Only diethylpropion is pregnancy category B, whereas the others drugs in this class are pregnancy category X. It has been demonstrated that diethylpropion and benzphetamine are secreted into breastmilk; insufficient data exist to suggest whether or not phentermine and phendimetrazine are present in breastmilk. All drugs in this class should be used in caution with breastfeeding mothers.
Although all 4 drugs are registered as controlled substances, benzphetamine and phendimetrazine are schedule III and phentermine and diethylpropion are schedule IV, despite evidence suggesting the potential for abuse to be extremely low.12,13 Phentermine has been approved for adults aged > 18 years, phendimetrazine has been approved for those aged > 17 years, diethylpropion has been approved for those aged > 16 years, and benzphetamine has been approved for those aged > 12 years.
There is a wealth of literature surrounding the effectiveness of this drug class for weight loss. One of the longest trials of phentermine was recently conducted as part of the initial component of a FDA study for the newly approved topiramate-phentermine combination. Weight loss at 6 months in the phentermine-only group was significantly higher at -5.8% compared with -1.5% with the placebo group in the last observation carried forward-Intent to treat (LOCF-ITT) analysis.14 Similarly, a long-term study looking at diethylpropion examined the use of diethylpropion for up to a year vs placebo. Participants administered diethylpropion lost a mean 9.8% of original weight vs 3.7% in the placebo group in the first 6 months alone.15
Several meta-analyses and review papers have been authored that examine and analyze the published data on this drug class overall and comparatively within this class. Haddock and colleagues in 2002 reviewed the numerous clinical trials associated with each drug in this class, in addition to several other classes, and found that although each drug demonstrated a significant advantage vs placebo in weight loss, there was not a specific drug that was significantly superior to any of the others.16
These results seem to be in relative agreement with additional studies like that published by Suplicy and colleagues, which demonstrated that several sympathomimetics were better than placebo in weight loss, and that there was little difference between the specific drugs in the class.17 However, it should be noted that as highlighted in a review by Ioannides-Demos and colleagues in 2005, the vast majority of studies that had been performed on this drug class focused on short-term use (< 16 weeks) and none of the sympathomimetics listed here have been approved for long-term use.18
Orlistat
Orlistat 120 mg was approved in 1999 as a reversible inhibitor of GI lipases that specifically reduced the absorption of dietary fat due to the inhibition of triglyceride hydrolysis.19 Orlistat was later approved in 2007 for release in a reduced dosage form (60 mg) for over-the-counter sales.20
Orlistat forms a covalent bond with the active serine residue site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inhibition of these enzymes causes dietary fat to remain undigested as triglycerides, which cannot be converted to absorbable free fatty acids and monoglycerides, leading to decreased calorie absorption. Orlistat is not systemically absorbed and is eliminated mainly through feces. Some metabolism occurs in the GI wall.21Orlistat is most known for its GI AEs. Because it is most active in the lumen of the GI system and reduces the absorption of triglycerides, many AEs are related to malabsorption. The most common issues 1 year after starting the drug were oily spotting (26.6% vs 1.3% placebo); flatus with discharge (23.9% vs 1.4% placebo); fecal urgency (22.1% vs 6.7% placebo); fatty/oily stool (20% vs 2.9% placebo); increased defecation (10.8% vs 4.1% placebo); and fecal incontinence (7.7% vs 0.9% placebo) (Table 1). Most of these AEs were greatly reduced after taking the drug for 2 years. Orlistat also has more serious AEs noted, including abdominal pain/discomfort; nausea; infectious diarrhea; rectal pain/discomfort; tooth disorder; gingival disorder; vomiting; upper respiratory infection; lower respiratory infection; ear, nose and throat symptoms; back pain; arthritis; myalgia; joint disorders; tendonitis; headache; dizziness; fatigue; sleep disorders; rash; dry skin; menstrual irregularity; vaginitis; urinary tract infection; and psychiatric disorders, although these did not differ markedly from placebo.
One of the most serious AEs reported was fulminate hepatic failure, though this AE is rare. Thirteen cases of liver injury were reported with the 120-mg prescription dose of orlistat and 1 case report in the U.S. involved the 60-mg over-the-counter dosage of orlistat.21,22 The FDA suggests that patients talk to their physicians about risks of liver failure, and that physicians should educate their patients about signs and symptoms of liver failure so that patients can stop taking orlistat and seek immediate medical help if symptoms occur.
One of the first published trials was the European Multicentre Orlistat Study Group, which included 743 participants with BMI between 28 kg/m2 and 47 kg/m2 from 15 different European centers. To test adherence, a 4-week single blind placebo lead-in was started with a hypocaloric diet. The first stage was completed by 688 patients who then proceeded to the double blind randomized control trial portion with a hypocaloric diet. From the start of lead-in to the end of year 1, the orlistat group weight decreased 10.2% (10.3 kg) vs 6.1% (6.1 kg) in the placebo group. The placebo subtracted difference between the groups was 3.9 kg (P < .001).23
A U.S.-based randomized double-blind placebo-controlled multicenter study included 796 obese patients with BMI between 30 kg/m2 and 44 kg/m2. Patients were assigned to 1 of 3 groups: placebo, orlistat 60 mg 3 times daily, or orlistat 120 mg 3 times daily. All groups were given a reduced energy diet. Patients in the orlistat 120 mg group lost significantly more weight than did the placebo group, -8.78% vs -4.26% respectively in year 1 in the completer analysis (P = .001). More participants who were treated with orlistat 120 mg lost 5% or more of their initial weight in year 1 compared with placebo, 50.5% vs 30.7% respectively (P < .001).24
In the XENDOS study the primary outcome measurement was time to onset of T2DM. Eligible participants were aged 30 to 60 years, with a BMI > 30 kg/m2. All patients had a 75-g oral glucose tolerance test and were required to have normal glucose tolerance or impaired glucose tolerance, but not T2DM. The double-blind randomized controlled trial included 3,305 subjects and compared a group taking 120 mg orlistat 3 times daily vs placebo. All patients were prescribed a reduced-calorie diet (800 kcal/d deficit) containing 30% of calories from fat. Patients were also encouraged to walk at least 1 kilometer daily in addition to their usual physical activity. Incidence of T2DM after 4 years was 6.2% in the orlistat group and 9.0% in the placebo group, reflecting a 37.3% risk reduction in the orlistat group (P = .0032).25,26
Lorcaserin
In 2012, lorcaserin HCl was FDA approved as a schedule IV drug for use as a weight loss medication as an adjunct to a reduced-calorie diet and increased physical activity. Lorcaserin is thought to act on 5-hydroxytryptamine-2c (5HT2c) receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, causing release of alpha-melanocortin-stimulating hormone (alpha-MSH), which in turn acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. At the maximum suggested dose of 10 mg twice daily, lorcaserin binds with 15 to 100 times greater affinity to 5HT2c receptors compared with 5HT2a and 5HT2b receptors respectively.
Indications for lorcaserin include patients with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 or greater with a weight-related comorbid condition such as hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea.
The efficacy of lorcaserin for weight loss has been evaluated in 3 separate trials. The trials were randomized, double blinded and placebo controlled. The BLOOM trial, which included 3,182 patients with a mean BMI of 36.2 kg/m2, evaluated the efficacy of lorcaserin as a weight loss adjunct.27 Patients with pre-existing valvular disease, uncontrolled hypertension, or a major psychiatric condition were excluded. After initial randomization, patients were assigned to receive either lorcaserin 10 mg twice daily or a placebo. The primary endpoint was a 5% weight reduction from baseline by the end of 2 years. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost ≥ 5% of their body weight (P <.001). The average loss for the lorcaserin group was 5.8 ± 0.2 kg and 2.2 ± 0.1 kg for the placebo group at 1 year (P < .001).
The BLOSSOM trial was a 1-year study of 4,008 patients aged 18 to 65 years. The trial evaluated the effects of lorcaserin on body weight, CVD risk factors, and safety in obese and overweight patients.28 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. The primary endpoint was the proportion of patients achieving at least 5% reduction in body weight. Completer analysis showed weight reduction in the placebo group was 4.0% and 7.9% in the lorcaserin group (P < .001). In the modified intent-to-treat/last observation carried forward analysis (MITT/LOCF), a statistically significant 47.2% of patients receiving lorcaserin 10 mg twice daily and 40.2% of patients receiving lorcaserin 10 mg once daily lost at least 5% of baseline body weight; compared with 25% of patients receiving placebo (P < .001). Weight loss of at least 10% was achieved by 22.6% of patients receiving lorcaserin 10 mg twice daily, and 17.4% of patients receiving 10 mg daily compared with 9.7% of patients in the placebo group (P < .001).