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Randomized Controlled Trial
. 2023 May 2;146(5):1821-1830.
doi: 10.1093/brain/awad003.

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

James L Mitchell  1   2   3 , Hannah S Lyons  1   2 , Jessica K Walker  1 , Andreas Yiangou  1   2 , Olivia Grech  1 , Zerin Alimajstorovic  1 , Nigel H Greig  4 , Yazhou Li  4 , Georgios Tsermoulas  1   5 , Kristian Brock  6 , Susan P Mollan  1   7 , Alexandra J Sinclair  1   2
Affiliations
Randomized Controlled Trial

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

James L Mitchell et al. Brain. .

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.

Keywords: cerebrospinal fluid; glucagon-like peptide 1; idiopathic intracranial hypertension; intracranial pressure; telemetric monitor.

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Conflict of interest statement

J.L.M. was funded by the UK Ministry of Defence for the duration of the study. O.G. reports scientific consultancy fees from Invex therapeutics (2020). A.Y. reports receiving speaker fees from Teva, UK, outside the submitted work. K.B. works for UCB. Professor Mollan reports other Invex Therapeutics, other Heidelberg engineering during the conduct of the study; other from Chugai-Roche Ltd, other from Janssen, other from Allergan, other from Santen, other from Roche, other from Neurodiem, outside the submitted work. Professor Sinclair reports personal fees from Invex therapeutics in her role as Director with stock holdings, during the conduct of the study (since 28.06.2019); other from Allergan, Novartis, Cheisi and Amgen outside the submitted work. All other authors declare no competing interests.

Figures

Figure 1
Figure 1
Consort diagram. Consort diagram describing the numbers and disposition of study subjects.
Figure 2
Figure 2
Primary outcomes. Mean change (SEM) of ICP in (A) ICP at 2.5 h; (B) ICP at 24 h; (C) ICP at 12 weeks. *P < 0.1 (significant level set at P < 0.1). Diurnal variability in ICP reflected in changes in ICP readings at different times of day observed in the placebo arm.
Figure 3
Figure 3
Monthly headache days and analgesia, visual acuity and BMI. Mean change (SEM) at 12 weeks of (A) monthly headache days, (B) monthly analgesia days, (C) visual acuity measured by logMAR and (D) body mass index (BMI). *P < 0.1 (significant level set at P < 0.1).
Figure 4
Figure 4
First 2.5 h, overnight ICP. Mean ICP (SEM) by arm measured (A) continuously over 2.5 h after dose and (B) hourly overnight. *P < 0.1 (significant level set at P < 0.1).
See this image and copyright information in PMC

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