Transcript The Skinny on Old and New Weight Loss Medications

The Skinny on Old and
New Weight Loss
Medications
Steven R Smith, MS, RPh, BCACP
TASHP
September 27, 2012
Objectives
1. State the rules that control the prescribing of
weight loss medicines in Ohio,
2. Given patient characteristics, select the best
weight loss medication,
3. Educate a patient on the expected success /
known risks of weight loss medications
Weight Loss Medicines
Dietary supplements (herbal)
OTC
Prescription
Dietary supplements
Dr. Oz
Uncontrolled claims on TV, in magazines, and on
the web
Claims fall under FDA and FTC
Not removed from the market until substantial
harm is proved
Endless list of ingredients / Proprietary blends
Dietary supplements
Supplement
How it works
Conjugated linoleic acid (CLA)
Feeling of fullness
Chromium
Trace element needed for insulin
action
Green tea extracts
Decreased appetite, fat burner
Guar gum
Dietary fiber
Senna
Laxative
Ephedra (ma huang)
Stimulant (off the market in US)
Hydroxycitric acid (Garcinia
combogia extract)
Promotes fat oxidation by
inhibiting ATP-citrate lyase
Gymnemia sylvestre
Decrease blood sugar
Dietary supplements
Supplement
How it works
Ginger root
Reduce nausea
Raspberry ketones
Fat burner
Ginseng
Adaptogenic
Coconut oil
MCT not stored in adipose tissue
but high in calories / fat
Apple cider vinegar
Drink before eating to decrease
appetite
Bitter orange
Contains stimulants (synephrine,
octopamine)
Caffeine (guarana)
Short acting stimulant, diuretic
Lipovarin
Contains synephrine
Dietary supplements
Supplement
How it works
Hoodia
Appetite suppressant (P57), FDA
warnings for false claims
Glucomannan (LipozeneR)
Dietary fiber to increase “fullness”
Chitosan
Sugar from the hard outer layers
of lobsters, crabs, shrimps. Blocks
absorption of fat
Licorice root
Adaptogenic
Cayenne powder
Fat burner
Magnolia bark extract
Cortisol blocker
(CortiSlim –FTC-false claims)
Other weight loss ideas
Sensa, Aroma Patch, SlimScents:
Alter taste / appetite by sense of smell
Ear Stapling:
Principles of accupuncture
OTC
Historical:
Phenylpropanolamine 75mg once daily
Increased strokes and other CV events
11/2000 – FDA advises to not make it
Officially off the market in 2005 due to concern
over its use to make amphetamines
200-500 strokes / year in 18-49 yo users
OTC
Orlistat (AlliR) 60mg up to three times daily with
meals became available in 2007
Blocks 25% of dietary fat absorption
The “Antabuse” of dieting
No more than 15gm of fat with the meal
Expected weight loss: 3 to 5 pounds / year
Prescription
Orlistat (XenicalR) 120mg up to 3 times a day
with meals approved in 1999
Blocks at least 25% of dietary fat absorption
Expected weight loss: 5 to 7 pounds / year
Drug interactions: cyclosporine, warfarin, T4
Take a multivitamin daily at bedtime
Orlistat
A meta-analysis of 29 studies where enrolled
patients had an average BMI of 36.7
Average weight loss compared to placebo
2.89kg (-3.51 to -2.27)
RR for diarrhea: 3.4, for flatulence: 3.1, for
bloating-abdominal pain-dyspepsia: 1.48
In a second year extension study:
1/3 on orlistat regained weight lost in 1st year
2/3 on placebo regained weight lost in 1st year
Orlistat Patient Education
Take it 60 minutes prior or with a meal or up to
60 minutes after.
Reduce the fat in your diet for 3 days prior to
starting orlistat.
Teach symptoms of liver disease: itching, yellow
eyes or skin, loss of appetite
Go to myalli.com for lots of good information
about fat in the diet and other tips to be
successful.
Prescription
Historical:
Amphetamine, dextroamphetamine,
methamphetamine, phenmetrazine were C-II
drugs no longer indicated for weight loss
Fenfluramine (PondominR), dexfenfluramine
(ReduxR) worked through serotonin and were
taken off the market in 1997 due to pulmonary
hypertension and heart valve disease.
Prescription
Historical:
Sibutramine (MeridiaR) works on serotonin at lower
doses, norepinephrine at higher dose.
Questionable efficacy / increased risk of CV event
so the FDA pressured Abbott to remove it from the
market in Oct, 2010
Rimonobant, a cannabinoid CB1 antagonist was on
the market in 56 other countries. FDA said it was
approvable in 2006, an advisory committee said not
to approve in 2007, Europe took it off the market in
2009. Sanofi-Aventis dropped pursuing it.
Prescription
Benzphetamine (DidrexR) – CIII is converted to
methamphetamine and amphetamine. Dose is 25
to 50mg up to 3 times daily.
Phendimetrazine (BontrilR) – CIII is a prodrug to
phenmetrazine (PreludinR – CII). Phenmetrazine
gained notoriety when the Beatles were found to
favor it. Phendimetrazine dose is 105mg
sustained release capsule daily or 17.5 to 35mg
tablets 2 or 3 times daily one hour AC.
What do we have today
Orlistat – previously discussed
Diethylpropion
Phentermine
Lorcaserin
Phentermine / Topiramate
Diethylproprion C-IV
25mg immediate release 2 or 3 times a day
75mg sustained release once daily
Meta-analysis of 13 studies, 6 to 52 weeks, from
1965-1983
Weight loss compared to placebo
3kg (-1.6 to 11.5kg)
Side effects as expected from a stimulant
Phentermine C-IV
Sustained release resin (ionamin): 15, 30,
37.5mg
Tablet: 37.5mg; Oral disintegrating: 15, 30mg
Meta-analysis of 9 studies, 2 to 24 weeks, from
1975-1999
Doses of 15 to 30mg daily
Weight loss compared to placebo: 3.6kg (0.6 to
6kg)
Side effects as expected from a stimulant
Fluoxetine
Meta-analysis of 9 studies using 60mg/day in
patients with baseline BMI of 35.5
6 month results: 0.9 to 9.1kg weight loss
12 month results: -0.4 to 14.5 kg
Side effects:
Nervous, sweating, tremor: RR 6.37
Nausea & vomiting: RR 2.68
Insomnia: RR 2.06
Other Antidepressants
Sertraline: only one study with negative results
Bupropion:
3 studies, avg baseline weight: 94.3kg
300-400mg/day
2.77 (1.1 to 4.5) kg weight loss
Side effect: dry mouth RR 2.99
So what’s new?
Two new drugs recently approved
Lorcaserin (BelviqR): a 5HT-2c agonist
Phentermine / Topiramate (QsymiaR)
Results now presented as (%) of body weight lost
with proportion losing 5% and losing 10%
Studies tending to be longer duration
BelviqR studies evaluated echocardiographic signs of
valvulopathy
QsymiaR studies evaluated depression/suicides
Lorcaserin
BLOSSOM Study design:
52 weeks on 10mg daily (1/5) vs. 10mg twice
daily(2/5) vs. placebo (2/5)
18 to 65 year olds
BMI =>30 or BMI =>27 with HTN, dyslipidemia,
CV disease, glucose intolerance, sleep apnea
Excluded if on on SSRI, recent use of other
weight loss medications, unable to participate in
moderate-intensity exercise, recent CV event,
major surgery, recent low calorie diet, 5kg change
in weight, bariatric surgery
Lorcaserin: BLOSSOM
Follow-up at 2 and 4 weeks then monthly
Reduce daily caloric intake to 600 kcal below
WHO equations for estimating daily energy
requirements using 1.3 for the activity factor (1.4
if patient already exercised => 1 hour/day)
Encouraged to exercise moderately for 30
minutes daily
Also Beck Depression Inventory-II,
echocardiograms, DEXA, and other testing
Lorcaserin: BLOSSOM
Primary endpoints:
Proportion achieving 5% weight loss
Mean weight change from baseline
Proportion achieving 10% weight loss
Assumed 15% of placebo would lose 5%, 40%
dropout at week 52: need 720 patients per group
Primary echocardiographic endpoint at week 52
using FDA criteria of aortic or mitral regurgitation
Lorcaserin: BLOSSOM
End point
Days on drug
L 10mg BID
1561 pts
257
L 10mg /day
771 pts
265
Placebo
1541 pts
242
5% weight loss
737 (47.2%)
Sig vs placebo
Sig vs L10/day
310 (42%)
Sig vs placebo
385 (25%)
10% weight
loss
353 (22.6%)
Sig vs placebo
134 (17.4%)
Sig vs placebo
150 (9.7%)
Base weight
100.3 kg
100.1 kg
100.8 kg
Change in wt
-5.8 kg
-4.7 kg
-2.9 kg
Base BMI
36.1
35.9
36
Change in BMI
-2.1
-1.7
-1
Lorcaserin: BLOSSOM
No effect on:
LDL cholesterol
Total cholesterol (sig diff, not clinically diff)
Triglycerides (sig diff, not clinically diff)
HgbA1c
Blood pressure
Heart rate
Echocardiographic valvulopathy
Different: Slight increase in HDL, Quality of Life
Lorcaserin: BLOOM
Same inclusion and exclusion as BLOSSOM
L: 10mg twice daily vs placebo
Primary endpoints same as BLOSSOM
2nd year extension study for those who achieved
5% or more body weight reduction
Stay on placebo if on it year one
If on L: randomized to continue L or get placebo
Lorcaserin: BLOOM
End points -1st
L 10mg BID
1538 pts
Placebo
1499 pts
5% weight loss
47.5%
P < 0.001
20.3%
10% weight loss
22.6%
P < 0.001
7.7%
Weight change
-5.8 kg
P < 0.001
-2.2 kg
2%
0.8%
0.8%
0.1%
Withdrawal due to
- Headache
- Dizziness
Lorcaserin: BLOOM
Secondary endpoints – year 1:
Total and LDL cholesterol (sig diff, not clinically)
Triglycerides reduced approximately 6%
Fasting glucose and insulin (sig diff, not clinically)
HgbA1c (sig diff, not clinically)
Quality of Life (sig diff, questionable clinical sig)
Beck Depression Inventory-II (not diff)
FDA-defined valvulopathy: no difference over the
two years
Lorcarserin: BLOOM
Year 2 continuation
67.9% of locaserin patients vs 50.3% of placebo
patients maintained their weight loss.(p<0.001)
Lorcaserin: BLOOM-DM
This trial was the first to enroll patients
diagnosed with diabetes mellitus type 2.
The design was the same as BLOSSOM.
37.5% of lorcaserin patients lost 5% or more of
their body weight compared to 16.1% of placebo
patients.
HgbA1c was reduced 0.9% in lorcaserin patients
compared to 0.4% in placebo patients.
Lorcaserin Summary
Modest weight loss. In fact, if the 5% mark is not
achieved by 12 weeks, stop the drug.
Daily exercise and 600 less kcal /day
Cost of a “venti latte” or $3.57
If per day, then $107 per month
If per tablet, then $214 per month
Side effects: headache, dizziness, fatigue, dry mouth,
and all the usual GI side effects
Pregnancy: X / C-IV
Lorcaserin Summary
Low abuse potential
Unknown what to expect if on SSRI’s also.
Inhibits CYP-2D6 but specifics are unexplored.
May take with or without food.
If DM patient with good control, watch for
hypoglycemia, adjust doses of DM meds.
Phentermine / Topiramate
QsymiaR (kyoo sim ee’ uh) is a combination of
immediate release phentermine HCl and
extended release topiramate
Phentermine, a stimulant and appetite
suppressant
Topiramate augments the activity of gammaamiobutyrate, modulates voltage-gated ion
channels, inhibits AMPA/kainite excitatory
glutamate receptors, inhibits carbonic anhydrase
P + T: CONQUER
Patients 18 to 70 years for 56 weeks
BMI 27 to 45
Two or more comorbidities (HTN,
hypertriglyceridemia, diabetes) and waist
circumference (=>102cm for men, =>88cm for
women)
Excluded uncontrolled HTN, uncontrolled
hypertriglyceridemia, DM-1, use of DM
medications other than metformin, hx of
nephrolithiasis, recurrent major depression /
suicidal behavior, TCA’s, MAOI’s
P + T: CONQUER
Assigned in 2:1:2 ratio
Placebo
P 7.5mg + T 46mg
P 15mg + T 92mg
Titration starting at P 3.75mg + T 23mg with
weekly increases in the 3.75 / 23 increments until
the assigned dose was achieved
P + T: CONQUER
All patients given:
A LEARN manual by Kelly D. Brownell, PhD
Lifestyle, Exercise, Attitude, Relationships,
Nutrition
Advised to implement lifestyle changes
Instructed to reduce calories by 500 kcal/day
Monthly visits
P + T: CONQUER
End points
5% weight loss
10% weight
loss
Avg weight loss
Placebo
979 pts
P7.5 / T46
488 pts
P15 / T92
981 pts
204 (21%)
303 (62%)
P<0.0001
687 (70%)
P<0.0001
72 (7%)
182 (37%)
P<0.0001
467 (48%)
P<0.0001
1.4 kg
8.1 kg
10.2 kg
P + T: CONQUER
Waist circumference: reduced 5.1 to 6.8 cm more
than placebo
Systolic but not diastolic BP reduced by 2 to 3 mm Hg
Total cholesterol reduced 1.6 to 3%, Triglycerides
reduced 12 to 15%, HDL raised 4 to 5%
HgbA1c reduced (sig diff, but not clinically)
Side effects: dry mouth, dysgeusia, paraesthesia,
insomnia, dizziness, anxiety, irritability, disturbance in
attention, tachycardia.
P + T: EQUIP
Assigned in 2:1:2 ratio
Placebo
P 3.75mg + T 23mg
P 15mg + T 92mg
Titration starting at P 3.75mg + T 23mg with
weekly increases in the 3.75 / 23 increments until
the assigned dose was achieved
P + T: EQUIP
Enrolled 18 to 70 year olds with BMI =>35 and
controlled hypertriglyceridemia, controlled
hypertension, and fasting blood sugar =<110.
Same titration as CONQUER study
Study design same as CONQUER study
P + T: EQUIP
End points
Placebo
514 pts
P3.75 / T23
241 pts
P15 / T92
512 pts
% weight loss
1.6%
5.1%
10.9%
5% weight loss
17.3%
44.9%
66.7%
10% weight
loss
7.4%
18.8%
47.2%
15% weight
loss
3.4%
7.3%
32.3%
Side effects: Paraesthesia, dry mouth, constipation,
dysgeusia, insomnia, depression, disturbance in attention,
anxiety, irritability.
P + T: SEQUEL
Patients who finished the CONQUER trial were
eligible to participate in an additional 52 week
continuation trial.
866 eligible / 676 participated
Results are calculated from baseline of the
CONQUER trial to 108 weeks
P + T: SEQUEL
End point
Placebo
227 pts
P7.5/T46
154 pts
P15/T92
295 pts
% weight loss
1.8%
9.3%
10.5%
5% weight loss
30%
75.2%
79.3%
10% weight
loss
11.5%
50.3%
53.9%
15% weight
loss
6.6%
24.2%
31.9%
20% weight
loss
2.2%
9.2%
15.3%
Qsymia titration
Take daily in the morning.
P 3.75mg / T 23mg for 14 days, then
P 7.5mg / T 46mg daily.
If do not lose 3% of body weight on this dose at
12 weeks, discontinue or escalate dose
To escalate: P 11.25mg / T 69mg daily for 14
days, then
P 15mg / T 92mg for 12 weeks then re-evaluate.
QsymiaR
Available via certified mail order pharmacies:
CVS
Walgreens
Prescriptions faxed
www.qsymia.com for patient guides, provider
guides, etc
Ohio Regulations
Ohio Medical Board
Rule 4731-11-03 Schedule II controlled
stimulants
May not use these for weight loss / management
Ohio Regulations
Rule 4731-11-04 Controlled substances for
weight reduction
May only use a C-III or C-IV for weight reduction if
it is FDA approved for that use
Patient must have made a good faith effort to lose
weight via other means
Physician does good exam
BMI =>30 or =>27 with comorbidities
Meets with the patient every 30 days face-to-face
to assess success
Ohio Regulations
Rule 4731-11-04 Controlled substances for
weight reduction
Duration of use matches how it was FDA
approved, ie “a few weeks” = 12 weeks
May use for maintenance of weight loss if FDA
approved for that manner of use
Must discontinue the medication if the patient is
not losing weight over a 30 day period.
Patient Education
Side effects / adverse effects specific to the
prescribed medication.
Treatment agreement on monthly appointments
and 30 day prescriptions
Importance of exercise / calorie restriction / lifestyle modification for both short term and long
term success.
If diabetes, knowledge of symptoms of
hypoglycemia and how to respond to them.
35 yo, wt 110kg, BMI 44.4, Read about
the new diet pills. Old pills didn’t work.
A. Phentermine / Topiramate
B. Locaserin
C. Orlistat
D. Life-style
55 yo, wt 150kg, BMI 55, Read about the new diet pills. Old
pills didn’t work. DM-2 (A1c=9.8%) on metformin and sitagliptin.
Controlled HTN on metoprolol, Lipids ok on simvastain.
A. Phentermine / topiramate
B. Locaserin
C. Orlistat
D. None are safe for her
42yo, lost his job, BMI=28.5, girlfriend says lose
some weight. Serious exercises 4 days/week, still
not losing weight. Ex-wife suing for custody of 2
kids. Nothing is going right in life. On citalopram
40mg daily. BP good on lisinopril / amlodipine.
A. Phentermine / topiramate
B. Locaserin
C. Orlistat
D. Get a new girlfriend
Conclusion
Medications for weight loss, both old and new,
produce modest benefit.
Life-style change, exercise, calorie restriction are
required.
How much are we willing to spend to lose 5 to 15
kg and what are the other health benefits
(mortality, strokes, MI’s, etc) ?