The GLP class: from one receptor to three

Behind the medicines that are suddenly everywhere lies a fifteen-year engineering story about a single gut hormone. Here is what the studies showed, step by step, and where the research is heading now.

• Native GLP-1 is degraded within minutes; the whole class is a series of answers to that one design question.
• The line runs from one receptor (liraglutide, semaglutide) to two (tirzepatide) to three (retatrutide).
• Evidence maturity does not track the number of receptors: retatrutide has had published phase 3 studies since 2026, but no completed cardiovascular outcomes trial and no approval.
• For weight there is one head-to-head comparison (SURMOUNT-5, 2025); the other numbers come from separate trials.

The question this whole field rests on is surprisingly simple. After a meal the gut releases a hormone that helps the pancreas regulate blood glucose: glucagon-like peptide-1, or GLP-1. That hormone does more than drive insulin. It suppresses glucagon (the counter-hormone that tells the liver to make sugar), it slows gastric emptying, and it reduces appetite via the brain regions that regulate hunger and satiety. A single molecule that touches both blood glucose and body weight: that is what makes GLP-1 such an attractive target.

One hormone, one problem

There was just one problem. Native GLP-1 is degraded within minutes. As a medicine the hormone itself is useless; it is gone before it can act. The whole class of medicines discussed here is, in effect, a series of answers to that one design question: how do you hold this effect long enough to use it?

The answer moved in a clear direction over fifteen years. First the field learned to engage one receptor for longer. Then two at once. And by now three. This piece follows that line, tracking at each step what the studies actually showed and, just as importantly, what they have not shown yet.

One receptor, made to last

The first breakthrough was not a smarter receptor but smarter packaging. Liraglutide was given a single fatty-acid chain, a C16 palmitoyl, that clings to albumin, a long-lived blood protein. While the molecule is bound to albumin it is not degraded. That extended the duration from minutes to about thirteen hours: enough for one injection a day (Knudsen et al., 2000). In the SCALE trial, 3,731 adults with obesity without diabetes received 3.0 mg liraglutide per day or placebo; the mean weight change over 56 weeks was −8.0% versus −2.6% (Pi-Sunyer et al., 2015).

Semaglutide took the same idea further. A longer fatty-acid tail and a small protection against degradation extended the duration from a day to a week (Lau et al., 2015). That difference, weekly rather than daily, is not a detail. It makes treatment easier to sustain, and the effects grew larger: in STEP 1, semaglutide 2.4 mg per week produced a mean weight change of −14.9% over 68 weeks in 1,961 participants without diabetes, versus −2.4% under placebo (Wilding et al., 2021).

For both agents the evidence reaches beyond weight and blood glucose. For liraglutide, LEADER, in 9,340 people with type 2 diabetes, showed a lower combined risk of cardiovascular events (13.0% versus 14.9%; Marso et al., 2016). For semaglutide, SUSTAIN-6 showed it first in diabetes (Marso et al., 2016), and SELECT then showed it in 17,604 people with cardiovascular disease but without diabetes: 6.5% versus 8.0% on the primary endpoint (Lincoff et al., 2023). That is a depth of evidence (large, completed outcome trials) that the newer agents simply do not have yet.

Two receptors at once

The next step was a molecule that mimics two gut hormones at once, rather than another, better GLP-1 agonist. Alongside GLP-1 there is a second incretin: glucose-dependent insulinotropic polypeptide, or GIP. Tirzepatide engages both receptors; it is a dual agonist (Coskun et al., 2018). The idea is that the two routes complement each other in driving insulin and energy metabolism.

Here is a detail that keeps the field busy. Tirzepatide does not engage the two receptors equally. Pharmacology describes it as an imbalanced agonist: it leans more toward the GIP receptor, and at the GLP-1 receptor it drives the cell in a somewhat skewed way (Willard et al., 2020). What that imbalance contributes to the final effect is not yet resolved. That is exactly the kind of question laboratory research can get a grip on.

The numbers were striking. For weight, SURMOUNT-1 showed a mean change of −20.9% at the highest dose (15 mg per week) over 72 weeks in 2,539 participants with obesity without diabetes, versus −3.1% under placebo (Jastreboff et al., 2022). And unlike most new agents, tirzepatide was also tested directly against a predecessor: in SURPASS-2, in 1,879 people with type 2 diabetes, it lowered HbA1c more than semaglutide 1 mg (Frías et al., 2021).

Three receptors

The third step adds another hormone: glucagon. That seems contradictory, because glucagon raises blood sugar. But combined with the two incretin routes, the glucagon component is associated mainly with higher energy expenditure: the body burns more, while the incretin routes keep blood sugar and appetite in check. Retatrutide engages all three receptors (GLP-1, GIP and glucagon).

Retatrutide calls for honesty about where the evidence stands. For a long time there were only phase 2 data: in the phase 2 obesity trial (338 participants), the mean weight change at the highest dose (12 mg per week) was −24.2% over 48 weeks, versus −2.1% under placebo (Jastreboff et al., 2023). In 2026 the first phase 3 publications followed. In TRIUMPH-1, the largest of them, in 2,339 participants with obesity without diabetes, the mean weight change at 12 mg per week was −25.0% over 80 weeks, versus −3.9% under placebo (Jastreboff et al., 2026). That is the highest number in this piece. What is still missing is what the older agents do have: a completed cardiovascular outcomes trial, and an approval. Neither exists as of the reference date.

The numbers side by side, and why to be careful

The table below places the weight studies side by side. Read it with this piece's key caveat in mind: with one exception, these are separate trials with different participants, doses and durations, not direct comparisons. The numbers show what each study reported on its own.

Until recently, for weight, no direct comparison existed at all. Since 2025 there is one: in SURMOUNT-5, tirzepatide and semaglutide were compared head-to-head in 751 people with obesity. At 72 weeks the mean weight change was −20.2% with tirzepatide versus −13.7% with semaglutide (Aronne et al., 2025). That is the first time two agents from this class have been measured against each other for weight in the same study, in the same people. It is exactly why the standalone numbers in the table should be read with care. A difference between two separate studies can come as much from the participants or the design as from the molecule; a difference within one study says far more.

Where the field is heading now

The story does not stop at blood sugar and weight. Over the past two years the research has shifted in two directions at once.

The first shift is toward new diseases. Fatty liver with inflammation (metabolic dysfunction-associated steatohepatitis, or MASH) is the clearest. In the phase 2 study SYNERGY-NASH, in participants with MASH and liver fibrosis, the inflammation resolved more often with tirzepatide than with placebo (at the highest dose 62% versus 10% at 52 weeks; Loomba et al., 2024). For semaglutide, the phase 3 study ESSENCE confirmed the picture: in 62.9% of participants on semaglutide 2.4 mg the steatohepatitis had resolved at 72 weeks, versus 34.3% on placebo (Sanyal, Newsome et al., 2025). What began as a diabetes medicine is now being studied as a treatment for a liver disease: a fact about those trials, not a promise.

The second shift is toward a wholly different hormone route. Alongside the incretins there is a satiety signal via amylin, a hormone co-released with insulin. Cagrilintide mimics it, and is studied in combination with semaglutide (the combination is called CagriSema in the research). In the phase 3 study REDEFINE 1, the mean weight change in the CagriSema arm was −20.4% at 68 weeks, versus −3.0% under placebo (Garvey et al., 2025). What is interesting is less the number than the idea: engaging two different satiety routes at once, rather than digging deeper into the same incretin route.

What we may and may not read into this

Three things deserve to be stated honestly. First, evidence maturity does not track the number of receptors. Semaglutide and liraglutide have large, completed cardiovascular trials; tirzepatide has a broad phase 3 programme with some outcomes still developing; retatrutide has had published phase 3 studies for weight and blood sugar since 2026, but its cardiovascular outcomes trial is still running and it is not approved anywhere. In this dossier, more receptors does not automatically mean “more proven”, rather “more recent, and still very much under study”.

Second, a larger number in a chart is not a ranking. The direct comparison from SURMOUNT-5 is valuable precisely because direct comparisons are so rare; for most combinations of agents and outcomes no head-to-head study exists, and then it stays at cautiously placing figures side by side.

Third, mechanistic questions remain open that are precisely interesting for research. What exactly is the contribution of the GIP component? What does tirzepatide's imbalanced signalling mean functionally? What role does the glucagon receptor play in the energy balance of a triple agonist, and under what conditions does it stay safe? And how do the amylin route and the incretin route reinforce each other in a combination like CagriSema? These are not rhetorical questions. They are where the field is actually working, and where well-characterized reference molecules, which is what these compounds are in a research context, prove their value.

Registered nurse with eleven years in psychiatry and founder of Peptalis. Writes the platform's knowledge layer: compound profiles, evidence reviews and the quality methodology. Works from primary literature (PubChem for chemistry, PubMed for studies) and states where evidence is absent.

Sources checked via PubMed · 18 references

• One hormone, one problem
• One receptor, made to last
• Two receptors at once
• Three receptors
• The numbers side by side, and why to be careful
• Where the field is heading now
• What we may and may not read into this

• Aronne et al. 2025 ↗
• Jastreboff et al. 2026 ↗
• Wilding et al. 2021 ↗
• Lincoff et al. 2023 ↗

• APPLICATIONSRetatrutide: the triple agonist and the horizon
• BASICSReading the evidence: dots and levels
• BASICSWhy most peptide research is still preclinical

Compounds in this article

• Retatrutide · In stock · Batch PEP-RET-2026-01 · HPLC 99.17% · released 20 Jun 2026 · Research profile · View in catalogue
• Liraglutide · Not in catalogue · Research profile
• Semaglutide · Not in catalogue · Research profile
• Tirzepatide · Not in catalogue · Research profile
• Cagrilintide · Not in catalogue · Research profile

For laboratory research use only. Not for human use.

SCIENTIFIC REFERENCES

These references are provided for informational and research purposes only. They do not constitute medical advice.

1. 01ReviewThe Discovery and Development of Liraglutide and Semaglutide.Knudsen LB, Lau J. Front Endocrinol (Lausanne). 2019;10:155.View on PubMed →
2. 02PreclinicalPotent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration.Knudsen LB, Nielsen PF, Huusfeldt PO, et al. J Med Chem. 2000;43(9):1664-9.View on PubMed →
3. 03PreclinicalDiscovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.Lau J, Bloch P, Schäffer L, et al. J Med Chem. 2015;58(18):7370-80.View on PubMed →
4. 04PreclinicalLY3298176, a novel dual GIP and GLP-1 receptor agonist.Coskun T, Sloop KW, Loghin C, et al. Mol Metab. 2018;18:3-14.View on PubMed →
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6. 06Human RCTTirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.Frías JP, Davies MJ, Rosenstock J, et al. N Engl J Med. 2021;385(6):503-515.View on PubMed →
7. 07Human RCTA Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management.Pi-Sunyer X, Astrup A, Fujioka K, et al. N Engl J Med. 2015;373(1):11-22.View on PubMed →
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13. 13Human RCTSemaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.Marso SP, Bain SC, Consoli A, et al. N Engl J Med. 2016;375(19):1834-1844.View on PubMed →
14. 14Human RCTSemaglutide and Cardiovascular Outcomes in Obesity without Diabetes.Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. N Engl J Med. 2023;389(24):2221-2232.View on PubMed →
15. 15Human RCTTirzepatide as Compared with Semaglutide for the Treatment of Obesity.Aronne LJ, Horn DB, le Roux CW, et al. N Engl J Med. 2025;393(1):26-36.The first head-to-head comparison for weight within this class (SURMOUNT-5).View on PubMed →
16. 16Human RCTTirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.Loomba R, Hartman ML, Lawitz EJ, et al. N Engl J Med. 2024;391(4):299-310.View on PubMed →
17. 17Human RCTPhase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.Sanyal AJ, Newsome PN, Kliers I, et al. N Engl J Med. 2025;392(21):2089-2099.View on PubMed →
18. 18Human RCTCoadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.Garvey WT, Blüher M, Osorto Contreras CK, et al. N Engl J Med. 2025;393(7):635-647.View on PubMed →

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