A comprehensive review examined the efficacy, safety, and practical considerations of antiobesity medications (AOMs) in adult and adolescent patients. 

Since 1999, obesity prevalence among U.S. adults had risen from 30% to 42% and was projected to affect nearly 1 in 2 U.S. adults by 2030. Worldwide, obesity affected 19% of women and 14% of men.

In the review, published in JAMA, investigators provided an in-depth analysis of currently approved AOMs and their role in obesity management. They conducted a literature search of PubMed between January 1, 2015, and February 27, 2024, using search terms such as "antiobesity agents," "obesity drug therapy," and "obesity pharmacotherapy." The search was limited to randomized clinical trials (RCTs), systematic reviews, and practice guidelines. A total of 744 articles were identified, with 88 included in the final review.

The review categorized AOMs into three groups based on their mechanisms of action: intragastrointestinal medications (orlistat), centrally acting medications (phentermine, phentermine-topiramate, and naltrexone-bupropion), and nutrient-stimulated hormone-based medications (liraglutide, semaglutide, and tirzepatide).

Among the key findings were:

• Nutrient-stimulated hormone-based medications, particularly semaglutide and tirzepatide, showed the greatest efficacy for weight loss.
• AOMs were recommended as adjunctive therapy to lifestyle interventions for adults with a body mass index (BMI) ≥ 30 or ≥ 27 with weight-related comorbidities.
• AOM use was associated with improvements in cardiometabolic outcomes, including reductions in blood pressure, hemoglobin A1c, and low-density lipoprotein (LDL) cholesterol.
• Common adverse effects varied by medication class but often included gastrointestinal symptoms, which could be managed through dose titration and dietary modifications.
• Long-term use of AOMs was often necessary to maintain weight loss, as discontinuation frequently led to weight regain.

A meta-analysis of 52 RCTs involving 16,964 participants found that orlistat was associated with 3.1% greater weight loss compared with placebo (95% confidence interval [CI] = 2.7%–3.5%). For centrally acting medications, a meta-analysis of 5 RCTs involving 3,407 participants reported that phentermine-topiramate was associated with 8.0% greater weight loss compared with placebo (95% CI = 6.7%–9.3%).

Nutrient-stimulated hormone-based medications demonstrated the highest efficacy. A meta-analysis of 18 RCTs involving 6,321 participants found that liraglutide was associated with 4.7% greater weight loss compared with placebo (95% CI = 4.1%–5.3%). For semaglutide, a meta-analysis of 5 RCTs involving 4,421 participants reported 11.4% greater weight loss compared with placebo (95% CI = 10.3%–12.5%). Tirzepatide 15 mg was associated with 12.4% greater weight loss compared with placebo in a meta-analysis of 6 RCTs involving 1,972 participants (95% CI = 7.5%–17.2%).

Detailed efficacy data showed that nearly 70% of the participants who received orlistat achieved ≥ 5% weight loss. More than two-thirds of the phentermine-topiramate 15/92-mg users achieved ≥ 5% weight loss. Nearly half of the naltrexone-bupropion users achieved ≥ 5% weight loss in a 56-week RCT. More than 60% of the participants treated with liraglutide achieved ≥ 5% weight loss. More than 85% of those taking semaglutide attained ≥ 5% weight loss. More than 90% of participants treated with tirzepatide 15 mg achieved ≥ 5% weight loss.

The review included data on AOM efficacy in adolescents. In a trial of adolescents with obesity, orlistat achieved significant decreases in BMI. Adolescents had a significant 10.4% reduction in BMI with phentermine-topiramate 15/92 mg compared with placebo. In a trial of adolescents with obesity, liraglutide attained a mean BMI reduction of 5% compared with placebo. In an RCT of adolescents with obesity, semaglutide attained a 16.1% BMI reduction compared with a 0.6% BMI increase for placebo.

The review highlighted significant improvements in cardiometabolic outcomes associated with AOM use:

• Orlistat: reduced waist circumference by approximately 10 cm, systolic blood pressure (SBP) by approximately 6 mmHg, and LDL cholesterol by approximately 9%
• Phentermine-topiramate: reduced waist circumference by approximately 11 cm, decreased SBP by approximately 3 mmHg, and reduced LDL cholesterol by approximately 6%
• Semaglutide: Reduced waist circumference by approximately 14 cm and SBP by approximately 6 mmHg
• Tirzepatide: Reduced waist circumference by approximately 19 cm, decreased SBP by approximately 8 mmHg, and reduced LDL cholesterol by 9%.

Several AOMs also demonstrated benefits for type 2 diabetes prevention and management. For instance, orlistat was associated with a 37.3% lower risk of incident type 2 diabetes compared with placebo in a 4-year RCT.

An RCT of 9,340 patients with type 2 diabetes reported that liraglutide reduced major adverse cardiovascular events (MACE) compared with placebo. In the SELECT trial (17,604 adults with BMI ≥ 27 and preexisting cardiovascular disease without type 2 diabetes), semaglutide 2.4 mg reduced MACE by 20% compared with placebo (absolute rates = semaglutide, 6.5%; placebo, 8.0%).

The investigators provided detailed data on AOM efficacy in patients with type 2 diabetes:

• Orlistat: In a meta-analysis of 7 RCTs (1,363 patients with type 2 diabetes), orlistat was associated with 2.0 kg greater weight loss (95% CI = 1.3–2.8) and 0.5% greater hemoglobin A1c reduction (95% CI = 0.3%–0.6%) than placebo.
• Phentermine-topiramate: Patients with type 2 diabetes achieved mean weight loss of 9.4% and hemoglobin A1c reduction of 1.6% at 12 months with phentermine-topiramate 15/92 mg compared with placebo.
• Naltrexone-bupropion: Patients with type 2 diabetes achieved mean weight loss of 5.0% and hemoglobin A1c reduction of 0.6% at 12 months compared with placebo.
• Liraglutide: Resulted in mean weight loss of 6.0% and mean hemoglobin A1c decrease of 1.6% among adults with type 2 diabetes and obesity.
• Semaglutide: Resulted in mean weight loss of 9.6% and mean hemoglobin A1c decrease of 1.6% among adults with type 2 diabetes and obesity.
• Tirzepatide: Resulted in mean weight loss of 14.7% and mean hemoglobin A1c decrease of 2.1% among adults with type 2 diabetes and obesity.

Further, the investigators provided detailed information on the safety profiles and common adverse effects of each AOM:

• Orlistat: Common gastrointestinal adverse effects included oily fecal spotting (27%), fecal urgency (22%), and steatorrhea (20%).
• Phentermine: Common adverse effects included xerostomia (7%–12%), insomnia (6%–11%), headache (10%–12%), and constipation (4%–8%).
• Phentermine-topiramate: Common adverse events included paresthesia (14%–20%), dry mouth (14%–19%), constipation (15%–16%), and dysgeusia (7%–9%).
• Naltrexone-bupropion: Common adverse effects included nausea (33%), constipation (19%), headache (18%), vomiting (11%), dizziness (10%), insomnia (9%), and xerostomia (8%).
• Liraglutide: The most common adverse effects were nausea (39%), diarrhea (21%), and constipation (19%).
• Semaglutide: Common adverse effects included nausea (44%), diarrhea (30%), vomiting (24%), constipation (24%), and abdominal pain (20%).
• Tirzepatide: Dose-dependent adverse effects commonly included nausea (25%–29%), diarrhea (19%–23%), constipation (11%–17%), and vomiting (8%–13%).

The review highlighted challenges with medication adherence in real-world settings:

• Orlistat: No patients prescribed orlistat continued to take the drug after 12 months in a large U.S. health system study.
• Phentermine-topiramate: Medication adherence declined over time (from 36% at 3 months to 13% at 12 months).
• Naltrexone-bupropion: Medication adherence was relatively low (from 34% at 3 months to 10% at 12 months).
• Liraglutide: Medication adherence declined over time (from 52% at 3 months to 17% at 12 months).
• Semaglutide: Medication adherence remained relatively high over time (63% at 3 months and 40% at 12 months).

The investigators discussed several promising emerging therapies:

• Semaglutide plus cagrilintide: In a phase Ib study of 96 patients, the combination therapy resulted in mean weight loss of 17.1% after a 20-week follow-up compared with 9.5% for semaglutide alone.
• Survodutide (dual glucagon/GLP-1 receptor agonist): In a phase II trial of 387 patients, the 4.8-mg dose attained weight loss of 14.9% compared with 2.8% for placebo at 46 weeks.
• Retatrutide (tri-agonist receptor agonist for GIP/GLP-1/glucagon): In a phase II trial of 338 patients, the 12-mg dose attained a mean weight loss of 24.2% after a 24-week follow-up compared with 2.1% for placebo.
• Oral semaglutide: In a clinical trial of 667 patients, oral semaglutide 50 mg daily attained weight loss of 12.7% (95% CI = −14.2% to −11.3%) compared with placebo.
• Orforglipron (oral nonpeptide GLP-1 receptor agonist): In a phase II trial of 272 patients, they attained weight reduction of 14.7%, compared with 2.3% for placebo, after a 36-week follow-up.

The review provided guidance on individualizing AOM selection based on patient characteristics and comorbidities. For example, semaglutide and tirzepatide were suggested as most appropriate for patients needing to achieve greater than 10% weight reduction, particularly among those with multiple weight-related conditions.

The investigators emphasized the importance of counseling patients on lifestyle modifications and dietary strategies to mitigate adverse effects. They also highlighted the need for regular follow-up to monitor adherence, as real-world studies found poor medication adherence in clinical practice.

Insurance coverage and affordability were identified as significant barriers to AOM access. The review noted that many patients in the United States may lack insurance coverage for AOMs, with Medicare not covering AOMs for obesity treatment alone and only a few states providing coverage through Medicaid.

The investigators emphasized that AOMs were effective adjunctive therapies to lifestyle changes for improved weight loss and health outcomes in adults with obesity. They noted the significant weight-loss efficacy of nutrient-stimulated hormone-based medications and their beneficial effects on cardiometabolic and kidney disease risk factors.

The review reported that since 1999, obesity prevalence among U.S. adults had risen from 30% to 42% and was projected to affect nearly 50% of U.S. adults by 2030. This comprehensive review provided insights for health care providers on the current landscape of pharmacological interventions for obesity management.

Conflict of interest disclosures can be found in the study.