Page data last changed: . Registry refreshes and identity assessments are separate from scientific content review.
The first GLP-1 receptor agonist ever approved — a lizard-venom peptide with a 2.4-hour half-life.
Also known as: AC 2993 · synthetic exendin-4 · Byetta / Bydureon (brands)
Part of the Metabolic & GLP-1 peptides cluster
Overview
Exenatide is the synthetic form of exendin-4, a 39-residue peptide from Gila monster venom that activates the GLP-1 receptor. It was the first incretin mimetic approved for type 2 diabetes (FDA 2005, EMA 2006), dosed twice daily because its half-life is only 2.4 hours; a once-weekly extended-release form followed in 2017. Head-to-head, semaglutide lowers HbA1c and weight more.
Source & context
Biological / chemical source: Synthetic form of exendin-4, a peptide from Gila monster (Heloderma suspectum) venom
Primary research or clinical context: Approved (FDA 2005, EMA 2006) for type 2 diabetes; once-weekly extended-release form approved 2017
What exenatide is
Exenatide is the synthetic, pharmaceutical form of exendin-4, a 39-amino-acid peptide found in the venom of the Gila monster, Heloderma suspectum (IUPHAR ligand 1135). It was the first in the class of compounds with activity similar to the human hormone GLP-1 (Barnett, Drugs of Today 2005) and is approved to treat type 2 diabetes in patients whose blood sugar is inadequately controlled by other antidiabetic medicines (IUPHAR clinical-use record). Its sequence — H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S — ends in an amidated serine, and its C-terminal tail is the segment later borrowed by tirzepatide and retatrutide.
Mechanism
Exenatide acts as a GLP-1 receptor agonist and mimics the action of endogenous GLP-1 in controlling blood sugar via improved insulin and glucagon secretion and decreased food intake (IUPHAR mechanism record). Because insulin stimulation occurs only when glucose is elevated, the risk of hypoglycaemia is greatly reduced; it also slows gastric emptying, reduces appetite and enhances β-cell function (Barnett, 2005). Unlike human GLP-1, exendin-4 has glycine rather than alanine at position 2, which makes it resistant to DPP-4 — the reason a venom peptide could be a drug at all.
Pharmacokinetics: why twice daily
Peak plasma concentration after subcutaneous injection is reached at 2.1 hours; the apparent volume of distribution after a single dose is 28.3 L; the terminal half-life is 2.4 hours; bioavailability estimated from animal studies is 65–75%; and elimination is predominantly by glomerular filtration followed by proteolytic degradation (Bray, American Journal of Health-System Pharmacy 2006). DPP-4 resistance therefore buys hours, not days — the kidney still clears the peptide — which is why the original product is injected twice daily and why later GLP-1 analogues added albumin-binding lipids to reach once-weekly dosing.
Clinical evidence
Phase 3 trials showed that 30 weeks of exenatide significantly reduced glycated haemoglobin and fasting and post-meal glucose when added to metformin, sulfonylureas or both, with an average weight loss of approximately 2 kg (Barnett, Expert Opinion on Pharmacotherapy 2007). In the SUSTAIN 3 head-to-head trial, 56 weeks of once-weekly semaglutide 1.0 mg reduced HbA1c by 1.5 percentage points versus 0.9 with exenatide extended-release 2.0 mg, and body weight by 5.6 kg versus 1.9 kg; 67% versus 40% of participants reached HbA1c below 7.0% (Ahmann et al., Diabetes Care 2018).
| Endpoint | Semaglutide 1.0 mg | Exenatide ER 2.0 mg |
|---|---|---|
| HbA1c change | −1.5 pts | −0.9 pts |
| Body weight change | −5.6 kg | −1.9 kg |
| HbA1c < 7.0% achieved | 67% | 40% |
Formulations and approvals
The immediate-release product (Byetta) is injected twice daily. An extended-release formulation for once-weekly administration, Bydureon BCise, was FDA-approved in October 2017 and from April 2018 can be used alongside basal insulin in adults with type 2 diabetes, with or without metformin (IUPHAR clinical-use record). ClinicalTrials.gov lists 377 registered studies naming exenatide as of September 2026, ranging from comparative-effectiveness studies to exploratory trials in multiple sclerosis (NCT07497399) and cerebral small-vessel disease (NCT05356104).
Safety notes
No published reports attribute hepatotoxicity to exenatide (LiverTox, NIDDK). Anaphylactic shock has been reported on re-exposure after an interruption in treatment (Liu et al., Medicine 2022), and a pan-European post-authorisation safety study is examining pancreatic cancer risk among users (NCT05663515). The lactation database notes that, as a 4,187-dalton peptide, the amount in milk is likely to be very low (LactMed).
Exenatide vs the modern GLP-1 analogues
Exenatide established the class; semaglutide, tirzepatide and retatrutide surpassed it on every efficacy measure by combining DPP-4 resistance with albumin binding for week-long exposure. What exenatide keeps is a short half-life — useful when rapid washout matters — and the longest post-marketing record of any GLP-1 agonist. The exendin-4 profile on this site covers the native venom peptide; the semaglutide-vs-tirzepatide and half-life comparison guides place exenatide in context.
Sequence of the selected reference form
Sequence backbone for the reference form: Exenatide39-residue parent peptide amide. Termini, stereochemistry and modifications are described below.
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
Analyze sequences in the playground →Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
The official BYETTA label defines the 39-residue exenatide sequence, Ser39 amidation and 4186.6 Da parent mass. Selected CID 45588096 supplies all37 stereocentres. The old linked CID omits every stereocentre.
- Molecular form
- Exenatide39-residue parent peptide amide
- Species
- Synthetic peptide identical in sequence to Heloderma suspectum exendin-4
- Termini (N / C)
- Free L-histidyl amino terminus / L-serinamide (Ser39-NH2)
Average reference mass · Molecular identity assessment: 2026-10-05
Reference policy updated: 2026-10-05
- PubChem PUG REST selected parent properties · 2026-10-05
- PubChem selected-parent biologic notation · 2026-10-05
- PubChem selected-parent identifiers with depositor attribution · 2026-10-05
- NIH GSRS independently selected parent record · 2026-10-05
- Official product label chemical description, selected parent distinguished from formulation · 2026-10-05
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
- Molecular formula
- C184H282N50O60S
- Average reference mass
- ≈ 4,186.6
- Plasma half-life
- ≈ 2.4 h (terminal); peak plasma at ≈ 2.1 h after subcutaneous injection
- Receptors
- GLP-1 receptor agonist; mimics endogenous GLP-1
- Backbone
- Exenatide39-residue parent peptide amide
- C-terminus
- L-serinamide (Ser39-NH2)
- Status
- Approved: FDA (2005), EMA (2006) for type 2 diabetes; extended-release once-weekly form (Bydureon BCise) FDA-approved October 2017
- PubChem CID: 45588096
- CAS RN: 141758-74-9
- UNII: 9P1872D4OL
Chemistry values: curated profile, PubChem.
Clinical development snapshot
ClinicalTrials.gov lists 378 registered studies with “Exenatide” as an intervention (snapshot 2026-10-01). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT05663515 | A Pan-European Post-Authorisation Safety Study: Risk of Pancreatic Cancer Among Type 2 Diabetes Patients Who I | — | recruiting | 2026-09-24 |
| NCT01988545 | GLP-1's Effect on Cardiac Parameters and Mesenteric Blood Flow | Not applicable | completed | 2026-09-15 |
| NCT07808879 | Comparison of [68Ga]Ga-HBED-CC-PEG6-Exendin-4 and [68Ga]Ga-HBED-CC-Exendin-4 PET/CT for Insulinoma Localizatio | Not applicable | recruiting | 2026-09-09 |
| NCT06725693 | Glucagon-like Peptide-1 Receptor PET/CT in GLP-1R Related Disease | — | recruiting | 2026-09-08 |
| NCT05220917 | Comparative Effectiveness and Safety of Four Second Line Pharmacological Strategies in Type 2 Diabetes Study | — | active not recruiting | 2026-08-13 |
| NCT07702461 | Determination of Resistance Training Status for Patients on Glucagon-Like Peptide-1 Receptor Agonists | — | recruiting | 2026-07-24 |
Exenatide — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Exenatide39-residue parent peptide amideAverage reference mass: 4,186.6 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- Trials1 registered study added on ClinicalTrials.gov (now 378).
- IdentifiersCross-linked to IUPHAR ligand 1135 and PubChem CID 53396299.
- TrialsClinicalTrials.gov snapshot added: 377 registered studies, highest phase 4.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Exenatide
What is Exenatide?+
Exenatide is the synthetic form of exendin-4, a 39-residue peptide from Gila monster venom that activates the GLP-1 receptor. It was the first incretin mimetic approved for type 2 diabetes (FDA 2005, EMA 2006), dosed twice daily because its half-life is only 2.4 hours; a once-weekly extended-release form followed in 2017. Head-to-head, semaglutide lowers HbA1c and weight more.
What Canadian product status is recorded for Exenatide?+
Canadian product status for Exenatide has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the length of the selected reference form for Exenatide?+
The selected reference form (Exenatide39-residue parent peptide amide) has 39 residues or residue-derived units in its backbone. Other forms in this family may have a different length.
What is exenatide?+
The synthetic form of exendin-4, a 39-residue Gila monster venom peptide that activates the GLP-1 receptor. Approved for type 2 diabetes since 2005 (Byetta) with a once-weekly form since 2017 (Bydureon BCise).
What is exenatide's half-life?+
About 2.4 hours, with peak plasma levels around 2.1 hours after injection. That is why the original product is dosed twice daily.
Is exenatide the same as exendin-4?+
Exenatide is synthetic exendin-4 manufactured as a medicine; the sequence is identical.
Exenatide vs semaglutide — which works better?+
In SUSTAIN 3, semaglutide 1.0 mg weekly reduced HbA1c by 1.5 points and weight by 5.6 kg over 56 weeks, versus 0.9 points and 1.9 kg with exenatide extended-release 2.0 mg.
Is exenatide a GLP-1?+
It is a GLP-1 receptor agonist, but its sequence comes from lizard venom rather than the human hormone.
Related peptides
References & further reading
- 1.Ahmann et al. (2018). Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3). Diabetes Care
- 2.Bray (2006). Exenatide. American Journal of Health-System Pharmacy
- 3.Barnett (2007). Exenatide. Expert Opinion on Pharmacotherapy
- 4.Barnett (2005). Exenatide. Drugs of Today
- 5.Liu et al. (2022). A case report of severe adverse reaction of exenatide: Anaphylactic shock. Medicine
- 6.PubChem — compound summary for Exenatide (CID 53396299)