HMD HISTORICAL RESEARCH GUIDELINE

HMD-HG-016-EN | Tirzepatide and GIP/GLP-1 coagonism

HMD HISTORICAL RESEARCH GUIDELINE

Milestone 16 | Tirzepatide and GIP/GLP-1 Coagonism

Conceptual transition from GLP-1 agonism to dual incretin agonism

Executive summary

This milestone documents the transition from selective GLP-1 receptor agonism toward a dual incretin architecture based on GIP and GLP-1. Tirzepatide represents the first broadly validated clinical model of this transition: a unimolecular agent designed to activate both receptors and produce relevant metabolic effects on glycemic control and body weight [1-4].

The historical importance of the milestone is not limited to the clinical efficacy reported in type 2 diabetes or obesity. Its importance lies in the conceptual shift it created: incretin pharmacology moved from an isolated GLP-1 line toward a receptor-ligand coagonism platform with potential to modulate complex metabolic systems [2,5].

Historical development of the milestone

The direct antecedent of the milestone lies in the idea that a single molecule could activate more than one incretin receptor. In 2013, Finan et al. described a unimolecular dual incretin agonist derived from GLP-1 and GIP sequences, with superior metabolic effects compared with selective agonism in experimental models [1].

In 2018, Coskun et al. introduced LY3298176 as a fatty-acid-modified dual GIP/GLP-1 receptor agonist designed for once-weekly administration. The study showed activation of both receptors, glucose-dependent insulin secretion and improved glucose tolerance in preclinical models, along with early clinical proof of concept in type 2 diabetes [2].

The clinical phase consolidated the milestone. In SURPASS-2, Frías et al. compared once-weekly tirzepatide with semaglutide in patients with type 2 diabetes and reported superiority of tirzepatide for reductions in HbA1c and body weight [3]. In SURMOUNT-1, Jastreboff et al. evaluated tirzepatide in adults with obesity or overweight without diabetes and reported substantial and sustained body-weight reductions over 72 weeks [4].

Figure 1. Documentary sequence of GIP/GLP-1 coagonism.

Table 1. Documentary chronology of the milestone

Physiological and pharmacological architecture

Tirzepatide is an agonist of the GIP and GLP-1 receptors. The Mounjaro regulatory label describes tirzepatide as an amino-acid sequence incorporating a C20 fatty-acid moiety to enable albumin binding and prolong half-life, allowing once-weekly administration [6].

From a historical perspective, the critical point is not only prolonged half-life. The critical point is that the molecule changed the interpretive framework of the field: the GLP-1 receptor was no longer the only dominant pharmacological axis, and GIP regained relevance as part of an integrated incretin architecture [5].

Figure 2. HMD model of unimolecular GIP/GLP-1 coagonism.

Table 2. HMD interpretive matrix of coagonism

Independent HMD analysis

HMD interprets this milestone as the first structural shift in modern incretin pharmacology after the consolidation of GLP-1. The transition from semaglutide to tirzepatide should not be understood merely as competition between molecules, but as a movement from a single-receptor logic toward receptor-ligand integration.

This transition created three methodological consequences. First, it required reconsideration of the role of GIP in obesity and type 2 diabetes. Second, it strengthened the idea that pharmacological weight loss may depend on combined neuroendocrine systems. Third, it prepared the field for later molecules with multiple agonism, including combinations involving amylin or glucagon.

In documentary terms, tirzepatide marks the point at which incretin science stops being a linear historical sequence and becomes a modular platform. After this milestone, the question is no longer whether GLP-1 works, but how many metabolic axes can be integrated without losing safety, tolerability or clinical utility.

Relationship with subsequent milestones

• It connects with Milestone 17 because coagonism prepares the ground for amylin combinations, especially cagrilintide and CagriSema.

• It connects with Milestone 18 because the dual GIP/GLP-1 rationale enables the transition toward triple GLP-1/GIP/glucagon agonism.

• It connects with Milestone 19 because it opens a systemic reading of incretins as a cardiometabolic, hepatic, renal and neuroendocrine platform.

References

1. Finan B, Ma T, Ottaway N, Muller TD, Habegger KM, Heppner KM, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):209ra151.

2. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3-14.

3. Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515.

4. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.

5. Nauck MA, D’Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol. 2022;21:169.

6. U.S. Food and Drug Administration. Mounjaro (tirzepatide) injection, for subcutaneous use: prescribing information. Silver Spring: FDA; 2025.

7. Gallwitz B. Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity. Front Endocrinol (Lausanne). 2022;13:1004044.