Exenatide
Exenatide is a GLP-1 receptor agonist derived from Gila monster saliva (exendin-4), approved for type 2 diabetes with twice-daily and once-weekly formulations.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C184H282N50O60S |
| Molecular Weight | 4186.63 g/mol |
| CAS Number | 141758-74-9 |
| IUPAC Name | Exendin-4 synthetic analog |
| Peptide Class | GLP-1 Receptor Agonist |
| Sequence Homology | 53% identity with human GLP-1(7-37) |
Structure
Exenatide is a synthetic version of exendin-4, a 39-amino acid peptide originally isolated from the venom of the Gila monster (Heloderma suspectum). Unlike native GLP-1, exenatide contains a glycine at position 2 rather than alanine, rendering it resistant to DPP-4 degradation. The C-terminal extension (positions 31-39) contributes to receptor binding affinity and protease resistance.
Mechanism of Action
Exenatide binds to and activates the GLP-1 receptor with potency comparable to native GLP-1. It enhances glucose-dependent insulin secretion from pancreatic beta cells, suppresses inappropriately elevated glucagon secretion, slows gastric emptying, and reduces food intake through central satiety mechanisms.
Clinical Applications
Exenatide was the first GLP-1 receptor agonist approved for type 2 diabetes (Byetta, 2005, twice-daily injection). A long-acting once-weekly formulation (Bydureon, 2012) uses extended-release microsphere technology. Clinical trials demonstrated HbA1c reductions of 0.8-1.9% with modest weight loss of 2-4 kg.
Pharmacokinetics
- Byetta (twice-daily): Half-life 2.4 hours, Tmax 2.1 hours
- Bydureon (once-weekly): Sustained release from PLG microspheres, Tmax ~7 weeks to steady state
- Metabolism: Proteolytic degradation and glomerular filtration
- Renal elimination: Primarily excreted by the kidney
Safety and Side Effects
Gastrointestinal effects (nausea 44%, vomiting 13%, diarrhea 13%) are common, particularly at treatment initiation. Exenatide carries a boxed warning for thyroid C-cell tumors. Rare cases of acute pancreatitis, including hemorrhagic or fatal forms, have been reported. Not recommended in patients with severe renal impairment (CrCl <30 mL/min).
References
- Eng, J., et al. (1992). Exendin-4: a potent analog of exendin-4. Endocrinology, 130, 72-78.
- Drucker, D.J., et al. (2008). Exenatide once weekly versus twice daily for the treatment of type 2 diabetes. Lancet, 372, 1240-1250.
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