Pharmacotherapy. Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice...

Pharmacotherapy

Obesity Pharmacotherapy Outline

• How to apply drug trial data to clinical practice• Principles of obesity medication use in clinical practice• Medications approved for long-term use

– sibutramine (Meridia)– orlistat (Xenical)

• Medications approved for short term use– phentermine– others rarely used: mazindol, diethylpropion

• Medications for use in special patients– the depressed obese patient – bupropion (Wellbutrin) and venlafaxine

(Effexor)– type 2 diabetes – metformin , pramlintide (Symlin), exendin-4 (Exenatide)– patients with neuropsychiatric problems - topiramate (Topamax) and

zonisamide (Zonegran)

• Medications in development

1. Mean responses describe how patients fare on average.2. The weight loss curves describe the tempo of weight loss.3. The placebo response indicates the strength of the behavioral

approach.

–8

–6

–4

–2

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Mea

n C

hang

e in

Wei

ght

(%)

Drug

Placebo

Treatment MonthNoteunits

Noteplateau

Placebo response indicates behavioral program

Applying Pharmacotherapy Trials to the Practice Setting – 6 Tips


4. Categorical responses indicate the chance an individual patient has of meeting key response levels, 5% and 10%.

5. Significance levels and n’s are important.

*P < 0.01 vs placebo†P < 0.001 vs placebo

(95)(95)

(107)(107)

0

10

20

30

40

50

60

70

80PlaceboPlacebo

1 mg 1 mg 5 mg 5 mg

10 mg 10 mg 15 mg 15 mg 20 20 30 30

(n=87)(n=87)

(99)(99)

mg (96)mg (96)mg (101)mg (101)

Drug (n)Drug (n)

*

†

†

†

†

*†

††

†

5% Responders 10% Responders

Pat

ien

ts (

%)

(98)(98)

Chances of response

note


6. There is no placebo effect in weight loss studies. The placebo represents the effect of the behavioral intervention.

WMD (Random)95% CI

Author 9, 2002

Author 5, 2000

Author 4, 2000

Author 3, 1999

Author 2, 1998

Author 1, 1998*

Author 7, 2000

Author 8, 2002

Total (95% CI)

Author 6, 2000

Study or Subcategory

-10 -5 0 105

Metanalyses use placebo-subtracted weight loss and demonstrate the effect of the medication independent of behavioral intervention.

Principles of Obesity Medication Use

• Lifestyle interventions are the foundation of medicating for obesity

• The behavioral approach should be implemented with knowledge of the medication’s mechanism of action – Orlistat with 30% fat diet– Sibutramine with meal plan that takes advantage of its satiety

promotion

• Obesity medications do not cure obesity, just as antihypertensives do not cure hypertension

• Not all patients respond to a weight loss medication. – If the drug’s use is not associated with weight loss within four weeks, it

should be stopped

• Medications work as long as they are used– Weight gain occurs on stopping medications, although there is some

evidence in support of efficacy of intermittent medication

Obesity PharmacotherapyOutline





(Effexor)– type 2 diabetes – metformin , pramlintide (Symlin), exendin-4

(Exenatide)– patients with neuropsychiatric problems - topiramate (Topamax) and



Antiobesity Drugs Approved for Long-Term Use: How They Work

Sibutramine Orlistat• FDA approved 1997

• Induces feeling of satiety– Less preoccupation, feeling

satisfied with less food

– Greater control of food

intake

– Need to monitor BP early in

program

• Once daily with or without

food

• FDA approved 1999

• Reduces absorption of

~30% dietary fat– Fat in diet passes

undigested

– Facilitates weight loss

– GI side effects

• 3 times daily with meals

and a vitamin supplement

recommended

Ryan DH et al. Obes Res. 1995;3(suppl 4):553S.

S = sibutramine = norepinephrine = serotonin

Norepinephrine

Serotonin SSSS

SSSS

SSSS

SSSS

Reuptake

Reuptake

Mechanisms of ActionSibutramine’s Active Metabolites Block Serotonin and Norepinephrine Reuptake

Other SNRIs

• Venlafaxine (Effexor)

– Widely used in depression

– Similar side effect profile to sibutramine, small blood pressure increases

– Produces some weight loss

Rudolph RL, Derivan AT. J Clin Psychopharmacol. 1996;16(suppl 2):54S.

Sibutramine Key Facts

• Multiple large clinical trials demonstrating:− Dose-related weight loss occurs for 6 months− Amount of weight loss related to intensity of behavioral

approach− Efficacy in weight loss maintenance demonstrated ≥ 2

years − Weight loss produces benefits in lipids, body composition

and is associated with mean blood pressure decrease− Trials in patients with hypertension and diabetes

• Favorable side effect profile: − No abuse potential− No valvuloplasty, no PPH

• Cautions− Blood pressure should be monitored− Should not use with MAOIs, erythromycin, ketoconazole

Sibutramine Produces Dose-Related Weight Loss

**10 and 15 mg are recommended doses

Placebo (n = 84)Sibutramine, mg (n)

1 (92)

Week

Mea

n W

eigh

t C

hang

e (lb

)

5 (103)

10 (95)

15 (94)

20 (89)

30 (96)

*

*

*

**

0

–5

–10

–15

–200 3 6 9 12 15 18 21 24

Bray GA et al. Obes Res. 1999;7:189.

Approveddose range

The Amount of Weight Loss with Sibutramine Is Related to the Intensity

of the Behavioral Intervention*

Wadden TA et al. Arch Intern Med 2001;161:218-227.

-5.2

-11.5

-17.1

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

% W

eigh

t Cha

nge

at 6

mon

ths

Sibutramine

Sibutramine+ Group Sessions

Sibutramine+ Group Sessions

+ Meal Replacements

* Weight loss at 6 months

STORM: 77% (ITT) Achieved > 5% Weight Loss at Six Months

James WPT et al. Lancet. 2000;356:2119.

*Same diet, exercise for sibutramine, placebo; P 0.001, sibutramine vs placebo for weight maintenance

230

210

1950 122 4 6 8 10 14 16 18 20 22 24

Month

Bod

y W

eigh

t (lb

)

Placebo

Sibutramine

Weight Loss Weight Maintenance

225

220

215

205

200

STORM: Sibutramine Promotes Weight Loss Maintenance*

230

210

1950 122 4 6 8 10 14 16 18 20 22 24

Month

Bod

y W

eigh

t (lb

)

Placebo

Sibutramine

Weight Loss Weight Maintenance

225

220

215

205

200

*Same diet, exercise for sibutramine, placebo; P 0.001, sibutramine vs placebo for weight maintenance


Following VLCD, Sibutramine Promotes Additional Weight Loss and

Weight Loss Maintenance

Sibutramine

Placebo

= very low calorie diet (VLCD)

P < 0.001 for months 1 to 12, sibutramine vs placebo

Mea

n W

eigh

t (lb

)

Treatment Month

233

229

224

220

217

211

207

202

198

194–1 0 1 2 3 4 5 6 7 8 9 10 11 12

Adapted with permission from Apfelbaum M et al. Am J Med. 1999;106:179.

Three Sibutramine Studies

1Bray GA et al. Obes Res. 1999;7:189. 2Apfelbaum M et al. Am J Med. 1999;106:179.3James WPT et al. Lancet 2000;356:2119-2125.

P 0.001 vs placebo

Percent Achieving Meaningful Weight Loss

67

35

84

54

6763

0

10

20

30

40

50

60

70

80

90

% A

ch

iev

ing

We

igh

t L

os

s

≥ 5%

≥ 10%

6 months treatment 1



Weight Loss with Sibutramine Is Associated with Improvements in Lipids

(STORM Data)

Weight loss = months 1–6; Weight maintenance = months 7–24; *P < 0.001; †P = 0.002; ‡P = 0.005; §P = 0.001 vs placebo

Sibutramine

Placebo

Triglycerides

–25

–20

–15

–10

–5

0

5

0 6 12 18 24

Month Assessed

% C

ha

ng

e

*†*

–25

–20

–15

–10

–5

0

5

0 6 12 18 24

Sibutramine

Placebo

VLDL-Cholesterol

Month Assessed

% C

hange

§‡*

Sibutramine

Placebo

HDL-Cholesterol

0

5

10

15

20

25

0 6 12 18 24

% C

ha

ng

e

Month Assessed

**

Adapted with permission from James WPT et al. Lancet. 2000;356:2119.

Weight Loss with Sibutramine Is Associated with Improvement in Waist Circumference

(STORM data)

NB: Same diet and exercise for both sibutramine and placebo

Sibutramine

44

43

42

41

40

39

38

0 122 4 6 8 10 14 16 18 20 22 24

Wai

st C

ircum

fere

nce

(in.)

Month

Placebo


Sibutramine and Blood Pressure

• Labeling instructions:

Warning.

Blood pressure and pulse. MERIDIA SUBSTANTIALLY INCREASES BLOOD PRESSURE IN SOME PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE IS REQUIRED WHEN PRESCRIBING MERIDIA. In placebo-controlled obesity studies, MERIDIA 5 to 20 mg once daily was associated with mean increases in systolic and diastolic blood pressure of approximately 1 to 3 mg relative to placebo…

-0.1+1.0*

+2.6*

+3.8*

Dose Related Effects of Sibutramineon Systolic Blood Pressure (SBP)C

hange in S

BP (

mm

Hg)

Sibutramine20 mgn=1126




Placebon=1944

0

2

4

6

8

10

-1 * p < 0.05 comparedto placebo

-0.1

Data on file, Abbott Laboratories.Data on file, Abbott Laboratories.

Sibutramine (n=1,898) Control (n=1,521)

30

25

20

15

10

5

0

Pat

ient

s (%

)

No > 0 – < 5 5 – < 10 10 – < 1515 – < 2020 – < 2525 – < 3030 – < 3535 – < 40 > 40increase

SBP or DBP increase (mmHg)

Maximum BP Changes vs. Baseline

Adapted from Sharma AM et al. NAASO 2003.

Post hoc analysis of 21 randomized placebo controlled trials of ≥ 12 weeks duration3419 overweight and obese patients with normal or controlled blood pressure

Sibutramine 10-15 mg n=1898; placebo n= 1521

STORM: Change in Vital Signs


Baseline to 24 Months in Sibutramine Treatment Group

Mean Change

Sibutramine Placebo

BP, mm HG

Systolic 0.1 - 4.7

Diastolic 2.3 - 1.6

Pulse rate (bpm) 4.1 - 1.9

In STORM most subjects reached 20 mg per study design

Blood Pressure is Lowered with Weight Loss Using Sibutramine

-5

-4

-3

-2

-1

0

1

2

3

< 5% weight loss > 5% weight loss > 10% weight loss

Placebo (n = 2255) Sibutramine (n = 4536)

Adapted from Sharma AM, Int J Obes Relat Metab Disord 2001;25 (Suppl 4): S20-S23.Adapted from Sharma AM, Int J Obes Relat Metab Disord 2001;25 (Suppl 4): S20-S23.

Although weight loss with sibutramine was not associated with equivalent BP reductions as placebo, a greater proportion of sibutramine treated patients achieved weight loss.

Ch

ang

e in

SB

P (

mm

Hg

)

78% 47%

22% 53% 6% 23%

% of treatment group

The Reality of Sibutramine’s BP Effects

• Mean BP changes in recommended dose range is ~ 1 mm Hg increase

• A few, < 5%, have unacceptable blood pressure increases while on sibutramine

• Significant weight loss, > 5%, is associated with mean BP decrease on sibutramine

• BP effects of sibutramine are blocked by beta blockers1

• BP effects of sibutramine are blocked by exercise program2

• In addition to peripheral effects, sibutramine may have central “clonidine-like” sympatholytic effects1

1. Birkenfeld AL et al. Circulation 2002;106: 2459-24652. Berube-Parent S et al. IJO 2001;25: 1144-1153

Tips for Managing Patients on Sibutramine

• Start at 10 mg once daily• Prescribe a sensible diet –

– Meal replacements for two meals and two snacks + one sensible meal per day

– Portion controlled diet with at least three meals per day

• Follow –up: – 4 pounds weight loss in first 4 weeks helps predict success– Monitor blood pressure. Use clinical judgement about

continuing

• Increase dose to increase weight loss, provided BP is well controlled. Decrease dose or discontinue for BP concerns

• Stay within recommended dose range of 5 to 15 mg • Encourage long term use

Antiobesity Drugs Approved for Long-Term Use: How They Work

Sibutramine Orlistat


• Induces feeling of satiety– Less preoccupation, feeling

satisfied with less food

– Greater control of food

intake

– Need to monitor BP early in

program

• Once daily with or without

food


• Reduces absorption of

~30% dietary fat– Fat in diet passes

undigested

– Facilitates weight loss

– GI side effects

• 3 times daily with meals

and a vitamin supplement

recommended

Lipase

Mucosal Cell

TG

FAMG

MicelleBile Acids

Intestinal Lumen

Orlistat

Orlistat Prevents Fat Digestion by Binding to Gastrointestinal Lipases

LipaseLipase

TG=triglyceride; MG=monoglyceride; FA=fatty acid

Orlistat: Key Facts• Multiple large clinical trials demonstrating

− Weight loss occurs for 6 months− Efficacy in weight loss maintenance demonstrated

≥ 4 years − Weight loss produces benefits in glycemic control,

lipids, waist circumference, BP− Trials in persons with diabetes and hypertension− Independent action on LDL cholesterol

• Favorable side effect profile − No abuse potential− No valvulopathy, no PPH

• Cautions− Vitamin supplement required for long term use− May interfere with cyclosporin absorption

• Likely to be available over the counter in 2006

36.4

15.4

51.6

27.3

0

10

20

30

40

50

60

% o

f Pat

ient

s

> 5% > 10%% of Weight Lost

Placebo + diet

Orlistat + diet

Meta-analysis of data derived from 4 clinical trials

Xenical® [package insert]. Nutley, NJ: Roche Laboratories, 1999.

Orlistat: 2-Year Efficacy

Effect of Long-Term Treatment With Orlistat (The XENDOS Study)

-4.1 kg

-6.9 kg

0 52 104 156 208-12

-9

-6

-3

0Placebo + lifestyle(n=557)

Orlistat + lifestyle(n=853)

Week

Wei

gh

t ch

ang

e (k

g)

p < 0.001 vs placeboTorgerson JS et al, Diabetes Care 2004; 27(1): 155-61.

Completers Data

Independent Effect of Orlistat on Plasma LDL-Cholesterol

Segal et al. FASEB J 1999;13:A873. Data pooled from 5 trials (N=1773)

0 – 5 5 – 10 10 – 15 > 15

Cha

nge

in P

lasm

a LD

L-C

hole

ster

ol C

once

ntra

tion

(mm

ol/L

)

Weight Loss Category (% initial body weight)

-0.3

0.0

-0.5

-0.4

-0.2

-0.1

-0.6

-0.8

-1.0

-0.9

-0.7

*

**

*

OrlistatPlacebo

*P < 0.01 vs placebo

Orlistat: Effect on Lipids and Waist Circumference

9.3

1.34

12.8

2.9

1

3

5

7

9

11

13

15

HDL-C TG

-2.6

-1.6

-3

-2.5

-2

-1.5

-1

-0.5

0

Waist Circumference

Xenical® [package insert]. Nutley, NJ: Roche Laboratories, 1999.

Orlistat 120 mg TID Placebo

Cha

nge

(in)

% C

hang

e

Orlistat: Effect on Blood Pressure in At-Risk Patients

-12

-10

-8

-6

-4

-2

0

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Orlistat + diet

Placebo + diet

Systolic (ISH, SBP 140 mm

Hg)

Diastolic (DBP 90 mm Hg)

Data on File (Ref 038-001).

mm Hg

P = 0.032 P = NS

mm Hg

Orlistat: Safety

Sjöström L et al. Lancet. 1998;352:167.

• There is concern about fat-soluble vitamin absorption

Adverse Events (AEs) at 1 Year

0%

3%1%

7%5%

7%

10%

18%20%

31%

0

5

10

15

20

25

30

35

Fatty/Oily Stool IncreasedDefecation

Oily Spotting Fecal Urgency FecalIncontinence

%

Placebo, n = 340Orlistat, n = 343

Tips for Managing Patients on Orlistat

• Discuss potential bowel effects and mechanism with patient

• Start at 120 mg before each meal• Prescribe a moderate fat diet –

– Caution patients about high fat meal or snack

• Metamucil has been shown to reduce bowel effects• For long term use, prescribe a multivitamin• Orlistat can interfere with cyclosporin absorption• Encourage long term use.

Drugs Approved by FDA for Short Term Use in Treating Obesity

Diethylpropion (1959) Tenuate IV

Phentermine (1959) Adipex-P, Ionamin IV

Benzphetamine* (1960) Didrex III

Phendimetrazine (1959) Bontril III

Methamphetamine Desoxyn II

Mazindol* (1973) Mazanor IV

Generic Name Trade Names DEA Schedule

Physicians’ Desk reference 59th Edition, 2005.

*not listed in PDR, but available

FDA Approved Drugs for Short Term Use

• Use of schedule II or III drugs for weight management is not recommended.

• These agents are sympathomimetic as reflected by the side effect profile (restlessness, insomnia, increase in pulse, increase in blood pressure and others).

• Intermittent use is the only means to abide by prescribing guidelines.

• The medications promote appetite reduction. They should be used with an energy deficit diet.

• Weight loss with these medications averages 5 - 7% above placebo.

0 4 8 12 16 20 24 28 32 36

Wei

ght

loss

(kg

)

Continuous Phentermine

Alternating Phentermine and Placebo

Continuous Placebo

Time in Weeks

0

5

10

15

16

32

0

Weight loss (lbs)

Weight Loss with Continuous and Intermittent Phentermine

Munro JF, et al. Br Med J 1968; 1:352-354.

Medicating the Depressed Obese Patient

• Many antidepressants produce weight gain

• Antidepressants associated with weight loss:– Bupropion (Wellbutrin)1

– Venlafaxine (Effexor)2

• Antidepressant associated with initial weight loss at higher doses, followed by weight regain:– Fluoxetine (Prozac)3

1. Anderson Obes Res 2002:10:633.2. PDR Edition 29, 2005.3. Darga et al, AJCN, 1991.

Treatment with Bupropion

0 10 20 30 40 50-15

-10

-5

0

Placebo

SR 400

SR 300

Weeks of Treatment

We

igh

t lo

ss (

%)

Anderson Obes Res 2002:10:633.

Week number1 3 5 7 9 13 21 29 37 45 5317

Placebo

Fluoxetine

N = 16

N = 14

N = 23

N = 22

We

igh

t Los

s (k

g)

Fluoxetine 60 mg and Weight Loss*

Darga et al, AJCN, 1991.

-16

-14

-12

-10

-8

-6

-4

-2

0

Medicating the Patient with Type 2 Diabetes

• Weight gain is associated with use of thioglitazones, sulfonylureas and insulin.

• Metformin is associated with small amounts of weight loss.

• Pramlintide is associated with weight loss.

Weight Change with Metformin in DPP Trial

-4

-3

-2

-1

0

1

Wei

ght C

hang

e (K

g)

0 6 12 18 24 30 36 42 48

Months in study

Metformin

+

Placebo

DPP NEJM 2002.

Pramlintide

• Pramlintide injection approved by FDA 3/2005.

• Indication: as an adjunct treatment in patients with T1DM or T2DM who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin.

• Synthetic analog of human amylin, designed to replace reduced amylin secretion that accompanies beta cell.

• Patients in clinical trials used less mealtime insulin and also had a reduction in body weight compared to patients taking insulin alone.

Exenatide

• Exenatide is an incretin mimetic

• Exenatide exhibits many of the same effects as the human incretin hormone GLP-1

– Improve blood sugar

– Weight loss

• The FDA’s action date for exenatide is April 30, 2005

Medicating the Neuropsychiatric Patient

• Many antiepileptics and antipsychotics produce weight gain.

• Two agents are associated with weight loss, topiramate and zonisamide.

• These agents are not approved for weight loss and are associated with substantial tolerability and toxicity issues that make them unacceptable for weight management in primary care.

• When medicating for neuropsychiatric disorders, a favorable weigh profile should be taken into account in choosing a medication.

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Weeks of Treatment

Wei

ght

Loss

(%

)

Placebo

64 mg/d

96 mg/d

192 mg/d

384 mg/d

Weight Loss with Topiramate

Bray et al Obes Res 2003 in press.

Zonisamide versus Placebo

0 2 4 6 8 10 12 14 16 18-8

-6

-4

-2

0

Placebo

Zonisamide

Week

Wei

ght

loss

(kg

)

Gadde IJO 2002 (Abs).

Medications Noted in ACP 2005 Pharmacotherapy Guidelines

Data Source

Weight Loss Period for

Weight Change

Mean Weight Change 95% CI

Sibutramine 29 RCTs 52 weeks 4.45 kg (5.29 - 3.62 kg)

Orlistat 22 RCTs 52 weeks 2.75 kg (3.31 - 2.20 kg)

Phentermine 9 RCTs 2 - 24 weeks 3.6 kg (6.0 - 0.6 kg)

Diethylpropion 13 RCTs 6 -52 weeks 3.0 kg (11.5 - 1.6 kg)

Bupropion 3 RCTs 24 - 52 weeks 2.77 kg (4.5 - 1.0 kg)

Fluoxetine 9 RCTs 52 weeks --Range -14.5 to

+0.4 kg

Annals Internal Medicine 2005;142:523-546.

Van Gaal et al. Lancet 2005;365:1389-97.

Rimonabant Weight Loss and Waist Change over 1 year

• Mean weight loss 4.8 kg greater than placebo

• Improvements in HDL, TG, Insulin and HOMA-IR greater than with weight loss alone

• Side effect profile favorable

Van Gaal et al. Lancet 2005;365:1389-97.

Obesity Pharmacotherapy: What Does the Future Hold?

• Epidemic of obesity and comorbidities is unabated.

• Understanding of biology underlying obesity continues to expand.

• New drugs are coming on market – rimonabant 2006.

• Look AHEAD, SOS are evaluating mortality benefit of weight loss.

• Obesity pharmacotherapy is gaining legitimacy.

• Medicating for obesity will follow the paradigm of other chronic diseases (HTN, DM).

• Medications for obesity will not cure obesity.

• Weight loss of 5-10% will be seen with new medications.

• Lifestyle will remain a cornerstone of medicating.

Obesity Pharmacotherapy: What Does the Future Hold?

Pharmacotherapy. Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice...

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