Dual and triple incretin receptor agonists compared with single glucagon-like peptide-1 receptor agonists for weight reduction
In adults with obesity, does a multi-receptor incretin agonist produce a larger reduction in body weight than a single glucagon-like peptide-1 receptor agonist?
§1Abstract
§1.1Review question
In adults with obesity, does a multi-receptor incretin agonist produce a larger reduction in body weight than a single glucagon-like peptide-1 receptor agonist?
§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, with and without type 2 diabetes, analysed separately. |
| Intervention | Dual GIP and GLP-1 receptor agonists, GLP-1 and glucagon receptor dual agonists, and triple receptor agonists. |
| Comparator | A single glucagon-like peptide-1 receptor agonist at its highest evaluated dose, directly or through placebo as a common comparator. |
| Outcomes | Percentage change in body weight at the primary analysis timepoint; 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 27 April 2026 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.[1,2]
§1.4Conclusion
Moderate certainty evidence indicates that multi-receptor agonists produce a larger mean weight reduction than single glucagon-like peptide-1 receptor agonists. One head-to-head trial supports the comparison directly for tirzepatide against semaglutide; the remainder of the network is indirect. The Institute downgrades one level for indirectness arising from differences in titration schedule, trial duration and background lifestyle intervention across the network, and notes that the transitivity assumption is not fully satisfied.
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: Dual and triple incretin receptor agonists compared with single glucagon-like peptide-1 receptor… received 7 submissions. Amendments arising are recorded in the amendment log and are traceable to a numbered submission.
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine 2022;387(3):205–216. doi:10.1056/NEJMoa2206038 · PMID 35658024
- Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. New England Journal of Medicine 2023;389(6):514–526. doi:10.1056/NEJMoa2301972 · PMID 37366315
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.