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Metabolic peptides

GLP-1 Peptides Explained: GLP-1, Semaglutide, Tirzepatide, Retatrutide

From endogenous GLP-1 to dual and triple agonists—an educational map of incretin peptide science and metabolic drug design.

By The Peptides Codex Editorial TeamIndividual review date not recorded

Endogenous GLP-1

GLP-1 is an incretin hormone from intestinal L-cells that enhances glucose-dependent insulin secretion and influences appetite pathways. Native peptide is short-lived due to DPP-4 cleavage—driving the entire analog industry.

Single agonists: exenatide to semaglutide

Exendin-4 (from Gila monster venom biology) inspired exenatide. Later human-GLP-1–based analogs used residue changes and fatty-acid side chains (e.g., semaglutide) for weekly pharmacokinetics in approved products.

Dual agonists: tirzepatide

Tirzepatide engages GIP and GLP-1 receptors. Dual agonism is a design bet that multi-receptor pharmacology can outperform single-pathway drugs for metabolic endpoints.

Triple agonists: retatrutide

Retatrutide adds glucagon receptor activity to the incretin story, aiming to influence energy expenditure as well as intake and glycemia. It is a major clinical-research topic and a high-volume educational query.

Amylin joins the cast

Cagrilintide and amylin biology appear in combination strategies with incretins. Metabolic peptide science is now a multi-hormone network problem, not a single-target story.

Approved drugs vs research powders

Pharmacy products are manufactured and labeled under drug law. Research-grade powders using the same INN names are a different legal and quality universe. Educational sites should never blur that line.

The incretin & metabolic co-agonist class at a glance

PeptideReceptorsLengthMass (Da)Half-lifeStatus
GLP-1GLP-1R30 aa≈ 3,297.6≈ 1–2 min (DPP-4 cleavage + renal clearance)Endogenous hormone — not a product
LiraglutideGLP-1R31 aa≈ 3,751.2≈ 13 h (once-daily dosing)Approved: Victoza (2010, T2D), Saxenda (2014, weight)
SemaglutideGLP-1R31 aa≈ 4,113.6≈ 7 days (≈ 145–165 h in clinical PK studies)Approved: Ozempic (2017, T2D), Rybelsus (2019, oral T2D), Wegovy (2021, weight)
TirzepatideGIPR + GLP-1R39 aa≈ 4,813.5≈ 5 days (≈ 117 h)Approved: Mounjaro (2022, T2D), Zepbound (2023, weight; 2024, obstructive sleep apnoea)
RetatrutideGIPR + GLP-1R + GCGR39 aa≈ 4,731≈ 6 daysInvestigational (phase 3)
CagrilintideAmylin / calcitonin37 aa≈ 4,409≈ 7–8 days (159–195 h across doses in the phase 1b study)Investigational (phase 3, as CagriSema with semaglutide)
SurvodutideGCGR + GLP-1R29 aa≈ 4,232Supports once-weekly dosing (published population estimates are on the order of several days)Investigational (phase 3: SYNCHRONIZE obesity programme; MASH programme)
MazdutideGCGR + GLP-1R34 aa≈ 4,476Supports once-weekly dosing (published estimates are on the order of several days)Approved in China (NMPA): chronic weight management (27 June 2025) and type 2 diabetes (2025)
AmycretinGLP-1R + amylin——Supports once-weekly subcutaneous dosingInvestigational (phase 2 results published 2025; later-phase trials under way)

Verified from PubChem, IUPHAR and the primary discovery papers cited on each profile. Half-lives are approximate population means from published pharmacokinetics.

Sources and what they cover

These primary studies, official records and standards cover the topics linked below. The scope notes distinguish laboratory findings, human trials and regulatory records. This is a selected bibliography, not a systematic review or verification of every sentence; absence of a study here does not prove that no study exists.

  1. Wilding et al. (2021) — STEP 1: once-weekly semaglutide in adults with obesity

    Randomized obesity trial with defined participants and endpoints; cross-trial percentages are not a head-to-head comparison.

    Relevant sections: Single agonists: exenatide to semaglutide

  2. Jastreboff et al. (2022) — SURMOUNT-1: tirzepatide for obesity

    Randomized obesity trial; not a direct comparison with retatrutide.

    Relevant sections: Dual agonists: tirzepatide

  3. Jastreboff et al. (2023) — Retatrutide for obesity, phase 2 trial

    Phase 2 obesity trial: studied regimens, weight and adverse events. Trial doses are not instructions for personal use.

    Relevant sections: Triple agonists: retatrutide

  4. Lau et al. (2021) — Cagrilintide for weight management, phase 2 trial

    Human monotherapy trial with studied doses and adverse events; distinct from CagriSema.

    Relevant sections: Amylin joins the cast

  5. Health Canada (2026) — unauthorized injectable peptides bought online

    Canadian safety and authorization notice for the products described. It does not establish approval status in every country.

    Relevant sections: Approved drugs vs research powders

FAQ

Is semaglutide a research peptide?+

Semaglutide is an approved active ingredient in prescription medicines in many countries. Unregulated powders sold as “research semaglutide” are not the same as licensed products.

Tirzepatide vs semaglutide?+

Semaglutide is a GLP-1 receptor agonist; tirzepatide is a dual GIP/GLP-1 agonist. Mechanisms and clinical programs differ—compare primary literature and labels, not anecdotes.

Related peptide profiles

GLP-1
Incretin
Glucagon-like peptide-1 (GLP-1) is a 30–31-residue incretin hormone released by intestinal L-cells after a meal. It potentiates glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying and reduces appetite — but survives only 1–2 minutes in circulation, which is why every GLP-1 drug is a re-engineered version of this sequence.
Semaglutide
Incretin analog
Semaglutide is a 31-amino-acid GLP-1 receptor agonist peptide (C187H291N45O59, ≈4,114 Da). It keeps 94% of the human GLP-1 sequence but substitutes Aib at position 8 to block DPP-4 cleavage, replaces Lys34 with Arg, and attaches a C18 fatty diacid to Lys26 through a γ-glutamate and two OEG spacers so the peptide binds albumin. The result is a half-life of about 7 days and once-weekly dosing in the approved products Ozempic and Wegovy (and once-daily oral dosing as Rybelsus).
Tirzepatide
Incretin dual agonist
Tirzepatide is a 39-amino-acid synthetic peptide (C225H348N48O68, ≈4,814 Da) that activates both the GIP and GLP-1 receptors. Its backbone is derived from GIP, with an exendin-4-like C-terminal tail, Aib residues at positions 2 and 13, and a C20 fatty diacid on Lys20 that binds albumin for a half-life of about 5 days. Approved as Mounjaro (type 2 diabetes, 2022) and Zepbound (weight management, 2023; obstructive sleep apnoea, 2024).
Retatrutide
Incretin triple agonist
Retatrutide (LY3437943) is an investigational 39-amino-acid peptide (C221H342N46O68, ≈4,731 Da) that activates three receptors — GIP, GLP-1 and glucagon. It shares its GIP-based scaffold and exendin-4 tail with tirzepatide, adds α-methyl-leucine and a second Aib, and carries a C20 fatty diacid on Lys17 for a half-life of about 6 days. In phase 2 it produced a mean weight change of −24.2% at 48 weeks; phase 3 trials are ongoing and it is not yet approved.
Cagrilintide
Amylin analog (dual amylin / calcitonin receptor agonist)
Cagrilintide is an investigational 37-amino-acid analogue of the pancreatic hormone amylin (C194H312N54O59S2, ≈4,409 Da). Six substitutions stop it forming amyloid fibrils, and a C20 fatty diacid on the N-terminal lysine binds albumin for a half-life of 7–8 days. It activates amylin and calcitonin receptors — not the GLP-1 receptor — which is why it is being developed in combination with semaglutide as CagriSema: −20.4% body weight at 68 weeks in the phase 3 REDEFINE 1 trial.
Survodutide
Dual GLP-1 / glucagon receptor agonist (investigational)
Survodutide (BI 456906) is an investigational 29-amino-acid glucagon-based peptide (C192H289N47O61, ≈4,232 Da) that activates both the glucagon and GLP-1 receptors. Developed by Boehringer Ingelheim and Zealand Pharma, it carries an Aib at position 2 and a C18 fatty diacid for once-weekly dosing. Phase 2 produced up to −14.9% body weight at 46 weeks and a large improvement in MASH; phase 3 trials are ongoing.
Mazdutide
Dual GLP-1 / glucagon receptor agonist (oxyntomodulin analog)
Mazdutide (IBI362 / LY3305677) is a once-weekly oxyntomodulin-based peptide (C207H317N45O65, ≈4,476 Da) that activates the GLP-1 and glucagon receptors. Originated by Eli Lilly and developed in China by Innovent, it became the first glucagon/GLP-1 dual agonist approved anywhere when China's NMPA authorised it for chronic weight management on 27 June 2025, with a type 2 diabetes approval following the same year. In the phase 3 GLORY-1 trial it produced −14.0% body weight at 48 weeks on 6 mg.
Amycretin
Unimolecular GLP-1 / amylin receptor co-agonist
Amycretin (NN9487) is an investigational Novo Nordisk peptide that activates both the GLP-1 receptor and amylin receptors from a single chain — the same two mechanisms CagriSema delivers with two separate peptides. In phase 1b/2a, once-weekly subcutaneous amycretin produced up to −24.3% body weight at 36 weeks; an oral formulation is also in development. Its sequence has not been published.

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