Exenatide
GLP-1 Receptor AgonistapprovedAlso known as: Byetta, Bydureon, Exendin-4, AC2993
The first GLP-1 receptor agonist approved for type 2 diabetes, originally derived from Gila monster venom, available in twice-daily and once-weekly formulations.
Overview
Exenatide is a synthetic version of exendin-4, a 39-amino acid peptide originally isolated from the saliva of the Gila monster (Heloderma suspectum). It was the first GLP-1 receptor agonist approved by the FDA (2005) for type 2 diabetes, pioneering an entirely new drug class. Exenatide shares approximately 53% homology with human GLP-1 but is resistant to DPP-4 degradation, giving it a much longer duration of action. Available as Byetta (twice-daily) and Bydureon (once-weekly extended-release microsphere formulation), exenatide effectively lowers blood glucose and promotes moderate weight loss. While it has been largely eclipsed by newer GLP-1 RAs like semaglutide and tirzepatide, exenatide remains historically significant and is still widely prescribed.
Mechanism of Action
Exenatide activates the GLP-1 receptor with similar potency to native GLP-1 but with greatly extended duration due to resistance to DPP-4 cleavage. It stimulates glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying, and reduces appetite via hypothalamic signaling. The extended-release Bydureon formulation uses poly(D,L-lactide-co-glycolide) microspheres that slowly release exenatide over weeks. Exenatide also promotes beta-cell proliferation and reduces beta-cell apoptosis in preclinical models.
Molecular Formula
C184H282N50O60S
Molecular Weight
4186.6 g/mol
Sequence
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
Dosage Protocols
Dose Range
5mcg – 10mcg
Frequency
Twice daily
Route
subcutaneous
Cycle Length
Ongoing / chronic
Start at 5mcg twice daily within 60 minutes before morning and evening meals. May increase to 10mcg twice daily after 1 month.
Source: FDA prescribing information (Byetta)
Side Effects
| Effect | Severity |
|---|---|
| Nausea | moderate |
| Vomiting | moderate |
| Diarrhea | mild |
| Injection site nodule | mild |
| Headache | mild |
| Pancreatitis | severe |
| Hypoglycemia | moderate |
Pros & Cons
First-in-class GLP-1 RA with the longest post-marketing safety track record (since 2005)
Available in both twice-daily and once-weekly formulations for flexibility
Effective blood glucose lowering with moderate weight loss (2-4 kg)
Demonstrated beta-cell protective effects in preclinical studies
Higher nausea rates than many newer GLP-1 RAs, especially the twice-daily formulation
Less weight loss and HbA1c reduction compared to semaglutide and tirzepatide
Bydureon requires reconstitution and can cause injection site nodules
No dedicated cardiovascular outcome trial showing MACE reduction (EXSCEL showed non-inferiority only)
Research Studies
Legal Status
FDA-approved (Byetta 2005, Bydureon 2012). Prescription-only. EMA-approved. Available globally for type 2 diabetes.
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