Transcript Judith Korner

Obesity 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
Obesity Trends* Among U.S. Adults
BRFSS, 1991, 1996, 2004
(*BMI 30, or about 30 lbs overweight for 5’4” person)
1991
1996
2004
No Data
<10%
10%–14%
15%–19%
20%–24%
≥25%
Medical Complications of Obesity
Pulmonary disease
abnormal function
obstructive sleep apnea
hypoventilation syndrome
Nonalcoholic fatty liver
disease
steatosis
steatohepatitis
cirrhosis
Gall bladder disease
Idiopathic intracranial
hypertension
Stroke
Cataracts
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
GERD
Severe pancreatitis
Gynecologic abnormalities
Cancer
abnormal menses
infertility
polycystic ovarian syndrome
breast, uterus, cervix
colon, esophagus, pancreas
kidney, prostate
Osteoarthritis
Skin
Gout
Phlebitis
venous stasis
Age-Adjusted Relative Risk
Relationship Between BMI and Risk of Type 2
Diabetes
93.2
100
Men
Women
75
54.0
50
42.1
40.3
27.6
21.3
25
1.0
0
<22
2.9
1.0
4.3
1.0
5.0
1.5
<23
23
23.9
24
24.9
8.1
2.2
15.8
25
26.9
27
28.9
4.4
6.7
29
30.9
11.6
31
32.9
33
34.9
35+
Body Mass index (kg/m2)
Chan J et al. Diabetes Care 1994;17:961.
Colditz G et al. Ann Intern Med 1995;122:481.
Slide Source:
www.obesityonline.org
Relationship Between Weight Gain in Adulthood and
Risk of Type 2 Diabetes Mellitus
6
Men
Relative Risk
5
Women
4
3
2
1
0
-10
-5
0
5
10
15
20
Weight Change (kg)
Willett et al. N Engl J Med 1999;341:427.
Slide Source:
www.obesityonline.org
Relationship Between BMI and
Cardiovascular Disease Mortality
Relative Risk of Death
3.0
Men
2.6
Women
2.2
1.8
1.4
1.0
Lean
Overweight
Obese
0.6
<18.5
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 >40.0
–
39.9
Body Mass index
Calle et al. N Engl J Med 1999;341:1097.
Slide Source:
www.obesityonline.org
Relationship Between BMI and Comorbidities
is Positive, Even in the “Normal” Range
Men
Women
6
6
5
5
4
4
3
3
2
2
1
1
0
0
<21
22
Type 2 diabetes
Cholelithiasis
Hypertension
Coronary heart disease
23
24
25
26
27
28
29
Body Mass Index
(kg/m2)
Willett WC, et al. N Engl J Med. 1999;341:427-434.
30
<21
22
23
24
25
26
27
28
Body Mass Index
(kg/m2)
29
30
Physical Exam
•Vitals (use appropriate size BP cuff )
•Height, Weight, Calculate BMI (kg/m2)
wt (lb) x 703
ht (in2)
Overweight ≥ 25
Obese ≥ 30
•Measure waist circumference
(>35 inches for women; >40 inches for men)
•Skin changes: acanthosis nigricans, pigmented striae
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.
9
Laboratory Tests
•Biochemistry Profile
•Thyroid Profile
•Lipid Profile
•Fasting Insulin and Glucose
Consider insulin resistance if insulin > 10U/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
Initiating a Discussion about Weight
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
Wadden, Obes Res 11:1140
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
Setting Realistic Goals
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
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
Goal Weight Loss Defined by Subjects
•Dream
•Happy
•Acceptable
•Disappointed
% Reduction
38%
31%
25%
17%
•Average goal weight reduction was 32%
Cornerstone of Weight Loss
Treatment
• Behavior Therapy, Diet, Exercise
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 nonfood 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.
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
Long-Term Weight Loss: Non-Pharmacologic Treatment
VLCD: ≤800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior
Wadden Annals of Int Med 119:688 1993
Weight Loss Treatment
• Behavior Therapy, Diet, Exercise
• Pharmacotherpy:
BMI  30, or  27 and 2 co-morbidities
Mechanisms of Action: Sibutramine and Active
Metabolites Block Serotonin, Norepinephrine, and
Dopamine Reuptake
MAO
S
S
REUPTAKE
Serotonin
S
S
Release
MAO
S
S
REUPTAKE
Norepinephrine
Release
S
S
S = sibutramine
 = norepinephrine,  = serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
Sibutramine: Efficacy
Mean Weight Change in 1 Year Trial
0
-2
Placebo (n = 76)
Mean -4
Weight
Change
-6
(%)
*
*
-8
10 mg qd (n = 79)
15 mg qd (n = 93)
-10
0
1
2
3
4
5
6
7
8
Treatment Month
*P < 0.01 vs placebo.
Bray et al, Obes Res 1996;4:263-270
9
10 11 12
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
Proportion of patients who maintained 5% and 10%
weight loss from baseline on sibutramine
5% Responders
6
12
18
24
10% Responders
MONTH
6
12
James PT et al. Effect of sibutramine on weight maintenance after weight loss: a
randomised trial. Lancet 2000; 356: 2119–25
18
24
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
Orlistat
Mechanism of Action
30% of fat not absorbed
Weight Change Over 104 Weeks
Weight Loss (%)
Placebo
Orlistat
0
Diet
Hypocaloric
Eucaloric
-4.5%
-5
-8.1%*
-10
-13
0
15
30
*P < 0.05 (vs placebo).
Sjöström L, et al. Lancet. 1998;352:167-172.
45
60
Week
75
90
104
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.
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
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
R. Steinbrook, NEJM 350, 2004
Other Options for Weight Loss
• Metformin
• Review patient’s
medications and consider
alternatives
Diabetes Prevention Program Research Group
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
Average Wt Loss
Placebo:
0.1 kg
Metformin: 2.1 kg
Lifestyle: 5.6 kg
50% ≥7% at 24 wk
38% ≥ 7% at most
recent visit
Decrease in daily
energy intake
Placebo:
249 kcal
Metformin: 296 kcal
Lifestyle: 450 kcal
Diabetes Prevention Program Research Group
Cumulative Incidence
of Diabetes (%)
Placebo
Metformin
Lifestyle
Year
Reduction in Incidence Compared with Placebo
Metformin:
31%
LifeStyle:
58%
Number needed to treat for 3 y to prevent 1 case of DM
Metformin:
13.9
NEJM 346: 393 2002
Lifestyle:
6.9
Impact of Anti-Diabetic Therapies on Weight
GAIN
NEUTRAL
Sulfonylurea
Glinide
TZDs
Metformin
Insulin
DPP4-Inhibitor
LOSS
GLP-1 agonist
Alpha-Glucosidase Pramlintide
Inhibitor
Nathan et al Diabetes Care 31:1-11, 2008
CNS Drug-Induced Weight Gain
Drugs that May
Promote Weight Gain
Antidepressants
– Paroxetine
– Mirtazapine
– MAOIs, TCAs
 Antiepileptic drugs
– Valproate
– Gabapentin
 Antipsychotics
– Clozapine, olanzapine,
risperidone, quetiapine
 Lithium

Drugs that Cause Little or No Weight
Gain or Weight Loss
Antidepressants
– Bupropion
– Venlafaxine
 Antiepileptic drugs
– Topiramate
– Lamotrigine
– Zonisamide
 Antipsychotics
– Ziprasidone
– Aripiprazole

MAOIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants.
Different Long-Term Effects of SSRIs on Body
Weight
*
3
2
1
Paroxetine (n = 47)
Sertraline (n = 48)
Fluoxetine (n = 44)
30
†P
= .015
†P
< .001
0
% Incidence of >7%
Weight Gain
Mean % Change in
Body Weight
4
-1
25
20
15
10
5
†P
†P < .003
0
Analysis is for treatment responders
*P < .001 compared to baseline, †P-values for comparison to paroxetine
Fava M, et al. J Clin Psychiatry. 2000;61:863-7.
< .016
Efficacy of topiramate for weight loss in obese
individuals: randomized double-blind placebocontrolled multicenter trial
Bray et al, Obesity Research, (2003) 11:722
Adverse Events with Topiramate
• Events were dose related and reversible after treatment
was stopped
• Paresthesia
• Psychomotor slowing
• Difficulty concentrating
• Fatigue
• Somnolence
A look into the future…
Sibutramine: Efficacy
Mean Weight Change in 1 Year Trial
0
-2
Placebo (n = 76)
Mean -4
Weight
Change
-6
(%)
-8
*
*
10 mg qd (n = 79)
15 mg qd (n = 93)
Why not ?
-10
0
1
2
3
4
5
6
Treatment
*P < 0.01 vs placebo.
Data on file, Knoll Pharmaceutical Company.
7
8
Month
9
10 11 12
Model of a weight-regulating feedback system
Hypothalamus
Vagus
Nerve
Autonomic
Nervous
System
External Factors
food availability,
palatability
Gut and Liver
Insulin
Pancreas
Leptin
Adipose Tissue
Adrenal Steroids
Adrenal Cortex
Aronne LJ. Adapted from Campfield LA, et al. Science. 1998;280:
Meal Size
Energy
Balance
and
Adipose
Stores
Food Intake
Energy
Expenditure
1383-1387; and Porte D, et al. Diabetologia. 1998;41:863-881.
Combination Therapies
Topiramate + Phentermine
Zonisamide + Buproprion
Bupropion + Naltrexone
Leptin + Pramlintide
Behavioral Mechanisms:
Is Extreme Ravenousness Required?
2 oz chocolate bar
20 oz cola
Total
=
=
=
260 kcal
252 kcal
512 kcal
Weight gain: 1 lb/week
Forbes GB, et al. Br J Nutr. 1986;56:1-9.
Allison DB, et al. Am J Psychiatry. 1999;156:1686-96.
Disparagement of obese individuals is
“the last socially acceptable form of prejudice.”
Stunkard and Sobal, 1995