Abstract / Summary
Obesity is a chronic disease associated with increased cardiometabolic risk, reduced quality of life, and higher mortality. Although injectable glucagon-like peptide-1 receptor agonists (GLP-1RAs) have substantially improved weight management, the requirement for injections remains a limitation for many patients. Orforglipron is a novel nonpeptide oral GLP-1RA currently under investigation for the treatment of overweight, obesity, and type 2 diabetes mellitus (T2DM). This systematic review evaluated the efficacy and safety of oral orforglipron in adults with overweight or obesity, with or without T2DM. A structured literature search was conducted using PubMed and ScienceDirect from database inception through December 2025. Randomized controlled trials evaluating oral orforglipron and reporting weight-related, glycemic, or metabolic outcomes were included. Six randomized controlled trials involving 6,022 participants were included in the qualitative synthesis, with follow-up durations ranging from 12 to 72 weeks. Across studies, treatment with orforglipron was associated with clinically meaningful reductions in body weight ranging from approximately −4.5% to −14.7%, with greater reductions generally observed in longer-duration studies and at higher doses. Improvements in glycated hemoglobin (HbA1c), fasting glucose, waist circumference, systolic blood pressure, triglycerides, and non-high-density lipoprotein cholesterol were also reported across several studies. Gastrointestinal adverse events, particularly nausea, vomiting, diarrhea, and constipation, were the most commonly reported safety outcomes and occurred more frequently during dose escalation and in higher-dose groups. Overall, current evidence suggests that oral orforglipron may represent a promising therapeutic option for weight reduction and glycemic improvement in adults with overweight or obesity; however, additional long-term randomized controlled trials are needed to further clarify optimal dosing strategies, long-term safety, and comparative clinical effectiveness.