GLP-1, GIP and Glucagon Receptor Agonists: An Evidence Overview

Verified against PubChem PUG-REST property and synonym records; IUPHAR/BPS Guide to Pharmacology ligand 13769 for retatrutide identity and CAS; PubMed for structural modifications. Fields marked “not verified” are ones we could not confirm against a primary chemical database — we leave them blank rather than guess.

Three receptors, and how fast the native ligands disappear

Incretin pharmacology centres on three class B G-protein-coupled receptors: the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). Agonist binding at these receptors initiates intracellular cascades, of which cyclic AMP accumulation is the most frequently quantified in cell-based reporter assays.

The engineering problem these compounds exist to solve is measurable and old. Deacon, Johnsen and Holst (1995) incubated GLP-1(7-36)amide in human plasma at 37 °C and measured a degradation half-life of 20.4 ± 1.4 minutes across six samples, forming an N-terminally truncated fragment confirmed by mass spectrometry and sequence analysis as GLP-1(9-36)amide. Inhibitors of dipeptidyl peptidase-IV, or dropping the temperature to 4 °C, prevented the metabolite forming entirely. No C-terminal metabolism was observed.

In vivo the picture is sharper still. Deacon et al. (1995, Diabetes) administered GLP-1(7-36)amide subcutaneously to eight patients with type II diabetes and eight healthy subjects. Thirty minutes after subcutaneous administration, the truncated metabolite accounted for 88.5 ± 1.9% of the rise in C-terminally measured immunoreactivity in the diabetic group and 78.4 ± 3.2% in the healthy group. After intravenous infusion, intact peptide represented only 19.9 ± 3.4% and 25.0 ± 4.8% of the increase respectively. The native hormone is largely inactivated before it can be sampled.

What the engineering actually changed

Semaglutide is the best-documented case because its design paper is explicit. Lau et al. (2015) describe two amino acid substitutions relative to human GLP-1 — Aib at position 8 and Arg at position 34 — plus derivatization at lysine 26 with a fatty diacid linked through a spacer chain. The Aib8 substitution blocks the dipeptidyl peptidase-IV cleavage site that Deacon's work had identified; the acyl chain drives albumin binding, which slows renal clearance.

The measured trade-off is stated plainly in that paper. Semaglutide's GLP-1 receptor affinity was 0.38 ± 0.06 nM, which the authors describe as three-fold lower than liraglutide's, while albumin affinity was increased. In mini-pigs, plasma half-life after intravenous administration was 46.1 hours and mean residence time after subcutaneous administration was 63.6 hours. Receptor potency was deliberately traded for exposure.

Tirzepatide and retatrutide extend the same logic across additional receptors. Both are fatty-acid-modified peptides. Coskun et al. (2018) characterized tirzepatide (LY3298176) as activating both GIP and GLP-1 receptor signaling in cell lines expressing recombinant or endogenous incretin receptors. Coskun et al. (2022) characterized retatrutide (LY3437943) in vitro as showing balanced GCGR and GLP-1R activity with greater GIPR activity — a relative description, given without a numeric potency triple in the abstract.

Single, dual, triple: what was measured in humans

The tirzepatide proof-of-concept programme (Coskun 2018, NCT02759107) ran three parts: single ascending dose and four-week multiple ascending dose studies in healthy subjects, then a four-week Phase 1b in patients with type 2 diabetes. A total of 142 human subjects received tirzepatide, dulaglutide or placebo. In the diabetic cohort, the 10 mg and 15 mg arms showed least-squares mean reductions in fasting serum glucose versus placebo of −49.12 mg/dL (95% CI −78.14 to −20.12) and −43.15 mg/dL (95% CI −73.06 to −13.21). In the healthy-subject multiple-dose arms, least-squares mean body-weight differences versus placebo were −1.75 kg, −5.09 kg and −4.61 kg at 1.5, 4.5 and 10 mg.

Retatrutide's Phase 2 obesity study (Jastreboff 2023, NCT04881760) enrolled 338 adults, 51.8% of them men, randomized across six subcutaneous once-weekly dose arms and placebo for 48 weeks. Least-squares mean percentage body-weight change at 48 weeks was −8.7% (1 mg), −17.1% (combined 4 mg), −22.8% (combined 8 mg) and −24.2% (12 mg), against −2.1% on placebo. A reduction of 15% or more occurred in 60%, 75% and 83% of the 4, 8 and 12 mg groups and 2% of placebo. The most common adverse events were gastrointestinal and dose-related, and dose-dependent heart-rate increases peaked at 24 weeks before declining.

The ladder metaphor and what it conceals

Presenting the three compounds as rungs on a receptor-engagement ladder implies that each additional receptor buys additional effect, and that the ordering has been demonstrated. As of August 2026 it has not been demonstrated by any completed head-to-head study that has posted findings.

The comparisons are running. NCT06662383 is a Phase 3, randomized, double-blind study of retatrutide against tirzepatide in 800 adults with obesity, sponsored by Eli Lilly, active but not recruiting, with primary completion scheduled for November 2026. NCT06260722 (TRANSCEND-T2D-2) is a Phase 3 open-label study of retatrutide against semaglutide in 1,250 adults with type 2 diabetes across 77 sites, also active and not recruiting, primary completion August 2026. Neither has posted outcome data. A 95-participant Phase 1 study of alpha- and beta-cell function (NCT06982859) includes both retatrutide and semaglutide arms and is likewise still running.

Until those report, every cross-compound comparison in circulation is assembled across trials with different populations, different durations, different endpoints and different comparators. The 24.2% figure from a 48-week obesity trial in people without diabetes and the −49 mg/dL figure from a four-week Phase 1b in diabetic patients are not points on a common scale.

Identity is not settled at the catalog level

Semaglutide and tirzepatide resolve cleanly. Semaglutide is PubChem CID 56843331, C187H291N45O59, roughly 4114 g/mol, CAS 910463-68-2, UNII 53AXN4NNHX. Tirzepatide is CID 163285897, C225H348N48O68, roughly 4813 g/mol, CAS 2023788-19-2 — though PubChem returns five distinct CIDs sharing that formula and weight, so a bare formula match does not fix which record is meant.

Retatrutide is messier. A PubChem name query on "retatrutide" returns nothing; the compound resolves only through substance records to CID 171390338, whose synonym list contains "Triple G", a Guide to Pharmacology identifier and several catalogue codes — but no CAS number, no ChEMBL identifier and not the INN itself. Identity was confirmed instead through IUPHAR/BPS Guide to Pharmacology ligand 13769, which records retatrutide as INN 12350, development code LY-3437943, CAS 2381089-83-2, formula C221H342N46O68, with PubChem CID 171390338 as its cross-reference.

Salt form is a separate and consequential axis. The US Food and Drug Administration states that semaglutide sodium and semaglutide acetate are different active ingredients from the base form used in approved products, that the agency does not have information on whether those salts share the same chemical and pharmacologic properties, and that it is not aware of a lawful basis for their use in compounding.

What is not known

The comparison that the single-dual-triple framing implies has not been completed. Two Phase 3 head-to-head trials are active but have not posted outcome data, so no direct evidence orders these three compounds against one another under matched conditions. Beyond that, the strongest human data are shorter and narrower than the framing suggests: the retatrutide obesity trial ran 48 weeks in 338 adults aged 18 to 75 who were explicitly screened to exclude type 1 and type 2 diabetes, recent cardiovascular events, active cancer within five years, significant depression or other mental illness within two years, and pregnancy or breastfeeding — so nothing in that dataset speaks to those groups. Tirzepatide's proof-of-concept data cited here came from four-week exposures. No study in this file extends past 48 weeks for retatrutide, and long-term outcome trials such as NCT06383390 (10,000 participants, primary completion February 2029) will not report for years. Pediatric data are absent. On the chemistry side, retatrutide has no openly verifiable published amino-acid sequence, no ChEMBL record retrievable by name, and no CAS number carried in its PubChem synonym list; its identity resolves only through a Guide to Pharmacology cross-reference. Whether material sold as any of these three peptides matches the characterized compound in salt form, purity or impurity profile has not been established by any published analytical comparison.

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