How six GLP-1-based drugs engage the GLP-1, GIP, and glucagon receptors, across the dose range tested in trials.
A side-by-side look at how the incretin drug class engages the three receptors it acts on, from the daily GLP-1 ancestor to the once-weekly triple
agonist. Milligrams on the label do not map cleanly onto receptor activity: the drugs weigh differently and differ many-fold in per-mole potency, and
they engage different combinations of the three receptor arms. Semaglutide and liraglutide are pure GLP-1 agonists; tirzepatide adds a GIP arm;
survodutide and cotadutide instead pair GLP-1 with glucagon; retatrutide carries all three. Dial a dose for any drug to see it on its own, or several to see their combined engagement. The view shown here is
receptor occupancy, which accounts for saturation, where past a point more drug barely moves the needle; the percent-of-trial-limit view instead scales raw activity against the highest dose tested.
Doses
Retatrutide (LY3437943)
0.0 mg/wk
0trial max 12 mg/wk
Tirzepatide (Zepbound / Mounjaro)
0.0 mg/wk
0trial max 15 mg/wk
Survodutide (BI 456906)
0.0 mg/wk
0trial max 4.8 mg/wk
Cotadutide (MEDI0382)
0.00 mg/day
0trial max 0.6 mg/day
Semaglutide (Ozempic / Wegovy)
0.0 mg/wk
0trial max 7.2 mg/wk
Liraglutide (Victoza / Saxenda)
0.0 mg/day
0trial max 3.0 mg/day
Presets:
Combined receptor activity · percent of highest dose tested in trialsReceptor occupancy · percent of each receptor's maximum
Share of the drug that's free to reach the receptor, since most of it is stuck to proteins in the blood: 1%
GLP-1 receptor cuts appetite, lowers blood sugar
0%
GIP receptor boosts insulin, may ease nausea (Borner 2021)
The grey curve is the universal saturation law: engagement = drive / (1 + drive), where drive is the effective concentration in units of that
receptor's own EC50. A point on the flat top is saturated, so more drug adds almost nothing there; a point on the rising slope still responds to dose.
With only the GLP-1 arm engaged, semaglutide and liraglutide put a single dot on the GLP-1 curve and nothing on the other two.
Activity profile · where the combined engagement goes
GLP-1GIPGlucagon
Model constants · verified receptor potencies & PK
Drug
Receptor
cAMP EC50
Native ligand EC50
Potency vs native
Source
Potency vs native = native EC50 ÷ drug EC50 (functional cAMP, human receptors, intrinsic / low-albumin conditions).
Tirzepatide and retatrutide potencies are Lilly's own cAMP assays (Coskun 2018, 2022). Semaglutide and liraglutide are pure GLP-1 agonists with no
meaningful GIP or glucagon activity; their GLP-1 receptor values are Novo's functional potencies relative to that assay's native GLP-1 control (Lau 2015),
then anchored to the model's native-GLP-1 EC50 so all six sit on one scale. That transplant is a close approximation, not an identity: Lau read a
luciferase reporter downstream of cAMP rather than cAMP directly.
Survodutide is a GLP-1 / glucagon dual with no GIP arm; its GLP-1 receptor and glucagon potencies are Boehringer's cAMP-assay values relative to that assay's own
native GLP-1 and glucagon controls (Zimmermann 2022), transplanted onto the model's native anchors the same way, on both arms.
Cotadutide (also GLP-1 / glucagon, no GIP) is anchored the same way from AstraZeneca's transfected-CHO cAMP assay (Henderson 2016) against its own native
GLP-1 and glucagon controls. Its widely cited fivefold GLP-1 bias is a physiological-albumin figure; the tool uses intrinsic (low-albumin) potencies, where
the GLP-1 lean is about twofold, and lets the free-fraction slider carry the albumin effect.
Occupancy view adds pharmacokinetics: apparent clearance CL/F tirzepatide 0.047, survodutide 0.047, retatrutide 0.035, semaglutide 0.05, cotadutide 1.05, liraglutide 1.2 L/h;
dosing interval 168 h for the weekly drugs and 24 h for once-daily liraglutide and cotadutide. All six are 98 to 99% albumin-bound, so the free drug that
engages receptors is a small, adjustable fraction. MW (Da): tirzepatide 4813.5, retatrutide 4731.4, survodutide 4231.7, semaglutide 4113.6, cotadutide 3728.0, liraglutide 3751.2.
What this does and does not show
Receptor potency is not clinical effect. This models how hard each receptor is engaged, not milligrams-to-pounds. The drugs recruit β-arrestin differently, so equal cAMP potency does not mean equal biology (Willard 2020).
Semaglutide and liraglutide are cross-assay anchored. Their GLP-1 receptor numbers come from a different lab and a different readout than the Lilly cAMP assays used for tirzepatide and retatrutide. The within-assay ratio to native GLP-1 is robust, but the absolute placement on the shared scale carries more uncertainty than the tirzepatide-to-retatrutide comparison does. Survodutide is anchored the same way from Boehringer's assay (Zimmermann 2022), so the same caveat applies to both its arms, and more so to its glucagon placement, because the shared glucagon scale is pinned to a different assay's native-glucagon control. Cotadutide is likewise cross-assay anchored, from AstraZeneca's assay (Henderson 2016).
The saturation view rests on one big assumption. The curve shape is exact (set by the EC50 ratios), but where each dose lands on it depends on the free-drug fraction reaching the receptor, which is genuinely uncertain. That is why it is a slider: watch how much the answer moves. Effective concentration at the target (CNS) may also be well below plasma.
Some combinations are unstudied. Every trial limit is drawn from single-drug studies. Stacking two drugs here is a model, not a validated regimen, and a bar over 100% in the first view means past anything a single-drug trial reached, not a safe or unsafe line.
Sources
Borner T, Geisler CE, Fortin SM, et al. GIP receptor agonism attenuates GLP-1 receptor agonist-induced nausea and emesis in preclinical models. Diabetes 2021;70(11):2545-2553.GIP-receptor signaling blocks emesis and illness behaviour from GLP-1 receptor activation (mouse, rat, musk shrew): basis for the GIP arm easing nausea. PMID 34380697. doi:10.2337/db21-0459
Coskun T, Sloop KW, Loghin C, 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. Molecular Metabolism 2018;18:3-14.Tirzepatide potencies and phase 1 PK (Fig 1B, Table 2). PMID 30473097; PMCID PMC6308032. doi:10.1016/j.molmet.2018.09.009
Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metabolism 2022;34(9):1234-1247.Retatrutide potencies and phase 1 PK (Fig 1B-D, Table S1, Table 1). PMID 35985340. doi:10.1016/j.cmet.2022.07.013
Henderson SJ, Konkar A, Hornigold DC, et al. Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes, Obesity and Metabolism 2016;18(12):1176-1190.Cotadutide GLP-1 receptor and glucagon cAMP potencies vs same-assay native ligands (Table 1). PMID 27377728. doi:10.1111/dom.12735
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine 2022;387(3):205-216.Tirzepatide max tested dose (15 mg). PMID 35658024. doi:10.1056/NEJMoa2206038
Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. New England Journal of Medicine 2023;389(6):514-526.Retatrutide max tested clinical dose (12 mg). PMID 37366315. doi:10.1056/NEJMoa2301972
Jungnik A, Arrubla Martinez J, Plum-Mörschel L, et al. Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/GLP-1 receptor agonist BI 456906. Diabetes, Obesity and Metabolism 2023;25(4):1011-1023.Survodutide phase 1 PK: apparent clearance CL/F, Vz/F, terminal half-life (Table S2). PMID 36527386. doi:10.1111/dom.14948
Lau J, Bloch P, Schäffer L, et al. Discovery of the once-weekly GLP-1 analogue semaglutide. Journal of Medicinal Chemistry 2015;58(18):7370-7380.Semaglutide and liraglutide GLP-1 receptor functional potency vs native GLP-1 (Tables 1, 3; BHK/luciferase, 0% HSA). PMID 26308095. doi:10.1021/acs.jmedchem.5b00726
le Roux CW, Steen O, Lucas KJ, et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes & Endocrinology 2024;12(3):162-173.Survodutide max tested dose (4.8 mg weekly). PMID 38330987. doi:10.1016/S2213-8587(23)00356-X
Nahra R, Wang T, et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a randomised phase 2b study. Diabetes Care 2021;44(6):1433-1442.Cotadutide clinical program, once-daily SC (100 / 200 / 300 µg). NCT03235050. doi:10.2337/dc20-2151
Saxenda (liraglutide) US Prescribing Information, Novo Nordisk.Liraglutide max obesity dose 3.0 mg daily; CL/F ~1.2 L/h; half-life ~13 h; >98% protein-bound. DailyMed: Saxenda label
Wegovy (semaglutide) US Prescribing Information, Novo Nordisk.Semaglutide apparent clearance CL/F ~0.05 L/h; half-life ~1 week; albumin-bound. DailyMed: Wegovy label
Wharton S, Freitas P, Hjelmesæth J, et al. Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes & Endocrinology 2025.Semaglutide highest tested dose (7.2 mg weekly). PMID 40961952. doi:10.1016/S2213-8587(25)00226-8
Willard FS, Douros JD, Gabe MBN, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 2020;5(17):e140532.Biased agonism: tirzepatide favors cAMP over β-arrestin recruitment at the GLP-1 receptor, so equal cAMP potency need not mean equal signaling. PMID 32730231. doi:10.1172/jci.insight.140532
Yu H, et al. Population pharmacokinetic modeling of cotadutide in participants with type 2 diabetes, chronic kidney disease, obesity and NASH. Clinical Pharmacokinetics 2024;63(2):255-267.Cotadutide apparent clearance CL/F ~1.05 L/h, half-life ~13 h, once-daily SC; pooled dose range 20 to 600 µg across 10 trials. PMID 38236561. doi:10.1007/s40262-023-01337-0
Zepbound (tirzepatide) US Prescribing Information, Eli Lilly.Plasma protein binding 99%; half-life ~5 days; Vd ~10.3 L. pi.lilly.com/us/zepbound-uspi.pdf
Zimmermann T, Thomas L, Baader-Pagler T, et al. BI 456906: discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Molecular Metabolism 2022;66:101633.Survodutide GLP-1 receptor and glucagon-receptor cAMP potencies vs native ligands (Fig 1B). PMID 36356832; PMCID PMC9679702. doi:10.1016/j.molmet.2022.101633
Research use only · Not medical advice · Receptor model, not a dosing recommendation
Brand names (Ozempic, Wegovy, Zepbound, Mounjaro, Victoza, Saxenda) are registered trademarks of their respective owners, used here for identification only; this tool is not affiliated with or endorsed by any manufacturer.