The effect of GLP-1RA exenatide on Idiopathic Intracranial Hypertension: Randomised Clinical Trial

Abstract

Therapeutics to reduce intracranial pressure are an unmet need. Pre-clinical data has demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 receptor signaling. Here, we translate these findings into patients by conducting a randomized, placebo controlled, double-blind trial to assess the effect of exenatide, a glucagon-like peptide-1 receptor agonist, on intracranial pressure in idiopathic intracranial hypertension. Telemetric intracranial pressure catheters enabled long-term intracranial pressure monitoring. The trial enrolled adult women with active idiopathic intracranial hypertension (intracranial pressure >25 cmCSF and papilloedema) who receive subcutaneous exenatide or placebo. The three primary outcome measures were intracranial pressure at 2.5 hours, 24 hours and 12 weeks and alpha set a priori at less than 0.1. Among the 16 women recruited, 15 completed the study (mean age 28+/-9, body mass index 38.1+/-6.2 kg/m2, intracranial pressure 30.6+/-5.1 cmCSF). Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 hours -5.7+/-2.9 cmCSF (p=0.048); 24 hours of -6.4+/-2.9 cmCSF (p=0.030); and 12 weeks -5.6+/-3.0 cmCSF (p=0.058). No serious safety signals were noted. This data provides confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlights the potential to utilise glucagon-like peptide-1 receptor agonist in other conditions characterised by raised intracranial pressure.

Letter: Cerebrospinal Fluid Shunting for Idiopathic Intracranial Hypertension: A Systematic Review, Meta-Analysis, and Implications for a Modern Management Protocol

“…Exenatide was successful in reducing ICP at 2.5, 24 hours, and 12 weeks. 12 To our final point, there is firm evidence that IIH is a metabolic disease encompassing a spectrum of systemic manifestations. There is 2-fold risk of cardiovascular disease, presence of insulin resistance, increased truncal adiposity, hyperleptinemia, fertility, and pregnancy complications.…”