Annals of Internal MedicineEfficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials

A systematic review of 26 randomized controlled trials evaluated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and co-agonists for weight management in adults with overweight or obesity without diabetes. The analysis included both commercially available medications and investigational agents, providing clinicians with comparative efficacy and safety data across multiple treatment options.

Study Design:

• 15,491 participants (72% female)
• Mean BMI: 30-41 kg/m²
• Mean age: 34-57 years
• Treatment duration: 16-104 weeks (median 43 weeks)
• 12 agents evaluated: 3 commercially available (liraglutide, semaglutide, tirzepatide) and 9 premarket agents

Key Findings:

• Weight loss outcomes (compared to placebo):
  • Tirzepatide (15mg weekly): 17.8% reduction at 72 weeks
  • Semaglutide (2.4mg weekly): 13.9% reduction at 68 weeks
  • Liraglutide (3.0mg daily): 5.8% reduction at 26 weeks
  • Retatrutide (12mg weekly): 22.1% reduction at 48 weeks
• Safety profile:
  • Adverse events: 80-97% for GLP-1 RAs vs 63-100% for placebo
  • Gastrointestinal events most common: 47-84% vs 13-63%
  • Treatment discontinuation: 0-26% vs 0-9%
  • Serious adverse events: 0-10% vs 0-12%

HCN Medical Memo
Although GLP-1 RAs demonstrate substantial efficacy for weight management, the varying dosing schedules and efficacy profiles warrant careful consideration of individual patient factors, including tolerance for injection frequency and gastrointestinal side effects. The favorable safety profile supports their role in long-term weight management strategies.

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