Role of Oral Glucagon-Like Peptide-1 Receptor Agonists in Weight Management for Individuals With Overweight or Obesity Without Diabetes: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND

Oral GLP-1 receptor agonists (GLP-1 RAs) offer a non-injectable option for weight management in adults with overweight/obesity without diabetes. This network meta-analysis (NMA) evaluated their effects on body weight.

METHODS

A frequentist random-effects NMA of RCTs comparing oral GLP-1 RAs with placebo in adults without diabetes was conducted by searching databases through 30 April 2026. The primary outcome was percent change in body weight, with secondary outcomes including other weight measures and weight thresholds. Analyses used R (netmeta), and certainty was assessed with CINeMA.

RESULTS

Nine RCTs (N = 5766; 20-72 weeks) evaluating oral semaglutide, orforglipron, danuglipron, and lotiglipron were included. All agents except low-dose (LoD) lotiglipron outperformed placebo in percent body weight reduction; high-dose (HiD) semaglutide (MD -11.6%) and orforglipron (MD -11.8%) showed the greatest effects. Orforglipron HiD produced the greatest absolute weight loss (MD -12.2 kg), whereas semaglutide HiD reduced BMI (MD -4.7 kg/m2) and waist circumference (MD -10.0 cm) the most. Danuglipron HiD, semaglutide HiD, and semaglutide LoD ranked highest for ≥ 5%, ≥ 10%, and ≥ 15% weight loss, respectively. Evidence certainty was low to moderate.

CONCLUSION

HiD oral semaglutide and orforglipron demonstrated the most consistent and substantial weight reductions though low-to-moderate certainty and lack of head-to-head comparisons constrain comparative inference.