The Skinny on Commonly Prescribed Antiobesity Medications

The prevalence of obesity was 39.8% among US adults in 2015-2016.¹Many common medical problems, such as cardiovascular and pulmonary diseases and diabetes, are related to obesity and can improve with weight loss.²Obesity-related conditions also include certain types of cancer, heart disease, stroke, and type 2 diabetes (T2D), all leading causes of prevent- able death.

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Behavioral modifications, exercise, and nutrition, are the cornerstones of obesity man- agement, but physiologic adaptations can occur with weight loss.

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Weight loss through lifestyle modifications alone can be limited and difficult to maintain.

Medication can address appetite and energy levels and improve adherence to lifestyle changes. These can be considered if patients have a body mass index (BMI) of 30 kg/m

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or greater or a BMI of 27 kg/m

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or greater with comorbidities, such as dyslipidemia, hypertension, obstructive sleep apnea, and T2D, according to the 2013 American College of Cardiology/American Heart Association/The Obesity Society guideline for the management of overweight and obesity in adults and the Endocrine Society’s clinical practice guidelines on the pharma- cologic management of obesity.

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COMMONLY PRESCRIBED MEDICATIONS

Phentermine (Adipex-P) was the first drug approved by the FDA for obesity. It is indicated for short-term use of about 3 months and is a sympathomimetic amine drug, which increases satiety. Phentermine is available in doses from 8 to 37.5 mg in capsule or tablet formulations. A 28-week randomized clinical trial (RCT) demonstrated a 5- to 6-kg weight loss in patients taking phentermine compared with a 1.5- kg weight loss with placebo.

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The most common adverse effects (AEs) include dizziness, dry mouth, insomnia, and irritability. Phentermine should be avoided in patients with anxiety, coronary artery disease, glaucoma, hyperthyroidism, uncontrolled hypertension, and a history of drug abuse and in women who are pregnant.

Orlistat (Xenical) inhibits lipases, decreases the breakdown and absorption of dietary fat (calories), and increases fecal fat loss. Dosage is either 60- or 120-mg capsules orally 3 times a day with a fat-containing meal. The results of a large long-term study comparing orlistat plus lifestyle changes with placebo with lifestyle changes demonstrated a modest weight loss after 4 years: 5.8 and 3 kg, respectively. Fifty-three percent of patients lost 5% or more of their initial body weight with orlistat.

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A meta-analysis of several trials confirmed the moderate efficacy of orlistat, with a mean placebo-subtracted difference of 3 kg at 12 months.

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Orlistat may improve lipid panel (total cholesterol and low-density lipoprotein) and lower both blood pressure and blood glucose, all conditions correlated with obesity.

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Primary AEs of orlistat relate to fat malabsorption and include fecal urgency, oily stool, and fecal incontinence reduction in absorption of fat-soluble vitamins. Other possible AEs are increased risk of cholelithiasis and urinary oxalate excretion. Patients should take vitamins A,D,E,andKhalfanhourbeforeor2to3hours after taking orlistat. Avoid orlistat in patients with malabsorption syndromes.

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Phentermine/topiramate (Qsymia) is a combination sympathomimetic amine and antiepileptic medication that is thought to suppress appetite by affecting gamma-aminobutyric acid, glutamate, and carbonic anhydrase. Doses range from an initial dose of 3.75/23 mg orally to a maximum dose of 15/92 mg, and the dosage can be escalated based on weight response. Data from a large, controlled, 56-week trial demonstrated dose-dependent weight loss of 7.8 to 9.8 kg with phentermine/ topiramate compared with 1.2 kg with the placebo. Between 62% and 70% of patients lost 5% or more of their body weight compared with 21% taking the placebo.

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The SEQUEL trial reported

an ongoing weight loss 52 weeks after the initial 56-week trial of 9.3% to 10.5% compared with the placebo (1.8%) and a significant reduction in the progression to diabetes in patients taking phentermine/topiramate.

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Dry mouth, constipation, and paresthesia are the most common AEs. Discontinue phentermine/topiramate gradually if there is inadequate weight loss by 12 weeks, and avoid use in pregnant women, as topiramate can cause an orofacial cleft in a developing fetus, and in patients with glaucoma or hyperthyroidism who take monoamine oxidase inhibitors. Topiramate use has been associated with increased risk of developing kidney stones, so it may be prudent to encourage patients to increase water intake.

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Lorcaserin (Belviq) is a schedule IV selective agonist of the serotonin 2C receptor that reduces food intake and increases satiety. The dosage is 10 mg orally twice daily. Data from large randomized trials show a modest effect on weight loss, with a mean difference in weight loss between active and placebo-treated groups of about 3 to 4 kg.

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AEs were mild, most commonly including headache, nausea, back pain, and nasopharyngitis. Lorcaserin should not be used during pregnancy, in patients with creatinine clearance of less than 30 ml/min, and among those taking serotonergic drugs, such as most antidepressants.

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Naltrexone/bupropion sustained release (SR) (Contrave) is a dopa- mine reuptake inhibitor and an opioid receptor antagonist that works by reducing appetite and food cravings. The initial dose is 8 mg of naltrexone and 90 mg of bupropion orally once daily, increased to a therapeutic dosage of 32 mg/360 mg. The results of multiple long- term controlled trials demonstrated moderate weight loss averaging 4% to 5%.

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Naltrexone/bupropion SR may be useful for smoking cessation and weight loss.

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Naltrexone/bupropion SR can increase blood pressure and heart rate, and long-term cardiovascular safety is unknown. The most common AEs are constipation, dizziness, dry mouth, insomnia, and nausea. Naltrexone/bupropion SR should not be used in patients with eating or seizure disorders or conditions that predispose them to seizures or by chronic opioid users. Bupropion is an antidepressant and has a black box warning about increased suicidality in patients younger than 24 years; it can also cause a false-positive urine test for amphetamines.

Liraglutide (Saxenda) is a once-daily subcutaneous injection of a glucagonlike peptide agonist and was initially approved for T2D. It is associated with decreased food intake and increased satiety, related to delayed gastric emptying. Dosage titration ranges from 0.6

to 3.0 mg per day. Efficacy data from 2 large RCTs in those with and without diabetes demonstrated a mean weight loss of 6% to 8% body weight at 56 weeks with liraglutide 3 mg compared with 2% to 2.6% with placebo.

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Liraglutide was also superior to the placebo for weight maintenance (6.2% vs 0.2%) in a 56-week RCT in patients on a low-calorie diet.

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The most common AEs of liraglutide were gastrointestinal in nature, including abdominal pain, diarrhea, nausea, and vomiting. Patients using insulin or other hypoglycemic medications may require a dose adjustment to avoid hypoglycemia. Pancreatitis can be a rare but serious complication, and patients must discontinue liraglutide if this occurs. Avoid using liraglutide in patients who are pregnant or have a family or personal history of medullary thyroid carcinoma and/or multiple endocrine neoplasia type 2.

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WHICH DRUG IS BEST?

The choice for obesity pharmacotherapy depends on drug AEs, contraindications, and patient comorbidities. For example, patients with seizure disorders and/or cardiac conditions should not use bupropion, while patients with migraines might benefit from topi- ramate and smokers from bupropion. Liraglutide and orlistatmay be good choices for patients with diabetes.

Patients should be monitored frequently, and if the medication is ineffective by 12 weeks, defined as weight loss of less than 5% at 3 months, discontinue and switch to an alternative therapy.

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PRACTICE IMPLICATIONS

Primary care providers should be familiar with the pharmacotherapy available to patients with obesity as an adjunct to behavioral, nutritional, and physical therapies. The objective of antiobesity therapy is to treat the metabolic biomechanical and psychosocial health consequences of obesity. Pharmacotherapy should be instituted to treat obesity only after careful analyses of patients’ behaviors and comorbidities. Close monitoring of efficacy, safety, and tolerability is imperative. If a patient’s response to a weight loss medication is effective (weight loss ≥5% of body weight at 3 months) and safe, continue the medication. If the medication is ineffective (weight loss <5% at 3 months) or if there are safe- ty or tolerability issues at any time, discontinue the medication and consider alternative medications or a referral for a new treatment approach.

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Jennifer L. Hofmann, MS, PA-C, is a clinical associate professor and full-time faculty and pharmacology courses instructor at Pace University-Lenox Hill Hospital PA Program in New York, New York. She is also a PA program adjunct professor for the Touro College School of Health Sciences in Bayshore, New York, and Nassau University Medical Centerin East Meadow, New York. In addition, she is a Stony Brook University PA Program postprofessional PA program clinical pharmacology seminar adjunct professor in New York.

Jean Covino, DHSc, PA-C, is a clinical professor at Pace University’s College of Health Professions in New York.

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