HMD HISTORICAL GUIDELINE SERIES

HMD HISTORICAL GUIDELINE SERIES

Retatrutide and GLP-1/GIP/glucagon multiagonism

Milestone 18 | Triple agonism, metabolic integration and next-generation incretin systems

Historical technical review and scientific curation document. It does not constitute therapeutic advice, a clinical indication, a use recommendation, commercial availability, or a claim of affiliation with manufacturers, academic institutions or cited investigators.

Executive summary

Retatrutide represents a milestone beyond dual GIP/GLP-1 agonism: an investigational molecule designed to activate the GIP, GLP-1 and glucagon receptors simultaneously. This architecture places it within the transition from single-receptor incretin therapies toward metabolic multiagonism systems [1,2].

In the phase 2 trial published in The New England Journal of Medicine, retatrutide produced substantial body-weight reductions in adults with obesity over 48 weeks, with a reported mean reduction of 24.2% in the 12 mg group [1]. In people with type 2 diabetes, the phase 2 trial published in The Lancet described clinically meaningful improvements in glycaemic control and robust body-weight reductions [2].

For HMD, this milestone should not be interpreted as a simple escalation of potency. Multiagonism requires a systems-level reading: incretin signaling, glucagon regulation, the hepatic axis, energy expenditure, gastrointestinal tolerability and body composition must be analysed as interdependent variables.

Milestone timeline

1. Historical context: from GLP-1 agonism to multiagonism

Previous milestones in this series described how GLP-1 moved from an insulinotropic intestinal hormone to a pharmacological platform for diabetes and obesity. The emergence of tirzepatide introduced a second conceptual layer: GIP/GLP-1 coagonism. Retatrutide extends that logic by incorporating glucagon as a third receptor axis [1,2].

Glucagon, historically associated with hepatic glucose output, is also involved in energy expenditure and hepatic metabolism. Its incorporation into a triple agonist should therefore not be read as a linear addition, but as a pharmacological strategy intended to balance anabolic, satiety-related and catabolic signals within a single molecule [3,4].

2. Receptor architecture

Retatrutide is described as a triple agonist of the GIP, GLP-1 and glucagon receptors. GLP-1 contributes satiety signaling, glycaemic control, glucagon modulation and gastrointestinal effects. GIP is related to insulinotropic and adipometabolic signaling. The glucagon component introduces an energy-expenditure and hepatic-metabolic dimension requiring careful interpretation [1,4].

The informal label “GLP-3” is not a scientific classification. Lilly states that retatrutide is an investigational triple agonist and that it has not been approved by regulatory agencies; clinical evaluation continues across development programs [5].

Table 1. Functional receptor architecture

3. Documented clinical evidence

In obesity, the phase 2 trial by Jastreboff et al. evaluated retatrutide over 48 weeks and reported high-magnitude weight reduction, with the trajectory suggesting that a plateau had not been reached by study completion [1].

In type 2 diabetes, Rosenstock et al. evaluated retatrutide versus placebo and an active comparator, reporting improvements in glycaemic control and body weight [2]. In metabolic liver disease, a phase 2 substudy reported effects on liver fat in participants with metabolic dysfunction-associated steatotic liver disease, connecting triple agonism with the hepatic-metabolic axis [3].

4. Independent HMD analysis

The HMD reading of milestone 18 is that retatrutide represents a paradigm shift: the target is no longer the stimulation of an isolated incretin pathway, but the modulation of a signal set affecting appetite, glucose, body weight, liver and energy expenditure.

The conceptual risk is assuming that more receptors automatically mean a better intervention. HMD proposes reading multiagonism as an architectural problem: efficacy, tolerability, lean-mass loss, metabolic adaptation, hepatic response and longitudinal sustainability must be evaluated as a system.

Table 2. Documentary reading of clinical progression

5. Link to subsequent milestones

The retatrutide milestone opens the final phase of the historical series: incretins as a systemic platform. After GLP-1, GIP/GLP-1 and amylin, triple agonism anticipates a field in which molecules are designed as integrated metabolic systems rather than isolated ligands.

References

1. Jastreboff AM, Kaplan LM, Frias JP, Wu Q, Du Y, Gurbuz S, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389:514-526. doi:10.1056/NEJMoa2301972.

2. Rosenstock J, Wysham C, Frias JP, Kaneko S, Lee CJ, Landó LF, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial. Lancet. 2023;402:529-544. doi:10.1016/S0140-6736(23)01053-X.

3. Sanyal AJ, Neutel J, DeLemos AS, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2 substudy. Nat Med. 2024;30:2037-2048. doi:10.1038/s41591-024-03018-2.

4. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740-756. doi:10.1016/j.cmet.2018.03.001.

5. Eli Lilly and Company. What to know about retatrutide. Lilly Medical Information. Updated June 2026.

6. Muller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi:10.1016/j.molmet.2019.09.010.