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Pharmacologic Treatment of Obesity: What is the skinny on diet pills

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Indications for treatment with weight loss medications. BMI greater than 30 ... Studies demonstrate that sibutramine effective for weight loss. ... – PowerPoint PPT presentation

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Title: Pharmacologic Treatment of Obesity: What is the skinny on diet pills


1
Pharmacologic Treatment of Obesity What is the
skinny on diet pills?
  • Stephanie E. Freeman, MD
  • Department of Internal Medicine
  • Resident Grand Rounds
  • May 6, 2003

2
Cases
  • Patient 1
  • 40 year old female, 400 pounds
  • PMH CHF, HTN, OSA
  • Doc, I know I need to lose weight. I am
    desperate. How about diet pills?
  • Patient 2
  • 30 year old female, 5 4, 130 pounds
  • PMH none
  • Im taking these diet pills I bought at the drug
    store. Are these safe ?

3
Statistics
  • More than 60 million Americans are overweight.
  • Overweight and obesity cause 300,000 deaths each
    year.
  • 50 of all women and 25 of all men report that
    they are trying to lose weight.
  • 30 billion dollars spent on weight loss products
    each year.

4
Definitions
  • Body Mass Index
  • Weight in kilograms/ (height in meters)2
  • Normal BMI 18.5-24.9
  • Overweight BMI 25-29.9
  • Obese BMI greater than 30
  • Morbid Obesity BMI greater than 40

5
Obesity-Associated Medical Conditions
  • Type II Diabetes
  • Hypertension
  • Asthma
  • Obstructive sleep apnea
  • Dyslipidemia

6
Treatment of Obesity
  • NIH recommends non-pharmacologic therapy (dietary
    modification and exercise) initially for six
    months
  • If weight loss less than 0.45 kg/month, consider
    addition of weight loss medications.

7
Indications for treatment with weight loss
medications
  • BMI greater than 30
  • BMI greater than 27 with 2 or more
    obesity-related conditions

8
Mechanisms of Action
  • Suppress Appetite
  • Inhibit digestion
  • Increase Metabolism

9
Appetite Suppressants
  • Noradrenergic Agents
  • Phentermine
  • Serotonergic Agents
  • Fenfluramine
  • Dexfenfluramine
  • Noradrenergic/Serotonergic Agents
  • Sibutramine

10
Phentermine
  • Noradrenergic Agent
  • Activates central alpha and dopamine receptors in
    the hypothalamus.
  • Enhances catecholamine transmission.
  • Increases sympathetic activity.
  • Decreases appetite.
  • The only FDA approved weight loss medication in
    this class.

11
Phentermine
  • Munro et al. 1968
  • The only long term, randomized double blind
    placebo controlled trial of phentermine.
  • 108 obese women for nine months
  • Phentermine 30 mg daily or
  • Intermittent phentermine or
  • Placebo
  • Weight Loss
  • Daily phentermine 12.2 kg
  • Intermittent phentermine 13.0 kg
  • Placebo 4.8 kg

12
Phentermine
  • Side Effects
  • Agitation
  • Insomnia
  • Irritability
  • Nervousness
  • Headache
  • Tachycardia
  • Hypertension
  • Contraindications
  • Hyperthyroidism
  • Glaucoma
  • Agitated states
  • Advanced arteriosclerosis
  • Cardiovascular disease
  • Moderate-severe hypertension
  • Drug abuse

13
Serotonergic Agents
  • Inhibit reuptake of serotonin.
  • Cause release of serotonin.
  • Decrease food-seeking behavior and food
    consumption.
  • Fenfluramine and Dexfenfluramine

14
Fenfluramine
  • Removed from market in 1997.
  • Associated with valvular heart damage.
  • Serotonin agonist activity responsible for valve
    damage.
  • Fenfluramine, dexfenfluramine, and
    phentermine-fenfluramine phen-fen withdrawn
    from market.
  • Dexfenfluramine also associated with primary
    pulmonary hypertension.

15
Serotonergic/Noradrenergic Agents
  • Sibutramine (Meridia)
  • Inhibits the uptake of serotonin and
    norepinephrine
  • Increases satiety
  • May increase metabolic rate

Yanovski and Yanovski. N Eng J Med. Feb
2002346591-602.
16
Sibutramine
  • Bray et al.
  • Design
  • 1047 obese subjects with BMIs between 30 and 40
  • After two-week run-in period, randomized to
    placebo or sibutramine (1mg, 5mg, 10 mg, 20 mg,
    or 30mg).
  • Hypocaloric diet and daily exercise
  • Trial lasted 24 weeks.

17
Sibutramine
  • Bray et al.
  • Results
  • Placebo group lost 1.3 kg.
  • Sibutramine group
  • 1mg, 2.4kg
  • 5mg, 3.7 kg
  • 10mg, 5.7kg
  • 15mg, 7.0 kg
  • 20mg, 8.2 kg
  • 30mg, 9.0kg

18
Sibutramine
  • Bray et al.
  • Exclusions
  • Hypertension
  • Diabetes
  • Cardiovascular disease

19
Sibutramine
  • Serrano-Rios et al.
  • Goal
  • Assess efficacy of sibutramine in type II
    diabetics
  • Design
  • 134 type II diabetic patients on sulphonylureas
  • BMIs greater than 27
  • Randomized to placebo or sibutramine 15mg daily
  • Six months

20
Sibutramine
  • Serrano-Rios et al.
  • Results
  • Weight loss
  • Placebo group lost 1.7 kg
  • Sibutramine group lost 4.5 kg
  • Hemoglobin A1C
  • Sibutramine group
  • Those losing 10, HgA1C fell by 1.8
  • Placebo group
  • HgA1C fell 0.7

21
Sibutramine
  • James et al.
  • Goal
  • To assess the long term efficacy of sibutramine
    for weight loss and weight maintenance.
  • Design
  • 605 patients with BMIs between 30 and 45
  • Six month weight loss phase
  • All patients received sibutramine 15 mg daily.
  • 18 month weight maintenance phase
  • Patients received placebo or sibutramine 15 mg
    daily.

22
Sibutramine
  • James et al.
  • Results
  • 261 patients completed the study.
  • Sibutramine group
  • 43 maintained 80 or more of weight loss.
  • Placebo group
  • 16 maintained 80 or more of weight loss.

23
Sibutramine
  • Studies demonstrate that sibutramine effective
    for weight loss.
  • Studies had drop-out rates of about 20.
  • Exclusion criteria
  • Hypertension, diabetes, heart disease, and other
    serious medical conditions

24
Sibutramine
  • Side effects
  • Dry mouth
  • Insomnia
  • Hypertension
  • Palpitations
  • Tachycardia
  • Dyspnea
  • Other Effects
  • Lower total cholesterol, LDL, triglyceride, and
    gout levels
  • Usage
  • Starting dose 10 mg daily
  • Increase to 15 or 20mg
  • Use longer than 2 years not recommended.

25
Digestive Inhibitors
  • Orlistat (Xenical)
  • Inhibits lipase
  • Decreases absorption of dietary fat
  • Leads to decreased absorption of calories
  • Leads to decreased body weight

26
Orlistat - Mechanism
Yanovski and Yanovski. N Eng J Med. Feb
2002346591-602.
27
Orlistat
  • Sjostrom et al.
  • Goal
  • Demonstrate efficacy for weight loss and slowing
    of weight regain
  • Design
  • 2 year study
  • 743 patients with BMIs between 28 and 47
  • Hypocaloric diet with 30 energy as fat
  • 4 week run in period with placebo

28
Orlistat
  • Sjostrom et al.
  • Design-continued
  • Weight loss phase
  • Randomized to placebo or orlistat 120 mg TID for
    52 weeks.
  • Weight maintenance phase
  • At end of year one, randomized to continue
    current regimen or to switch regimens for 52
    weeks.

29
Orlistat
  • Sjostrom et al.
  • Results
  • Year one (weight loss phase)
  • Placebo group lost 6.1 kg
  • Orlistat group lost 10.3 kg
  • Year two (weight maintenance phase)
  • Placebo-Orlistat group lost 3.6 kg
  • Placebo-Placebo group regained 2 of weight
  • Orlistat-Placebo group regained 4 of weight
  • Orlistat-Orlistat group regained 2 of weight
  • Continuous Orlistat
  • 57 maintained weight loss 5
  • Continuous Placebo
  • 37 maintained weight loss 5

30
Orlistat
Sjostrom et al. Lancet. July 18, 1998352167-172.
31
Orlistat
  • Hanefeld et al.
  • Goal
  • To show efficacy of orlistat in Type II DM
  • Design
  • 492 Type II DM patients with BMIs greater than 27
    who were receiving treatment with sulphonylureas
    or no treatment for their diabetes
  • Randomized to receive placebo or Orlistat 120 mg
    tid

32
Orlistat
  • Hanefeld et al.
  • Results
  • Weight loss
  • Placebo group
  • lost 3.7 kg
  • 31.6 lost more than 5
  • Orlistat group
  • lost 5.7 kg
  • 51.3 lost more than 5
  • Glycemic Control
  • Placebo group
  • Hemoglobin A1C 8.6 to 8.1
  • Orlistat group
  • Hemoglobin A1C 8.6 to 7.7

33
Orlistat
  • Studies
  • Demonstrate efficacy
  • Have drop-out rates of about 20-25
  • Extensive exclusion criteria
  • Hypertension
  • Diabetes mellitus (except study by Hanefeld et
    al)
  • Cardiovascular disease
  • Other effects
  • Decreased total cholesterol
  • Decreased LDL
  • Improved glycemic control
  • Side effects
  • Abdominal pain
  • Flatulence
  • Greasy stools
  • Lasts

34
Orlistat
  • May decrease absorption of fat-soluble vitamins.
  • The dose is 120 mg tid with meals.
  • May be taken up to one hour after meals.
  • Use for longer than two years not recommended.

35
Ephedrine/Ephedra
  • Ephedrine
  • Increases the release of norepinephrine
  • Suppresses appetite
  • Increases metabolism
  • Synthetic form of ephedra
  • Ma Huang
  • Caffeine
  • Often combined with ephedrine/ephedra
  • Decreases the breakdown of NE
  • Acts in synergy with ephedrine/ephedra

36
Ephedrine/Ephedra
  • Metabolife
  • Ingredients
  • Ephedra alkaloids
  • 12 mg
  • Caffeine
  • 40 mg
  • Directions
  • One to two caplets
  • BID-TID or every 4 hours
  • On empty stomach
  • One hour before meal
  • Do not exceed 8 caps/day

37
Ephedrine/Ephedra
  • Shekelle et al.
  • Meta-analysis
  • Goal
  • Review the safety and efficacy of ephedrine and
    ephedra

38
Ephedrine/Ephedra
Shekelle et al. JAMA. March 26, 2003289537-1545.
39
Ephedrine/Ephedra
  • Shekelle et al.
  • Adverse events
  • Examined 50 trials
  • Grouped events into categories
  • Psychiatric symptoms
  • Autonomic hyperactivity
  • Upper GI symptoms
  • Palpitations
  • Hypertension
  • Headaches

40
Shekelle et al. Serious Adverse Events
  • Ephedrine
  • Three deaths
  • Two myocardial infarctions
  • One psychiatric event
  • One seizure
  • Ephedra
  • Two deaths
  • Three Myocardial infarctions
  • Nine strokes
  • Three psychiatric events

41
Ephedrine/Ephedra
  • Serious Adverse Events
  • ½ occurred in people younger than 30
  • Steve Bechler
  • 23 year-old baseball player
  • Died 2/17/03 after collapsing in spring training
  • Had been taking Xenadrine RFA-1
  • Contains ephedra
  • Coroner links death to the drug.

42
Ephedrine/Ephedra
  • Effective for short term (less than six months)
    weight loss
  • Not FDA approved
  • Side effects
  • Psychiatric disturbances, autonomic
    hyperactivity, upper GI symptoms
  • Case reports
  • Death, MI, CVA

43
Weight-loss Medications Conclusions
  • There are only three FDA-approved weight loss
    medications
  • Phentermine
  • Sibutramine (Meridia)
  • Orlistat (Xenical)
  • Must be used in conjunction with diet and exercise

44
Conclusions
  • Reassess if weight loss is less than 2.0 kg in
    the first month.
  • The average weight loss attributed to weight loss
    medications is 5 of initial body weight.
  • Use for longer than 2 years is not recommended.

45
Conclusions
  • Although weight loss drugs produce clinically
    important weight loss, the magnitude of weight
    loss with pharmacotherapy is rarely sufficient to
    bring the morbidly obese down to a healthy
    weight.

Glazer, Gary. Arch Intern Med. Aug 13/27
20021814-1823.
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