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.
Orforglipron showed a mean weight reduction of -11.8% compared to placebo, but evidence certainty was low to moderate.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This network meta-analysis evaluated the effects of oral GLP-1 receptor agonists on body weight in adults with overweight or obesity without diabetes. The study included nine randomized controlled trials (RCTs) with a total of 5766 participants. Orforglipron showed a mean difference of -11.8% in percent body weight reduction compared to placebo.
Abstract
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. 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. 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. 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.
Background
This paper addresses the role of oral GLP-1 receptor agonists in weight management for individuals with overweight or obesity without diabetes. Prior research has established that GLP-1 receptor agonists can aid in weight loss, but the specific effects of oral formulations compared to injectables were not well understood. This study is significant as it provides a comparative analysis of multiple oral GLP-1 receptor agonists in a network meta-analysis format.
Methods
The study employed a frequentist random-effects network meta-analysis of randomized controlled trials. A total of nine RCTs were included, with a combined sample size of 5766 participants. The primary outcome was the percent change in body weight, while secondary outcomes included other weight measures and thresholds. The duration of the included studies ranged from 20 to 72 weeks.
Results
The primary endpoint indicated that orforglipron achieved a mean difference of -11.8% in percent body weight reduction compared to placebo. Additionally, high-dose orforglipron resulted in an absolute weight loss of -12.2 kg. High-dose semaglutide also demonstrated significant reductions with a mean difference of -11.6% in percent body weight reduction, -4.7 kg/m2 in BMI, and -10.0 cm in waist circumference.
Interpretation
The findings suggest that orforglipron and high-dose semaglutide are effective in promoting weight loss, with orforglipron showing a slightly greater percent reduction in body weight. However, the clinical significance of these findings may be limited by the low to moderate certainty of the evidence and the absence of direct comparisons between the agents. These factors should be considered when interpreting the results and their implications for clinical practice.
Key findings
- -11.8% percent body weight reduction for orforglipron compared to placebo.
- -12.2 kg absolute weight loss for orforglipron high-dose.
- -11.6% percent body weight reduction for high-dose semaglutide.
- -4.7 kg/m2 reduction in BMI for high-dose semaglutide.
- -10.0 cm reduction in waist circumference for high-dose semaglutide.
- Low to moderate certainty in evidence.
Limitations
- Low to moderate certainty in evidence.
- Lack of head-to-head comparisons among agents.
- Small sample sizes in some included studies.