The Skinny on Old and New Weight Loss MedicationsSteven R Smith, MS, RPh, BCACPTASHPSeptember 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 placebo2.89kg (-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.

PrescriptionHistorical:

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 placebo3kg (-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 approvedLorcaserin (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 L 10mg BID1561 pts

L 10mg /day771 pts

Placebo1541 pts

Days on drug 257 265 242

5% weight loss 737 (47.2%)Sig vs placeboSig 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 BID1538 pts

Placebo1499 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 kgP < 0.001

-2.2 kg

Withdrawal due to- Headache- Dizziness

2%0.8%

0.8%0.1%

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: BLOOMYear 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 $3.57If 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 gamma-amiobutyrate, modulates voltage-gated ion channels, inhibits AMPA/kainite excitatory glutamate receptors, inhibits carbonic anhydrase

P + T: CONQUER

Patients 18 to 70 years for 56 weeksBMI 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 ratioPlacebo

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, PhDLifestyle, Exercise, Attitude, Relationships, Nutrition

Advised to implement lifestyle changes

Instructed to reduce calories by 500 kcal/day

Monthly visits

P + T: CONQUER

End points Placebo979 pts

P7.5 / T46488 pts

P15 / T92981 pts

5% weight loss 204 (21%) 303 (62%)P<0.0001

687 (70%)P<0.0001

10% weight loss

72 (7%) 182 (37%)P<0.0001

467 (48%)P<0.0001

Avg weight loss 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 ratioPlacebo

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 Placebo514 pts

P3.75 / T23241 pts

P15 / T92512 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 Placebo227 pts

P7.5/T46154 pts

P15/T92295 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 / life-style 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) ?