZDs Alpha-Glucosidase Inhibitor
Pramlintide
Insulin DPP4-Inhibitor
Nathan et al Diabetes Care 31:1-11, 2008
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Drugs that MayDrugs that MayPromote Weight GainPromote Weight Gain
Drugs that Cause Little or No Weight Drugs that Cause Little or No Weight Gain or Weight LossGain or Weight Loss
AntidepressantsAntidepressants– ParoxetineParoxetine– MirtazapineMirtazapine– MAOIs, TCAsMAOIs, TCAs
Antiepileptic drugsAntiepileptic drugs– ValproateValproate– GabapentinGabapentin
AntipsychoticsAntipsychotics– Clozapine, olanzapine, Clozapine, olanzapine,
risperidone, quetiapinerisperidone, quetiapine LithiumLithium
AntidepressantsAntidepressants– Bupropion Bupropion – VenlafaxineVenlafaxine
Antiepileptic drugsAntiepileptic drugs– TopiramateTopiramate– LamotrigineLamotrigine– ZonisamideZonisamide
AntipsychoticsAntipsychotics– ZiprasidoneZiprasidone– AripiprazoleAripiprazole
CNS Drug-Induced Weight GainCNS Drug-Induced Weight Gain
MAOIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants.
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Different Long-Term Effects of SSRIs on Different Long-Term Effects of SSRIs on Body WeightBody Weight
-1
0
1
2
3
4
0
5
10
15
20
25
30
Me
an
% C
han
ge
inB
od
y W
eig
ht
% In
cid
en
ce o
f >
7%
W
eig
ht
Ga
in
Paroxetine (n = 47)Sertraline (n = 48)Fluoxetine (n = 44)
†P = .015
†P < .001†P < .003
†P < .016
*
*P < .001 compared to baseline, †P-values for comparison to paroxetine
Fava M, et al. J Clin Psychiatry. 2000;61:863-7.
Analysis is for treatment responders
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Bray et al, Obesity Research, (2003) 11:722
Efficacy of topiramate for weight loss in obese individuals: randomized double-blind placebo-
controlled multicenter trial
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Adverse Events with Topiramate
• Events were dose related and reversible after treatment was stopped
• Paresthesia• Psychomotor slowing• Difficulty concentrating• Fatigue• Somnolence
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A look into the future…
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Sibutramine: EfficacyMean Weight Change in 1 Year Trial
**PP < 0.01 vs placebo. < 0.01 vs placebo.Data on file, Knoll Pharmaceutical Company.Data on file, Knoll Pharmaceutical Company.
Treatment MonthTreatment Month
00
MeanMeanWeightWeightChangeChange
(%)(%)
-8-8
10 mg qd (n = 79)10 mg qd (n = 79)
15 mg qd (n = 93)15 mg qd (n = 93)
-10-10
-6-6
-4-4
-2-2
00
11 22 33 44 55 66 77 88 99 1010 1111 1212
Placebo (n = 76)Placebo (n = 76)
**
**Why not ?
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Vagus Nerve
Food IntakeGut and Liver
Pancreas
AutonomicNervousSystem
Hypothalamus
Energy Expenditure
Adipose Tissue
Aronne LJ. Adapted from Campfield LA, et al. Science. 1998;280: 1383-1387; and Porte D, et al. Diabetologia. 1998;41:863-881.
Adrenal Cortex
Energy Balance
and Adipose Stores
Meal Size
Adrenal Steroids
Leptin
Insulin
External Factorsfood availability,
palatability
Model of a weight-regulating feedback systemModel of a weight-regulating feedback system
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Combination Therapies
Topiramate + Phentermine
Zonisamide + Buproprion
Bupropion + Naltrexone
Leptin + Pramlintide
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Behavioral Mechanisms: Behavioral Mechanisms: Is Extreme Ravenousness Required?Is Extreme Ravenousness Required?
2 oz chocolate bar = 260 kcal
20 oz cola = 252 kcal
Total = 512 kcal
Forbes GB, et al. Br J Nutr. 1986;56:1-9.Allison DB, et al. Am J Psychiatry. 1999;156:1686-96.
Weight gain: 1 lb/weekWeight gain: 1 lb/week
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Disparagement of obese individuals is “the last socially acceptable form of prejudice.”
Stunkard and Sobal, 1995