The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial

Abstract

Therapeutics to reduce intracranial pressure are an unmet need. Preclinical data have demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 (GLP-1) receptor signalling. Here, we translate these findings into patients by conducting a randomized, placebo-controlled, double-blind trial to assess the effect of exenatide, a GLP-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 h, 24 h 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 h −5.7 ± 2.9 cmCSF (P = 0.048); 24 h −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. These data provide confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlight the potential to utilize GLP-1 receptor agonist in other conditions characterized by raised intracranial pressure.

Considerations from venous stenosis to metabolic underpinnings in Idiopathic Intracranial Hypertension

“…Reduction of ICP is one of the therapeutic aims in IIH. This has been successfully achieved, as evidenced through randomised control trials (RCT), with the carbonic anhydrase inhibitor acetazolamide (9), bariatric surgery (10), and most recently reported the Glucagon-like peptide-1 (GLP-1) receptor agonist, Exenatide (11). While dural VSS (DVSS) (12), and indeed CSF shunting (13) have been shown to reduce ICP, none have been subject to the rigor of an RCT.…”

Guidelines of the International Headache Society for Controlled Clinical Trials in Idiopathic Intracranial Hypertension

“…There have been few RCTs in IIH and a small number of cohort studies (Table 1 and 2) (12)(13)(14)(15)(16)(17)(18)(19)(20). Choice of the primary outcome has varied between visual field status, as assessed using automated perimetry performed on the Humphrey field analyzer, and ICP as measured by lumbar puncture (Tables 1, 2 and 3).…”

“…The 2015 Cochrane review concluded that there is a lack of evidence to guide management of IIH (11), as there are few published randomized clinical trials (RCTs) and only a few open label trials (Table 1 and 2) (12)(13)(14)(15)(16)(17)(18)(19)(20). To date, research has been sporadic due to the relative rarity of the disease but with the increasing incidence and prevalence of the disease there is an unmet medical need for effective acceptable interventions.…”

Author Response: Association of Amount of Weight Lost After Bariatric Surgery With Intracranial Pressure in Women With Idiopathic Intracranial Hypertension

“…A randomized controlled trial demonstrated that exenatide significantly reduced ICP in active IIH at 2.5 hours, 24 hours, and 12 weeks. 4 Therefore, we believe the reduction in ICP observed at 2 weeks could be driven by GLP-1 and has the potential—after further investigation—to rival the current surgical practices to save vision in fulminant IIH.…”