Oral Semaglutide 25 mg Versus Orforglipron 36 mg in Obesity: A Population-Adjusted Indirect Treatment Comparison.
Oral semaglutide 25 mg was associated with greater body weight loss and fewer discontinuations due to adverse events compared to orforglipron 36 mg, but these findings are based on indirect comparisons.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This study aimed to compare the effects of oral semaglutide 25 mg versus orforglipron 36 mg on body weight loss and tolerability in adults with overweight or obesity. The analysis indicated that oral semaglutide resulted in a greater percentage change in body weight compared to orforglipron. Discontinuation rates due to adverse events were also higher with orforglipron.
Abstract
<h4>Aims</h4>This study aimed to indirectly compare the effects of oral semaglutide 25 mg versus orforglipron 36 mg on body weight loss, other cardiometabolic biomarkers, and tolerability in adults with overweight (body mass index [BMI] ≥ 27 kg/m<sup>2</sup> and at least one obesity-related complication) or obesity (BMI ≥ 30 kg/m<sup>2</sup>), without diabetes, using data from OASIS 4 and ATTAIN-1.<h4>Materials and methods</h4>Individual patient data from OASIS 4 and aggregate data from ATTAIN-1 informed anchored indirect treatment comparisons (ITCs). Baseline differences in sex, body weight and normoglycaemic status were adjusted for using population-adjustment methods. Efficacy (percentage body weight change, categorical body weight loss thresholds, other cardiometabolic biomarkers) and tolerability outcomes (treatment discontinuation due to any adverse event [AE] and due to gastrointestinal [GI] AEs) were analysed.<h4>Results</h4>Population-adjusted analyses showed a significantly greater percentage change from baseline in body weight with oral semaglutide 25 mg than with orforglipron 36 mg, with mean differences (MDs) of -3.2%-points (95% confidence intervals [CIs]: -5.9, -0.4; treatment-regimen estimand) and -3.0%-points (95% CI: -5.8, -0.3; efficacy estimand). Discontinuation was higher with orforglipron (due to any AE: odds ratio [OR]: 4.1 [95% CI: 1.3, 13.0] and due to GI AEs: OR: 13.9 [95% CI: 2.0, 96.0]).<h4>Conclusions</h4>In this ITC, oral semaglutide 25 mg was associated with greater body weight loss and fewer discontinuations due to any AEs and due to GI AEs compared with orforglipron 36 mg. These findings provide insight into the comparative effectiveness and tolerability in the absence of head-to-head clinical trials.
Background
This paper addresses the comparative effectiveness of oral semaglutide and orforglipron in managing body weight among adults with obesity or overweight. Prior studies have established the efficacy of these treatments individually, but direct comparisons are limited. Understanding the differences in weight loss and tolerability between these two options is crucial for informed clinical decision-making.
Methods
The study utilized individual patient data from OASIS 4 and aggregate data from ATTAIN-1 to conduct anchored indirect treatment comparisons (ITCs). The population included adults with a BMI ≥ 27 kg/m² and at least one obesity-related complication or a BMI ≥ 30 kg/m², without diabetes. The primary outcomes measured were percentage body weight change and treatment discontinuation due to adverse events.
Results
The primary endpoint indicated that oral semaglutide 25 mg resulted in a mean difference in percentage change from baseline in body weight of -3.2%-points (95% CI: -5.9, -0.4) compared to orforglipron 36 mg. Additionally, the odds ratio for discontinuation due to any adverse event with orforglipron was 4.1 (95% CI: 1.3, 13.0), and for gastrointestinal adverse events, it was 13.9 (95% CI: 2.0, 96.0).
Interpretation
These findings suggest that oral semaglutide may lead to greater weight loss compared to orforglipron, with a statistically significant but clinically small mean difference. The higher odds ratios for discontinuation due to adverse events with orforglipron raise concerns about its tolerability. However, the reliance on indirect comparisons and the absence of direct head-to-head trials limit the conclusions that can be drawn.
Key findings
- Mean difference in percentage change from baseline in body weight: -3.2%-points (95% CI: -5.9, -0.4; treatment-regimen estimand)
- Mean difference in percentage change from baseline in body weight: -3.0%-points (95% CI: -5.8, -0.3; efficacy estimand)
- Discontinuation due to any adverse event with orforglipron: odds ratio (OR) 4.1 (95% CI: 1.3, 13.0)
- Discontinuation due to gastrointestinal adverse events with orforglipron: OR 13.9 (95% CI: 2.0, 96.0)
Limitations
- Relies on indirect treatment comparisons, not head-to-head trials
- No direct evidence from clinical trials
- Potential confounding factors not fully addressed
- Population-adjusted methods may introduce bias