MEDICAL MANAGEMENT OF MEDICAL MANAGEMENT OF OBESITYOBESITY

Selected TopicsSelected Topics

Patient evaluation

Diet

Exercise

Obesity medications

Case 1Case 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)

Underweight <18.5

Normal 18.5 – 24.9

Overweight 25.0 – 29.9

Obesity I 30.0 – 34.9

II 35.0 – 39.9

Extreme Obesity III >40

Flegal, JAMA, 2005

BMI AND MORTALITY: BMI AND MORTALITY: OverallOverall

Combined NHANES I, II, and III data set

BMI 25-59 y 60-69 y ≥70 y

<18.5 1.38 2.30 1.6918.5-<25 1.00 1.00 1.0025 to <30 0.83 0.95 0.9130 to <35 1.20 1.13 1.03≥35 1.83 1.63 1.17

Case 1 (continued)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 ApproachAn Office-Based Approach

Make the diagnosis (and communicate it)

Assess readiness for change

Prescribe diet and exercise

Consider medications and surgery

NCEP, JAMA 2001

METABOLIC SYNDROMEMETABOLIC 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

Esposito JAMA, 2004

LIFESTYLE CHANGES AND ERECTILE LIFESTYLE CHANGES AND ERECTILE DYSFUNCTIONDYSFUNCTION

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

BMI EF score over 22Diet 31.2 17 (31%)

Control 35.7 3

p=0.001

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 2Case 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 THERAPYDIET THERAPY

• 48 RCT’S

• Average weight loss 8% over 3-12 months

Anderson, Am J Clin Nutr, 2001

VLCD’s vs LCD’s: VLCD’s vs LCD’s: Meta-analysis of 29 U.S. StudiesMeta-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):

1y 2y 3y 4y 5y

LCDs 7.2 4.2 3.5 2.8 2.0

VLCDs 16.1 9.7 7.8 7.0 6.2

Dansinger, JAMA 2005

COMPARISON OF ATKINS, ORNISH, COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONEWEIGHT WATCHERS, AND ZONE

Intention to treat at 1 year Atkins Ornish WW Zone

Wt Loss (kg) 2.1 3.3 3.0 3.2Completers (%) 53 50 65 65

Completers at 1 year Atkins Ornish WW Zone

Wt Loss (kg) 3.9 6.6 4.6 4.9

160 patients, randomly assigned

Dansinger, JAMA, 2005

COMPARISON OF ATKINS, ORNISH, COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONEWEIGHT 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

DIET APPROACHESDIET APPROACHES Diets

low cal (low fat, low carbohydrate), meal replacement

Commercial programsWeight 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

Wei, JAMA 1999

FITNESS AND MORTALITYFITNESS AND MORTALITYAerobics Center Longitudinal StudyAerobics Center Longitudinal Study

CV death (RR) normal overweight obese

Fit 1.0 1.5 1.6Not fit 3.1 4.5 5.0

Total death (RR) normal overweight obese

Fit 1.0 1.1 1.1Not fit 2.2 2.5 3.1

25,714 men, 44 years old, 14 year observational study

Hu FB, NEJM 2004

FITNESS AND OBESITYFITNESS AND OBESITYNurses Health StudyNurses Health Study

Total death (RR)

normal overweight Active 1.00 1.91

Not active 1.55 2.42

116,564 women, 24 year observational study

Wing and Hill, Ann Rev Nutr, 2001

SUCCESSFUL WEIGHT LOSS SUCCESSFUL WEIGHT LOSS MAINTENANCEMAINTENANCE

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 SUCCESSFUL WEIGHT LOSS MAINTENANCEMAINTENANCE

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

Case 3Case 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.

Glazer, Arch Int Med 2001

“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

OFF-LABEL USESertraline – 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 7.3 kg lossplacebo 2.5 kg loss

3,040 obese people, US, 2-years (2004)

rimonabant 7.6 kg lossplacebo 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

Obesity

Food Intake-peripheral•GI peptides (CCK)•Pancreatic peptides (GLP-1, enterostatin, amylin)

Food Intake-central•Monoamines (NA, 5-HT, DA)•Peptides (NPY, AGRP, POMC, CART, CRH, insulin)

Fat Absorption•Lipase inhibitors•Fatty acid transportersFat Metabolism

•DGAT•Adipocyte differentiation

Thermogenesis•Thyroid hormones•Β3-adrenergic agonists•UCPs

Leptin

Vagus

Bray, Nature, 2000

PRINCIPLES OF DRUG THERAPYPRINCIPLES 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