Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Obesity Management in Adults With and Without Type 2 Diabetes: A Systematic Review

Abstract

Objective: This systematic review aimed to assess the efficacy and safety of GLP-1 RAs in adults with obesity or overweight, by comparing different GLP-1 RAs, identifying the most effective agents, and evaluating adverse effects. Methods: We systematically searched Embase, MEDLINE, and Cochrane for phase 3 and 4 randomized controlled trials (RCTs) with a minimum duration of 40 weeks. Included studies compared GLP-1 RAs to placebo or to each other in adults with obesity (BMI ≥ 30 kg/m2) or overweight (BMI ≥ 27 kg/m2), with or without type 2 diabetes (T2DM). We excluded crossover trials, open-label studies, early-phase trials, and studies focusing on specific subpopulations. Results: A total of 22 RCTs involving 41,757 participants were included. Among adults with T2DM, the greatest weight reductions were observed with tirzepatide 15 mg (−9.5 kg at 40 weeks; 72% lost ≥ 5% of baseline weight) and semaglutide 2.4 mg (−9.6% body weight at 68 weeks; 69% lost ≥ 5%). In participants without T2DM, semaglutide 2.4 mg (−14.9% body weight at 68 weeks) and tirzepatide 15 mg (−20.9% at 72 weeks) produced the most substantial effects, while semaglutide 50 mg was also effective in nondiabetic patients. Liraglutide 3 mg showed modest efficacy. Across trials, GLP-1 RAs were consistently associated with a higher frequency of gastrointestinal adverse events compared to placebo, including nausea (14%–28% vs. 5%–10%), vomiting (6%–12% vs. 2%–4%), and diarrhea (8%–20% vs. 4%–7%). The risk of pancreatitis and serious adverse events remained comparable to placebo. Conclusions: GLP-1 RAs, especially semaglutide and tirzepatide, are effective for weight management. Liraglutide may remain a viable, cost-effective alternative.