Mechanism of Action
GLP-1 Receptor Blockade
Avexitide (exendin 9-39) competitively blocks the GLP-1 receptor without activating it. By preventing endogenous GLP-1 from binding, it reduces glucose-dependent insulin secretion and the amplification of insulin release seen postprandially after Roux-en-Y gastric bypass surgery. This directly addresses the hyperinsulinism underlying post-bypass hypoglycemia.
Glucagon Restoration
GLP-1 receptor activation normally suppresses glucagon secretion. Avexitide blockade restores postprandial glucagon release, which counteracts hypoglycemia by stimulating hepatic glucose production. The restoration of the glucagon counterregulatory response is a key component of its therapeutic effect.
Research Summary
Post-Gastric Bypass Hypoglycemia
Phase 3Phase 2 trials demonstrated that continuous subcutaneous infusion of avexitide significantly reduced hypoglycemic episodes in PGBH patients following gastric bypass surgery. Glucose nadir values improved and time spent in hypoglycemia decreased by approximately 70% versus placebo. Phase 3 trials are ongoing.
Congenital Hyperinsulinism
Phase 2Avexitide has shown efficacy in diazoxide-unresponsive congenital hyperinsulinism, reducing hypoglycemic episodes in pediatric patients. It represents a non-surgical alternative for patients who would otherwise require near-total pancreatectomy.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| PGBH treatment | 30-60 mg/day | Continuous SC infusion | Subcutaneous pump |
| Acute testing | 0.1-1 pmol/kg/min | Continuous | IV infusion |
FDA Breakthrough Therapy Designation. Not yet approved. Investigational use only.
Interactions
Safety Profile
Avexitide is generally well tolerated. Common adverse effects include injection site reactions and mild gastrointestinal symptoms. By blocking GLP-1 receptor signaling, it may increase appetite and food intake as a side effect. Long-term cardiovascular effects of sustained GLP-1 receptor blockade require monitoring given the known cardioprotective role of GLP-1. No serious adverse events identified in Phase 2 trials.
References
- [1]Craig CM et al. (2017). Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycaemia. Diabetes, Obesity and Metabolism, 20(4), 923-930.
- [2]Salehi M et al. (2012). Hypoglycemia after gastric bypass surgery: current concepts and controversies. Journal of Clinical Endocrinology and Metabolism, 99(7), 2236-2245.