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

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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

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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.

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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

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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.

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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

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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.

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Digestive Inhibitors

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

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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

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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.

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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

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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

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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

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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.