Oral compared with injectable presentations of glucagon-like peptide-1 receptor agonism
Does an oral presentation of a glucagon-like peptide-1 receptor agonist achieve an efficacy and tolerability profile comparable with an injectable presentation?
§1Abstract
§1.1Review question
Does an oral presentation of a glucagon-like peptide-1 receptor agonist achieve an efficacy and tolerability profile comparable with an injectable presentation?
§1.2PICO frame
Table 1. The registered PICO frame. Any change made after protocol registration is recorded in the amendment log at §5 and is identified there as post hoc.
| Element | As registered |
|---|---|
| Population | Adults with obesity or type 2 diabetes. |
| Intervention | An oral peptide or oral non-peptide glucagon-like peptide-1 receptor agonist. |
| Comparator | An injectable glucagon-like peptide-1 receptor agonist, or placebo as the common comparator. |
| Outcomes | Change in glycated haemoglobin; percentage change in body weight; discontinuation for adverse events. |
§1.3Method in brief
An indirect and mixed-treatment comparison across interventions connected by a common comparator. Transitivity is assessed explicitly and reported before any estimate is presented. The protocol was registered with the Institute's secretariat before the search was executed. The search was run on 25 October 2024 across 8 sources and is reproduced in full at §2. Screening, extraction and certainty assessment were performed independently by two members of the secretariat with disagreement resolved by a third.
§1.4Conclusion
Moderate certainty evidence indicates that oral presentations can achieve efficacy in the range of injectable glucagon-like peptide-1 receptor agonists when sufficient doses are achieved, and that the bioavailability constraint of oral peptide delivery is overcome by dose escalation rather than by an improvement in the absorption mechanism. The comparison is predominantly indirect, relying on placebo as a common comparator across separate trials of oral and injectable agents. The Institute notes a critical distinction between the oral peptide agent and the oral small-molecule agents: the peptide requires a permeation enhancer, a fasting administration window, and cold-chain distribution, whereas the small-molecule oral agents have none of these constraints. These logistical properties, rather than efficacy differences, are the factors most likely to determine real-world use and adherence.
The conclusion rests on 24 contributing studies, listed with their extracted data at §3 and summarised outcome by outcome at §4.
§1.5Limitations
§1.6Consultation
This review was released for public comment before ratification. Draft synthesis: Oral compared with injectable presentations of glucagon-like peptide-1 receptor agonism received 15 submissions. Amendments arising are recorded in the amendment log and are traceable to a numbered submission.