Clinical Review & Education
From The Medical Letter on Drugs and Therapeutics
Two Drugs for Weight Loss appetite and is considered unlikely to cause the hallucinations, cardiac valvulopathy, and pulmonary hypertension that have been associated with activation of other serotonin receptor subtypes.2
In 2012, the FDA approved one new drug and a new combination of 2 old drugs as adjuncts to lifestyle changes for chronic weight management. Lorcaserin (lor-ca-SER-in; Belviq – Arena/Esai) is a selective serotonin 2C receptor agonist (Table 1). Qsymia (Vivus) is a fixed-dose combination of the weight-loss drug phentermine and an extended-release (ER) formulation of topiramate. The new products are approved for use in obese patients (body mass index [BMI] of ⱖ30 kg/m 2 ) and for patients who are overweight (BMI ⱖ27 kg/m2) and have one weight-related risk factor such as hypertension, dyslipidemia or type 2 diabetes.
Clinical Studies
Older Drugs for Weight Loss1 The lipase inhibitor orlistat is modestly effective (patients have lost 2.5-3.2 kg more than with placebo over 1-4 years), but it causes unpleasant adverse effects such as flatulence with discharge, oily spotting and fecal urgency. The sympathomimetic amines, which are approved by the FDA only for short-term use to initiate diet-induced weight loss, are all controlled substances; methamphetamine has a high abuse potential and probably should not be used. All sympathomimetics can increase heart rate, raise blood pressure, and cause nervousness and insomnia.
Approval of lorcaserin was based on 3 randomized double-blind trials in obese or overweight adults; the first-year results are listed in Table 3.3-5 In the first trial (BLOOM), patients who lost ⱖ5% of their body weight after one year on lorcaserin were randomized to continue the drug or switch to placebo for a second year. By the end of the second year, patients who continued on lorcaserin had regained about 25% of the initial weight loss, and those who took lorcaserin during the first year and placebo during year 2 had lost an average of only 1.2 kg more than those who had taken placebo for both years.3 The BLOOM-DM trial was conducted in patients with type 2 diabetes who were also being treated with metformin, a sulfonylurea or both. HbA 1c decreased by 0.9% with lorcaserin twice daily, by 1.0% with lorcaserin once daily, and by 0.4% with placebo.5 Adverse Effects
Lorcaserin (Belviq) Activation of the serotonin 2C receptor (Table 2), which is found mainly in the central nervous system, is thought to suppress
Headache, nausea, and dizziness were the most frequent adverse effects reported with lorcaserin in clinical trials. The discontinuation rates were 50%, 45% and 36% in the 3 studies. Cardiac val-
Table 1. Some FDA-Approved Drugs for Treatment of Obesitya Some Available Formulations
Drug Lorcaserin—Belviq (Arena/Esai) Phentermine/topiramate ER—Qsymia (Vivus)
Usual Daily Dosage
Costb
10 mg tabs
10 mg bid
$199.50
7.5/46, 15/92 mgc
7.5/46-15/92 mg once
170.70 Abbreviation: ODT, orally disintegrating tablets.
Lipase inhibitor Orlistat Xenical (Genentech)
120 mg caps
120 mg tid
$469.80
Allid (GSK)
60 mg caps
60 mg tid
44.00
Sympathomimetic amines
a
Weight loss drugs, including over-the-counter medications, are not recommended for use during pregnancy.
b
Cost of 30 days’ treatment with the lowest strength available based on wholesale acquisition cost (WAC). Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) August 5, 2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies /drug-pricing-policy. Actual retail prices may be higher. Medicare does not cover obesity drugs.
c
Also available in 3.75/23 and 11.25/69 mg capsules which are intended for use only during titration.
d
Available over the counter.
Benzphetamine Generic Didrex (Pfizer) Diethylpropion—generic
25-50 mg once to 50 mg tid
24.90
50 mg tabs 25 mg, 75 mg ER tabs
25 mg tid or 75 mg once
19.80
35 mg tabs
35 mg bid to 70 mg tid
50.40
15-37.5 mg once
19.50
79.20
Phendimetrazine Generic Bontril PDM (Valeant)
8.40
Phentermine Generic Adipex-P (Teva) Suprenza (Akrimax)
15, 30, 37.5 mg caps, 37.5 mg tabs 37.5 mg tabs
37.5 mg once
62.70
15, 30 mg ODT
15-30 mg once
110.70
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Clinical Review & Education From The Medical Letter on Drugs and Therapeutics
vulopathy did not occur more frequently with lorcaserin than with placebo. Euphoria has been reported with doses ⱖ40 mg. Belviq is a schedule IV controlled substance.
by 12 weeks, the drug should be discontinued. Lorcaserin is contraindicated for use during pregnancy.
Phentermine/Topiramate (Qsymia) Drug Interactions
Lorcaserin inhibits CYP2D6; it has increased peak serum concentrations of dextromethorphan, a 2D6 substrate, by 76%. Serotonin syndrome occurred in 2 patients during the clinical trials; one of these patients was also taking dextromethorphan. Dosage and Administration
The dosage of lorcaserin recommended by the manufacturer is 10 mg twice daily. If the patient has not lost at least 5% of baseline weight
Table 2. Pharmacology
Phentermine is a sympathomimetic amine that has been available in the US for many years for short-term (weeks) treatment of obesity. When it was used with fenfluramine (“phen-fen”), the combination was associated with heart valve abnormalities; fenfluramine has since been withdrawn from the market. There have been only rare reports of valvular disease occurring in patients taking phentermine alone. Topiramate (Topamax, and others) is approved for use in epilepsy and migraine, but not for weight control. It has produced significant weight loss in some clinical trials; the mechanism is unclear. Clinical Studies
Drug class
Selective serotonin 2C receptor agonist
Formulation
10-mg tablets
Route
Oral
Tmax
1.5-2 h
Half-life
11 h
Metabolism
Extensively metabolised in the liver by multiple enzymes to inactive metabolites
Execretion
Urine (92%), feces (2%)
Approval of Qsymia was based on two 56-week trials in which patients were randomized to placebo or to one of 2 doses of phentermine/topiramate; the 1-year results are listed in Table 4.6,7 In an extension of the CONQUER trial, patients who volunteered to continue their study regimens for an additional 52 weeks lost (in total after 2 years) an average of 9.3% (9.6 kg) and 10.5% (10.9 kg) of their body weight, compared to a loss of 1.8% (2.1 kg) in the placebo group.8
Table 3. Lorcaserin Clinical Trials No.
Mean Weight Loss (52 weeks)
% Patients with ≥5% Weight Loss
BLOOM3 (average baseline wt: 100 kg) Lorcaserin 10 mg bid
1538
5.8 kg
47.5
Placebo
1499
2.2 kg
20.3
BLOSSOM4 (average baseline wt: 100 kg) Lorcaserin 10 mg once daily 10 mg bid Placebo
801
4.7 kg
40.2
1602
5.8 kg
47.2
1601
2.9 kg
25.0
BLOOM DM5 (average baseline wt: 102-106 kg) Lorcaserin 10 mg once daily 10 mg bid Placebo
95
5.0 kg
44.7
251
4.7 kg
37.5
248
1.6 kg
16.1
Table 4. Qsymia Trials No.
Mean Weight Loss (56 weeks)
% Patients with ≥5% Weight Loss
EQUIP6 (average baseline wt: 115-118 kg) Phentermine/topiramate ER 3.75/23 mg
241
6.0 kg
44.9
15/92 mg
512
12.6 kg
66.7
514
1.9 kg
17.3
Placebo CONQUER7 (average baseline wt: 103 kg) Phentermine/topiramate ER 7.5/46 mg
498
8.1 kg
62
15/92 mg
995
10.2 kg
70
994
1.4 kg
21
Placebo
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From The Medical Letter on Drugs and Therapeutics Clinical Review & Education
Adverse Effects
Pregnancy
Adverse effects that occurred in >5% of patients taking phentermine/topiramate ER and were significantly more frequent than with placebo included dry mouth, paresthesia, constipation, dysgeusia and, with the higher dose, insomnia. Cognitive difficulties affecting attention, concentration and memory were reported. The discontinuation rate of the combination was about 40% in the one-year trials. Topiramate is a carbonic anhydrase inhibitor; metabolic acidosis and kidney stones can occur. Antiepileptic drugs, including topiramate, have been reported to increase the risk of suicidal ideation and behavior. Qsymia is a schedule IV controlled substance.
Topiramate has been associated with a 2- to 5-fold increased risk of oral clefts when taken in the first trimester of pregnancy. Qsymia is contraindicated for use during pregnancy and is available only through a restricted access program (Qsymia REMS) designed to prevent fetal exposure to the drug.
Drug Interactions
Topiramate is a mild inducer of CYP3A4 and a mild inhibitor of CYP2C19. Serum potassium concentrations were lower in patients who took both topiramate and hydrochlorothiazide than in those who took either drug alone. Topiramate taken with valproic acid has been associated with hyperammonemia, with and without encephalopathy. Serum concentrations of topiramate decreased about 40% when the drug was taken with phenytoin or carbamazepine. Phentermine is contraindicated while taking, and for 14 days after stopping, a monoamine oxidase (MAO) inhibitor because of the risk of hypertensive crisis.
Dosage and Administration
Phentermine/topiramate ER is taken once daily, preferably in the morning to prevent insomnia. The recommended dosage is 3.75/23 mg for 14 days followed by 7.5/46 mg. If a 3% weight loss is not achieved after 12 weeks on the 7.5/46 mg dose, the dosage may be increased to 11.25/69 mg for 14 days, and then to 15/92 mg. If the patient does not achieve at least a 5% decrease in weight after 12 weeks on the highest dose, the drug should be discontinued gradually; abrupt withdrawal of topiramate can cause seizures even in patients with no history of epilepsy.
Conclusion Both lorcaserin (Belviq) and the phentermine/topiramate ER combination (Qsymia) taken as adjuncts to diet and exercise may be effective in increasing weight loss in the first year of use, but much less so in the second year. Qsymia appears to be more effective than lorcaserin, but may cause more troublesome adverse effects.
ARTICLE INFORMATION
REFERENCES
Once a month, JAMA selects for publication one article previously published in The Medical Letter.
1. Diet, drugs and surgery for weight loss. Treat Guidel Med Lett. 2011;9(104):17-22.
Previous Publication: This article was previously published: The Medical Letter on Drugs and Therapeutics. September 3, 2012;54(1398):69-71. Cost and availability information have been updated for this publication. ©The Medical Letter Inc.
2. Hurren KM, Berlie HD. Lorcaserin: an investigational serotonin 2C agonist for weight loss. Am J Health Syst Pharm. 2011;68(21):2029-2037.
About The Medical Letter: The Medical Letter is a nonprofit organization that publishes biweekly new drug evaluations and treatment recommendations. The Medical Letter does not accept advertisements, gifts, grants, or donations. Financial support comes solely from sales of subscriptions, books, software, continuing education materials, and licenses. http://www.medicalletter.org Editors: Mark Abramowicz, MD, Editor in Chief; Gianna Zuccotti, MD, MPH, Executive Editor; JeanMarie Pflomm, PharmD, Editor
3. Smith SR, Weissman NJ, Anderson CM, et al; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245-256. 4. Fidler MC, Sanchez M, Raether B, et al; BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96(10):3067-3077. 5. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of
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lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring). 2012;20(7):1426-1436. 6. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20(2):330-342. 7. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341-1352. 8. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95(2):297-308.
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