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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 Patient 1 40 year old female, 400+ pounds PMH: CHF, HTN, OSA

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pharmacologic treatment of obesity what is the skinny on diet pills

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

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

“I’m taking these diet pills I bought at the drug store. Are these safe ?”

Cases
statistics
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.
definitions
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
obesity associated medical conditions
Obesity-Associated Medical Conditions
  • Type II Diabetes
  • Hypertension
  • Asthma
  • Obstructive sleep apnea
  • Dyslipidemia
treatment of obesity
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.
indications for treatment with weight loss medications
Indications for treatment with weight loss medications
  • BMI greater than 30
  • BMI greater than 27 with 2 or more obesity-related conditions
mechanisms of action
Mechanisms of Action
  • Suppress Appetite
  • Inhibit digestion
  • Increase Metabolism
appetite suppressants
Appetite Suppressants
  • Noradrenergic Agents
    • Phentermine
  • Serotonergic Agents
    • Fenfluramine
    • Dexfenfluramine
  • Noradrenergic/Serotonergic Agents
    • Sibutramine
phentermine
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.
phentermine11
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
phentermine12
Side Effects

Agitation

Insomnia

Irritability

Nervousness

Headache

Tachycardia

Hypertension

Contraindications

Hyperthyroidism

Glaucoma

Agitated states

Advanced arteriosclerosis

Cardiovascular disease

Moderate-severe hypertension

Drug abuse

Phentermine
serotonergic agents
Serotonergic Agents
  • Inhibit reuptake of serotonin.
  • Cause release of serotonin.
  • Decrease food-seeking behavior and food consumption.
  • Fenfluramine and Dexfenfluramine
fenfluramine
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.
serotonergic noradrenergic agents
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 2002;346:591-602.

sibutramine
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.
sibutramine17
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
sibutramine18
Sibutramine
  • Bray et al.
    • Exclusions
      • Hypertension
      • Diabetes
      • Cardiovascular disease
sibutramine19
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
sibutramine20
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%
sibutramine21
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.
sibutramine22
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.
sibutramine23
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
sibutramine24
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.

Sibutramine
digestive inhibitors
Digestive Inhibitors
  • Orlistat (Xenical)
    • Inhibits lipase
    • Decreases absorption of dietary fat
    • Leads to decreased absorption of calories
    • Leads to decreased body weight
orlistat mechanism
Orlistat - Mechanism

Yanovski and Yanovski. N Eng J Med. Feb 2002;346:591-602.

orlistat
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
orlistat28
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.
orlistat29
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%
orlistat30
Orlistat

Sjostrom et al. Lancet. July 18, 1998;352:167-172.

orlistat31
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
orlistat32
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
orlistat33
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 < 4 days

Orlistat
orlistat34
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.
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

Ephedrine/Ephedra
ephedrine ephedra36
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
ephedrine ephedra37
Ephedrine/Ephedra
  • Shekelle et al.
    • Meta-analysis
      • Goal
        • Review the safety and efficacy of ephedrine and ephedra
ephedrine ephedra38
Ephedrine/Ephedra

Shekelle et al. JAMA. March 26, 2003;289:537-1545.

ephedrine ephedra39
Ephedrine/Ephedra
  • Shekelle et al.
    • Adverse events
      • Examined 50 trials
      • Grouped events into categories
        • Psychiatric symptoms
        • Autonomic hyperactivity
        • Upper GI symptoms
        • Palpitations
        • Hypertension
        • Headaches
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

Shekelle et al. Serious Adverse Events
ephedrine ephedra41
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.
ephedrine ephedra42
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
weight loss medications conclusions
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
conclusions
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.
conclusions45
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 2002;1814-1823.