Discussion
Headache, nausea, IIH, traumatic brain injury, meningitis, stroke, Weight loss, headache, headaches and visual loss
SIDE EFFECT, MENINGITIS, STROKE, HYDROCEPHALUS, OPTIC NERVE, SECONDARY, PATHOGENESIS, SYNDROME, TYPE 2 DIABETES, DISEASES
This is the first randomized controlled trial comparing the efficacy of the GLP-1 receptor agonist exenatide, with placebo to reduce ICP in patients with active IIH. We have found a significant and clinically meaningful reduction in ICP in the treatment arm as compared to the placebo arm both acutely and after 12 weeks of dosing. The drug was safe and well-tolerated. This trial establishes the successful translation of preclinical data into humans and is the first to demonstrate a new drug treatment for IIH that significantly reduces ICP in IIH.The hallmark of IIH is raised ICP, which causes headaches and visual loss (through compression of the optic nerve and papilloedema).A significant reduction in ICP was also noted after prolonged dosing at 12 weeks (−4.1 mmHg equivalent to −5.6 cmCSF; Headache is a key disabling feature for IIH patients and listed in the top 10 priority areas for research by patient groups.There was a significant improvement in visual acuity between the trial arms at 12 weeks (Weight loss has been shown to reduce ICP in IIH.Exenatide is widely used to treat type 2 diabetes and has an established long-term safety record (licensed in 2005).This is the first trial, to our knowledge, to use telemetric intracranial monitoring to measure ICP in IIH. Patient input into the trial design advocated for telemetric ICP monitoring over multiple lumbar punctures to facilitate data validity and reduce patient discomfort from multiple lumbar punctures. This has permitted detailed characterization of ICP changes and the ability to measure ICP for prolonged periods over several weeks without further invasive procedures.This study has several limitations. As an early phase study, it was powered to the primary end points of ICP reduction with single and repeated dosing. Thus, the study was underpowered to detect differences in patient-centred outcomes and secondary clinical end points such as headache and visual field perimetry. Powering the study for those end points would have required a large increase in number of participants; however, telemetric ICP monitors would not be feasible in large trial cohort. No stratification was used at randomization and groups were unmatched for baseline headache days and visual field perimetry. Additionally, patients with minimal visual field defects were not excluded as in prior studies, thus making the study more clinically representative, but visual effects more difficult to detect due to the ceiling effect of the measurement. With the main side effect of exenatide being nausea, patients could have been unmasked; however, the primary end point was a physiological measure, which should minimize this risk.The results of this study may have wide reaching implications for many other diseases of raised ICP as the drug does not target the specific pathogenesis of IIH, but CSF secretion. Given the tolerability of exenatide and its direct and early effect on ICP, it may be beneficial in other conditions such as hydrocephalus, traumatic brain injury, raised ICP in stroke and meningitis and space flight–associated neuro-ocular syndrome. In addition, GLP-1 receptor agonists have been shown to demonstrate neuroprotective properties and hence may have additional benefits in conditions such as traumatic brain injury.We had previously identified a novel pathway to modulate ICP in an animal model.