MEDICAL MANAGEMENT OF
OBESITY
Selected Topics
 Patient evaluation

Diet

Exercise

Obesity medications
Case 1
50 year old man, in good health, no
history of cigarettes, in for check up.
BMI 32.
Should you tell him he is obese?
CLASSIFICATION OF OVERWEIGHT
AND OBESITY BY BMI
Obesity Class
BMI (kg/m2)
I
II
III
<18.5
18.5 – 24.9
25.0 – 29.9
30.0 – 34.9
35.0 – 39.9
>40
Underweight
Normal
Overweight
Obesity
Extreme Obesity
BMI AND MORTALITY:
Overall
Combined NHANES I, II, and III data set
BMI
<18.5
18.5-<25
25 to <30
30 to <35
≥35
25-59 y
60-69 y
≥70 y
1.38
1.00
0.83
1.20
1.83
2.30
1.00
0.95
1.13
1.63
1.69
1.00
0.91
1.03
1.17
Flegal, JAMA, 2005
Case 1 (continued)
You tell him he is obese.
He says, “ I’m not interested in weight loss. I
just want a refill of my viagra.”
What is your response? How much of a
work up should you perform?
An Office-Based Approach
Make the diagnosis (and
communicate it)
Assess readiness for change
Prescribe diet and exercise
Consider medications and
surgery
METABOLIC SYNDROME
Fulfill 3 or more criteria:
 Waist: men > 102 cm ( > 40 in); women > 88 cm ( > 35
in)
 HDL: men < 40; women < 50
 Triglycerides: ≥150 mg/dl
 BP: ≥130/85 (or use of medications)
 Fasting glucose: ≥110 mg/dl
ICD-9: 277.7
NCEP, JAMA 2001
LIFESTYLE CHANGES AND ERECTILE
DYSFUNCTION
 RCT 110 obese men, 35-55 with ED, 2 years
 Detailed advice to achieve 10% weight loss vs
general info re food choices and exercise
Diet
BMI
31.2
Control
35.7
EF score over 22
17 (31%)
3
p=0.001
Esposito JAMA, 2004
GOALS OF MANAGEMENT

Be as fit as possible at current weight

Prevent further weight gain

If successful at 1 and 2, begin weight
loss
Case 2
50 year old woman, in good health, in for
check up. BMI 32 with metabolic
syndrome.
She says, “ I have to lose weight, and I
am planning on doing that. I am about
to try the Atkins diet.”
DIET THERAPY
• 48 RCT’S
• Average weight loss 8% over
3-12 months
VLCD’s vs LCD’s:
Meta-analysis of 29 U.S. Studies
• Weight loss studies with > two year f/u
• 13 VLCDs, 14 LCDs
• Mostly observational studies (few RCT’s)
Weight loss (as % of initial weight):
LCDs
VLCDs
1y
7.2
16.1
2y
4.2
9.7
3y
3.5
7.8
4y
2.8
7.0
5y
2.0
6.2
Anderson, Am J Clin Nutr, 2001
COMPARISON OF ATKINS, ORNISH,
WEIGHT WATCHERS, AND ZONE
160 patients, randomly assigned
Intention to treat at 1 year
Wt Loss (kg)
Completers (%)
Atkins
2.1
53
Ornish
3.3
50
WW
3.0
65
Zone
3.2
65
Ornish
6.6
WW
4.6
Zone
4.9
Completers at 1 year
Wt Loss (kg)
Atkins
3.9
Dansinger, JAMA 2005
COMPARISON OF ATKINS, ORNISH,
WEIGHT WATCHERS, AND ZONE
 Each group: 25% lost 5%, 10% lost 10% of initial
weight
 Each diet reduced LDL/HDL by 10%
 No significant effects on BP or glucose
 Weight loss associated with adherence, but not
diet type
 CRP and insulin reductions associated with
weight loss, but not diet
Dansinger, JAMA, 2005
DIET APPROACHES
 Diets
low cal (low fat, low carbohydrate),
meal replacement
 Commercial programs
Weight Watchers™, Jenny Craig™,
TOPS™, Overeaters Anonymous™,
Nutrisystem.com,™ Shapedown,™
The Solution™
 Internet programs (by RDs)
Fitday.com, Dietwatch.com,
Cyberdiet.com, eDiets.com,
Shapeup.org
FITNESS AND MORTALITY
Aerobics Center Longitudinal Study
25,714 men, 44 years old, 14 year observational study
CV death (RR)
normal
Fit
1.0
Not fit
3.1
overweight
1.5
4.5
obese
1.6
5.0
Total death (RR)
normal
Fit
1.0
Not fit
2.2
overweight
1.1
2.5
obese
1.1
3.1
Wei, JAMA 1999
FITNESS AND OBESITY
Nurses Health Study
116,564 women, 24 year observational study
Total death (RR)
Active
Not active
normal
1.00
1.55
overweight
1.91
2.42
Hu FB, NEJM 2004
SUCCESSFUL WEIGHT LOSS
MAINTENANCE
 3000 subjects in National Weight Control
Registry: 30-lb weight loss for 1-year
 Average weight loss 30kg (10 BMI units less),
average weight maintenance 5.5 years
 45 years old, 80% women, 97% Caucasian
 46% overweight as child, 46% one parent obese,
27% both parents
Wing and Hill, Ann Rev Nutr, 2001
SUCCESSFUL WEIGHT LOSS
MAINTENANCE
High levels of physical activity
 Women 2545 kcal/week, men 3293 kcal/week
(1-hour moderate intensity per day
 Only 9% report no physical activity
Diet low in fat, high in carbohydrate
 1381 kcal day, 24% fat, 19% protein, 56% CHO
 4.87 meals or snacks/day
 Fast food 0.74/week
Regular self-monitoring of weight
 44% weigh once per day; 31% once per week
Wing and Hill, Ann Rev Nutr, 2001
Case 3
46 year old woman, in good health, in for check
up. BMI 42 with metabolic syndrome.
In 1996 she lost 20 pounds on phen-fen. She
wants a new weight loss drug and a referral
for weight loss surgery.
“LONG TERM” PHARMACOTHERAPY OF
OBESITY
Review of all RCT’s more than 36 weeks published since 1960
Weight loss in excess of placebo:
% of initial
kg’s
Phen-fen
11.0%
9.6 kg
Phentermine
8.1%
7.9 kg
Sibutramine
5.0%
4.3 kg
Orlistat
3.4%
3.4 kg
Dexfenfluramine
3.0%
2.5 Kg
Fluoxetine
-0.4%
-0.4 kg
Diethyproprion
-1.5%
-1.5 kg
Glazer, Arch Int Med 2001
OFF-LABEL USE
Sertraline – SSRI
– More selective 5-HT uptake inhibitor
– In Phase III trials now
Buproprion – NA re-uptake inhibitor
– RCT of 327 obese pts, 24 weeks;
– Wt. loss: 2% placebo vs. 5% in 300/400 mg
Topiramate – CA inhibitor
– RCT in 385 obese pts; dose-ranging; 24 wks
– Wt loss: -2.6% placebo vs. -5 to -6% w/drug
OTHER DRUGS OFF-LABEL
Amantadine
Other SSRIs (fuvoxamine, venlafaxine, citalopram, others)
H2 blockers (cimetidine)
Metformin
– Wt loss: -2 kg with drug vs. -0 kg with placebo vs. -4 kg
with lifestyle in DPP
Zonisamide – antiepileptic
– Wt loss: -5.9 kg with drug vs. 0.9 kg with placebo
DRUGS IN PHASE III TRIALS
Axokine - Ciliary Neurotrophic Factor analog
– CNTF structurally related to IL-6
– Anorexigenic effect from inhibition of NPY
– SQ injections
Rimonabant – Cannabinoid 1 receptor
– Selective antagonist of CB1 - CNS action
– Oral
RIMONABANT (Acomplia™)
 1,507 severely obese people, Europe, 2-years
(2005)
rimonabant
placebo
7.3 kg loss
2.5 kg loss
 3,040 obese people, US, 2-years (2004)
rimonabant
placebo
7.6 kg loss
2.3 kg loss
RIMONABANT (Acomplia™)
Side Effects
Nausea: 13.7% with drug vs. 5.5% on placebo
Dizziness: double with drug
Diarrhea: double with drug
Depression: 2.8% vs. 1.6%
Drop outs: 19% with drug vs. 13% with placebo
Future Drug Targets
Food Intake-central
•Monoamines (NA, 5-HT, DA)
•Peptides (NPY, AGRP, POMC,
CART, CRH, insulin)
Leptin
Vagus
Food Intake-peripheral
•GI peptides (CCK)
•Pancreatic peptides (GLP-1,
enterostatin, amylin)
Obesity
Thermogenesis
•Thyroid hormones
•Β3-adrenergic agonists
•UCPs
Fat Absorption
Fat Metabolism
•Lipase inhibitors
•Fatty acid transporters
•DGAT
•Adipocyte differentiation
Bray, Nature, 2000
PRINCIPLES OF DRUG THERAPY
•
NIH: BMI > 30 kg/m2 or 27 kg/m2 with co-morbidity
(but in practice almost never)
•
Motivated to begin structured exercise and low
calorie diet
•
Begin medications at completion of one month
successful diet and exercise
•
Continue medications only if additional weight
loss achieved in first month with meds
The Magic Formula