Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review

Background: With rising obesity rates, pharmacological interventions are increasingly used in non-diabetic adults. While being effective in managing weight, these agents frequently cause gastrointestinal (GI) side effects, affecting adherence and long-term outcomes. Objective: To systematically evaluate the frequency, severity, and types of GI adverse effects (AEs) associated with anti-obesity medications in obese adults without diabetes. Methods: Following PRISMA 2020 guidelines, PubMed, Google Scholar, BMJ, and Web of Science were searched (last search July 2025). Eligible studies included randomized controlled trials, non-randomized trials, cohort studies, cross-sectional, and case-control studies. Only reports of GI AEs in non-diabetic adults were included. Risk of bias was assessed using Cochrane RoB 2 and Newcastle-Ottawa scales. Results: Out of 733 articles screened, 12 studies met predefined inclusion criteria, including one large cohort of 18,386 participants, along with randomized and observational trials of smaller size. The most frequently reported GI symptoms were nausea, vomiting, diarrhea, and constipation, predominantly with GLP-1 receptor agonists such as semaglutide and tirzepatide, especially during dose escalation. Orlistat commonly linked to steatorrhea and flatulence, while phentermine was associated with reduced GI motility. Newer agents, including retatrutide and orforglipron, also demonstrated notable GI side effect profiles. Natural products and investigational agents reported fewer adverse events but lacked long-term data and standardized reporting. Limitations: Evidence was limited by heterogeneity in study design and inconsistent reporting of GI outcomes. Conclusion: GI side effects are common across anti-obesity medications, particularly GLP-1 receptor agonists. Although generally mild to moderate, these symptoms can impact adherence and lead to treatment discontinuation. Tailored titration schedules, proactive patient counseling, and standardized adverse event reporting may improve tolerability. Further research is warranted to evaluate long-term GI outcomes and compare safety across emerging pharmacologic agents.