Approved Medications Can Stimulate Weight Loss

The traditional formula for weight loss is simple: induce a negative energy balance by increasing physical activities and reducing caloric intake.¹ Yet obesity is not a simple health problem. Individuals who struggle with obesity report difficult life changes, few ways to lose weight and keep it off, and yo-yo dieting.

Guidelines call weight loss of at least 5% from baseline clinically significant, indicating that it improves cardiometabolic risk factors.² That seems like good news. For instance, that would mean a 200-lb individual who loses just 10 lb should see significant improvements. However, most 1 individuals with obesity lose little weight with lifestyle changes alone. Approximately one-third who lose more than 5% of their weight return to their original weight within 1 year. More than half return to their starting weights at 2 years and almost all do so within 5 years.³

When lifestyle interventions are unsuccessful, most obesity control guidelines recommend adjunct medication.^2,3 Because central and peripheral hormonal signaling controls energy intake,⁴ investigators have targeted numerous mechanisms to develop medications. FDA-approved antiobesity medications for chronic weight management include 5 options. Potential mechanisms for obesity medications include appetite/energy intake reduction, calorie absorption reduction, and promotion of energy expenditure.^1-3

Glucagon-Like Peptide 1 Receptor Agonists

The FDA approved the injectable glucagon-like peptide 1 (GLP-1) receptor agonists liraglutide (Saxenda) in 2014 and semaglutide (Wegovy) in 2021
for long-term weight management (Table^5,6). GLP-1 regulates blood glucose after meals by inhibiting glucagon secretion and enhancing insulin secretion from pancreatic β-cells in a glucose-dependent manner.⁷ It induces postprandial satiety and fullness, reduces appetite and food consumption, and slows gastric emptying.⁸ Three randomized controlled trials (RCTs) found weight loss of 4.7% to 8% in liraglutide-treated patients.^9-11 In clinical trials, semaglutide treated was associated with an approximate 15% weight loss over a 68-week period.⁵

Naltrexone/Bupropion

Naltrexone/bupropion (Contrave) combines an opioid antagonist with an antidepressant. Four large RCTs documented weight loss of 5% to 6.1%
in naltrexone/bupropion-treated patients.^12-15 Contraindications include abrupt alcohol discontinuation, anorexia or bulimia nervosa, benzodiazepines, monoamine oxidase inhibition during the first 14 days of use, seizure, uncontrolled hypertension, and use of antiepileptic drugs or barbiturates. This medication also requires gradual dose escalation, starting with 1 tablet (8 mg/90 mg) for 1 week, and ultimately reaching 2 tablets twice daily (the maximum dose) at week 4. Common adverse effects (AEs) include constipation, dizziness, dry mouth, headache, nausea, and vomiting.⁷ Clinicians should monitor for depression or suicidal ideation.^6,16

Orlistat

The FDA approved orlistat (Xenical) in 1999, and it is available as an OTC formulation (Alli) for individuals 12 years or older.¹⁷ Orlistat inhibits gastrointestinal and pancreatic lipases, blocking absorption of approximately one-third of consumed fatty acid and triglyceride hydrolysis but having no effect on appetite.² In a large RCT, participants had a total body weight loss of 2.4% after 4 years. Orlistat decreased type 2 diabetes (T2D) risk in the treatment arm (9%) compared with the placebo arm (6.2%).¹⁸ It also improved blood pressure, insulin sensitivity, and lipid profiles.¹⁸

Patients should take orlistat with or within 1 hour of meals.¹⁷ Because nonabsorbed fats remain in the intestine, almost all patients will report some fecal incontinence, flatus with discharge, frequent bowel movements, and steatorrhea. Using a fiber-contain- ing supplement such as psyllium, can reduce gas- trointestinal AEs. Orlistat prevents the lipid-soluble vitamins from being absorbed, so patients may need vitamin A, D, E, and K supplementation with long-term use.²

Phentermine/Topiramate

The FDA approved phentermine/topiramate extend- ed release (Qsymia), a schedule IV-controlled sub- stance, for long-term obesity management in 2012. It suppresses appetite through mechanisms that remain unclear. Three RCTs found significant mean weight reduction ranging from 7.8% to more than 10% over 1 to 2 years. It was also associated with improved blood pressure, fasting glucose and insulin levels, lipid profiles, and waist circumference.¹⁶

Patients take phentermine/topiramate once daily in the morning to avoid drug-related insomnia. Clinicians gradually escalate the dose from 3.75 mg/23 mg for 2 weeks to 7.5 mg/46 mg in the following weeks. After 3 months, they may increase the dose to 15 mg/92 mg if patients have not lost 3% of baseline weight. If patients lose less than 5% of weight or are intolerant to the drug, clinicians should gradually discontinue phentermine/topiramate to avoid seizure risk.⁸ Common AEs are constipation, dizziness, dry mouth, dysgeusia, insomnia, and paresthesia. Clinicians must periodically monitor creatinine, electrolytes, and heart rate.⁷ Contraindications observed are uncontrolled cardiovascular disease, chronic kidney disease, glaucoma, hypertension, hyperthyroidism, and inhibition of monoamine oxidase within 14 days. Women of childbearing age should avoid pregnancy, as the drug is linked to fetal oral clefts.⁸

Conclusion

With 5 drugs available to manage obesity, clinicians should consider each drug’s mechanism of action before prescribing. Orlistat is more suitable for individuals who tend to eat fatty foods. The GLP-1 receptor agonists have no neuropsychiatric safety concerns and may be options for patients with comorbid mental disorders or T2D.¹⁹

Jeannette Y. Wick, MBA, RPh, FASCP, is the assistant director of the Office of Pharmacy Professional Development at the University of Connecticut School of Pharmacy in Storrs.

References

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