Pharmacotherapy

1
Pharmacotherapy
2
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

3
Applying Pharmacotherapy Trials to the Practice
Setting 6 Tips

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.

Note units
Treatment Month
0
1
2
3
4
5
6
7
8
9
10
11
12
0
2
Note plateau
Placebo response indicates behavioral program
Mean Change in Weight ()
4
6
8
4
Applying Pharmacotherapy Trials to the Practice
Setting 6 Tips

• Categorical responses indicate the chance an
  individual patient has of meeting key response
  levels, 5 and 10.
• Significance levels and ns are important.

80

Placebo
(n87)

70

Drug (n)

60
1 mg
(95)
5 mg
50
(107)

10 mg
(99)
Patients ()


40

15 mg
(98)
30
mg (96)
20
30
mg (101)
20


10
0
5 Responders
10 Responders
P lt 0.01 vs placebo P lt 0.001 vs placebo
5
Applying Pharmacotherapy Trials to the Practice
Setting 6 Tips

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

WMD (Random)95 CI
Study or Subcategory
Author 1, 1998
Author 2, 1998
Author 3, 1999
Author 4, 2000
Author 5, 2000
Author 6, 2000
Author 7, 2000
Author 8, 2002
Author 9, 2002
Total (95 CI)
Metanalyses use placebo-subtracted weight loss
and demonstrate the effect of the medication
independent of behavioral intervention.
6
Principles of Obesity Medication Use

• Lifestyle interventions are the foundation of
  medicating for obesity
• The behavioral approach should be implemented
  with knowledge of the medications 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 drugs 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

7
Obesity PharmacotherapyOutline

• 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

8
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
9
Mechanisms of Action
Sibutramines Active Metabolites Block Serotonin
and Norepinephrine Reuptake
S sibutramine? norepinephrine ?
serotonin
Ryan DH et al. Obes Res. 19953(suppl 4)553S.
10
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.
199616(suppl 2)54S.
11
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

12
Sibutramine Produces Dose-Related Weight Loss
0
Placebo (n 84)
Sibutramine, mg (n)
5
1 (92)

5 (103)
10
Mean Weight Change (lb)

10 (95)

15 (94)
15

20 (89)

30 (96)
20
Week
10 and 15 mg are recommended doses
Bray GA et al. Obes Res. 19997189.
13
The Amount of Weight Loss with Sibutramine Is
Related to the Intensity of the Behavioral
Intervention
Weight loss at 6 months
Wadden TA et al. Arch Intern Med
2001161218-227.
14
STORM 77 (ITT) Achieved gt 5 Weight Loss at
Six Months
Weight Loss
Weight Maintenance
230
Placebo
225
220
215
Body Weight (lb)
210
205
200
Sibutramine
195
0
12
2
4
6
8
10
14
16
18
20
22
24
Month
Same diet, exercise for sibutramine, placebo P
? 0.001, sibutramine vs placebo for weight
maintenance
James WPT et al. Lancet. 20003562119.
15
STORM Sibutramine Promotes Weight Loss
Maintenance
Weight Loss
Weight Maintenance
230
Placebo
225
220
215
Body Weight (lb)
210
205
200
Sibutramine
195
0
12
2
4
6
8
10
14
16
18
20
22
24
Month
Same diet, exercise for sibutramine, placebo P
? 0.001, sibutramine vs placebo for weight
maintenance
James WPT et al. Lancet. 20003562119.
16
Following VLCD, Sibutramine Promotes Additional
Weight Loss and Weight Loss Maintenance
233
229
224
220
Placebo
217
Mean Weight (lb)
211
207
202
198
Sibutramine
194
12
1
0
1
2
3
4
5
6
7
8
9
10
11
Treatment Month
P lt 0.001 for months 1 to 12, sibutramine vs
placebo
very low calorie diet (VLCD)
Adapted with permission from Apfelbaum M et al.
Am J Med. 1999106179.
17
Three Sibutramine Studies
Percent Achieving Meaningful Weight Loss
6 months treatment 1
24 months treatment 3
12 months treatment 2
1Bray GA et al. Obes Res. 19997189. 2Apfelbaum
M et al. Am J Med. 1999106179. 3James WPT et
al. Lancet 20003562119-2125.
P ? 0.001 vs placebo
18
Weight Loss with Sibutramine Is Associated with
Improvements in Lipids(STORM Data)
Triglycerides
VLDL-Cholesterol
5
5
0
0
Placebo
Placebo
5
5
Change
10
10
Change


?



?
?
?
15

15
?
?
?
Sibutramine
?
?
?
?
Sibutramine
?
?
?
20
20
?
25
25
0
6
12
18
24
0
6
12
18
24
Month Assessed
Month Assessed
HDL-Cholesterol
25


?
?
Sibutramine
20
?
?
?
15
Change
Weight loss months 16 Weight maintenance
months 724 P lt 0.001 P 0.002 P
0.005 P 0.001 vs placebo
Placebo
10
5
?
?
0
Adapted with permission from James WPT et al.
Lancet. 20003562119.
0
6
12
18
24
Month Assessed
19
Weight Loss with Sibutramine Is Associated with
Improvement in Waist Circumference (STORM data)
44
43
Placebo
42
Waist Circumference (in.)
41
40
Sibutramine
39
38
0
12
2
4
6
8
10
14
16
18
20
22
24
Month
NB Same diet and exercise for both sibutramine
and placebo
James WPT et al. Lancet. 20003562119.
20
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

21
Dose Related Effects of Sibutramineon Systolic
Blood Pressure (SBP)
Sibutramine 15 mg n1924
Sibutramine 10 mg n1318
Sibutramine 20 mg n1126
Sibutramine 30 mg n128
Placebo n1944
10
8
6
3.8
Change in SBP (mmHg)
4
2.6
1.0
2
-0.1
-0.1
0
-1
p lt 0.05 compared to placebo
Data on file, Abbott Laboratories.
22
Maximum BP Changes vs. Baseline
Post hoc analysis of 21 randomized placebo
controlled trials of 12 weeks duration3419
overweight and obese patients with normal or
controlled blood pressureSibutramine 10-15 mg
n1898 placebo n 1521
30 25 20 15 10 5 0
Control (n1,521)
Patients ()
No gt 0 lt 5 5 lt 10 10 lt 15 15 lt 20 20 lt
25 25 lt 30 30 lt 35 35 lt 40 gt 40 increase
SBP or DBP increase (mmHg)
Adapted from Sharma AM et al. NAASO 2003.
23
STORM Change in Vital Signs
Baseline to 24 Months in Sibutramine Treatment
Group
Mean Change 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
James WPT et al. Lancet. 20003562119.
24
Blood Pressure is Lowered with Weight Loss Using
Sibutramine
22
53
6
23
78
47
Change in SBP (mmHg)
of treatment group
Although weight loss with sibutramine was not
associated with equivalent BP reductions as
placebo, a greater proportion of sibutramine
treated patients achieved weight loss.
Adapted from Sharma AM, Int J Obes Relat Metab
Disord 200125 (Suppl 4) S20-S23.
25
The Reality of Sibutramines BP Effects

• Mean BP changes in recommended dose range is
  1 mm Hg increase
• A few, lt 5, have unacceptable blood pressure
  increases while on sibutramine
• Significant weight loss, gt 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 2002106
   2459-2465
2. Berube-Parent S et al. IJO 200125 1144-1153

26
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

27
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
28
Orlistat Prevents Fat Digestion by Binding to
Gastrointestinal Lipases
Intestinal Lumen
Mucosal Cell
TG
Orlistat
FA
MG
Bile Acids
Micelle
TGtriglyceride MGmonoglyceride FAfatty acid
29
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

30
Orlistat 2-Year Efficacy
60
Placebo diet
51.6
Orlistat diet
50
36.4
40
of Patients
27.3
30
15.4
20
10

0
gt 5
gt 10
of Weight Lost
Meta-analysis of data derived from 4 clinical
trials
Xenical package insert. Nutley, NJ Roche
Laboratories, 1999.
31
Effect of Long-Term Treatment With Orlistat (The
XENDOS Study)
Completers Data
p lt 0.001 vs placebo
Torgerson JS et al, Diabetes Care 2004 27(1)
155-61.
32
Independent Effect of Orlistat on Plasma
LDL-Cholesterol
Data pooled from 5 trials (N1773)
Segal et al. FASEB J 199913A873.
33
Orlistat Effect on Lipids and Waist
Circumference
Orlistat 120 mg TID
Placebo
15
0
12.8
13
-0.5
11
9.3
-1
9
Change (in)
-1.5
Change
7
-1.6
-2
5
2.9
-2.5
3
1.34
-2.6
-3
1
Waist Circumference
HDL-C
TG
Xenical package insert. Nutley, NJ Roche
Laboratories, 1999.
34
Orlistat Effect on Blood Pressure in At-Risk
Patients
Systolic (ISH, SBP ? 140 mm Hg)
Diastolic (DBP ? 90 mm Hg)
mm Hg
mm Hg
0
0
-1
-2
-2
-4
-3
Orlistat diet
-4
-6
Placebo diet
-5
-8
-6
-7
-10
-8
-12
P 0.032
P NS
-9
Data on File (Ref 038-001).
35
Orlistat Safety
Adverse Events (AEs) at 1 Year

• There is concern about fat-soluble vitamin
  absorption

Sjöström L et al. Lancet. 1998352167.
36
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.

37
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

38
Drugs Approved by FDA for Short Term Use in
Treating Obesity
Generic Name Trade Names DEA
Schedule
Diethylpropion (1959) Tenuate
IV Phentermine (1959) Adipex-P,
Ionamin IV Benzphetamine (1960) Didrex
III Phendimetrazine (1959) Bontril III Metha
mphetamine Desoxyn II Mazindol (1973)
Mazanor IV
Physicians Desk reference 59th Edition, 2005.
not listed in PDR, but available
39
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.

40
Weight Loss with Continuous and Intermittent
Phentermine
0
0
5
Weight loss (lbs)
16
10
15
32
Time in Weeks
Munro JF, et al. Br Med J 1968 1352-354.
41
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

42
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 200210633. 2. PDR Edition
29, 2005. 3. Darga et al, AJCN, 1991.
43
Treatment with Bupropion
0
Placebo
-5
SR 300
Weight loss ()
-10
SR 400
-15
0
10
20
30
40
50
Weeks of Treatment
Anderson Obes Res 200210633.
44
Fluoxetine 60 mg and Weight Loss
N 23
0
Placebo
-2
-4
N 16
-6
Weight Loss (kg)

-8
N 22
N 14
-10
Fluoxetine
-12
-14
-16
1
3
5
7
9
13
21
29
37
45
53
17
Week number
Darga et al, AJCN, 1991.
45
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.

46
Weight Change with Metformin in DPP Trial

Placebo
Metformin
0 6 12 18 24 30 36
42 48
Months in study
DPP NEJM 2002.
47
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.

48
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 FDAs action date for exenatide is April
  30, 2005

49
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.

50
Weight Loss with Topiramate
Bray et al Obes Res 2003 in press.
51
Zonisamide versus Placebo
0
Placebo
-2
Zonisamide
-4
Weight loss (kg)
-6
-8
0
2
4
6
8
10
12
14
16
18
Week
Gadde IJO 2002 (Abs).
52
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 2005142523-546.
53
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

54
Van Gaal et al. Lancet 20053651389-97.
55
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 20053651389-97.
56
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.

57
Obesity Pharmacotherapy What Does the Future
Hold?

• 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.