Human physiology of intra-cranial pressure and the biological role of GLP-1 agonists

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Mitchell, James Lee ORCID: https://orcid.org/0000-0001-6785-9352 (2022). Human physiology of intra-cranial pressure and the biological role of GLP-1 agonists. University of Birmingham. Ph.D.

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Abstract

Pre-clinical data demonstrates the ability of Exenatide, a GLP-1R agonist, to reduce CSF secretion and intracranial pressure (ICP) in an in vivo model. Existing GLP-1R agonists are widely used to treat obesity and diabetes (but do not cause hypoglycaemia).
In the IIH Pressure trial 16 female participants with active idiopathic intracranial hypertension (IIH) were recruited and 15 randomised in a placebo controlled, double-blind trial of Exenatide. Participants were randomised 1:1 to Exenatide (10mcg twice daily sub-cutaneous) or placebo for 12 weeks. Telemetric, intraparenchymal ICP monitors (Raumedic) recorded ICP over 12 weeks. The primary outcomes were ICP at 2.5 hrs, 24 hrs, and 12 weeks.
At baseline BMI was 38.1(6.2) kg/m2 and ICP 30.6(5.1) cmCSF. ICP, the primary endpoint, fell significantly (2.5 hours -5.7(2.9) cmCSF (p=0.048), 24 hours -6.4 (2.9) cmCSF (p=0.030) and 12 weeks - 5.6 (3.0) cmCSF (p=0.058)). Monthly headache days fell in the Exenatide treated cohort (-7.7 (9.2) p=0.069) and vision improved (logMar acuity -0.1 (0.04) p=0.004).
ICP physiology was studied using a standardized protocol. Intracranial pressure (ICP) has been thought to vary diurnally. This study evaluated diurnal ICP measurements and quantifies changes in ICP occurring with changes in body posture in active IIH.
This prospective observational study utilized the IIH pressure cohort prior to randomization. Changes in ICP in the supine position were evaluated. Then, the ICP was measured in the standing, sitting, supine, left lateral decubitus positions and with coughing and bending. Ultimately, changes in ICP over the course of 24 hours were recorded.
15 women were included, mean (standard deviation) age 29.5 (9.5) years, body mass index 38.1 (6.2) kg/m2, and baseline ICP of 21.2 (4.8) mmHg). ICP rose with the duration in the supine position 1.2 (3.3) mmHg at over 5-minutes (p=0.175), 3.5 (2.8) mmHg over 30-minutes (p=0.0002) and by a further 2.1 (2.2) mmHg over 3 hours (p=0.042). Mean ICP decreased by 51% when moving from the supine position to standing (21.2 (4.8) mmHg to 10.3 (3.7) mmHg respectively, p=0.0001). Mean ICP increased by 13% moving from supine to the left lateral decubitus position (21.2 (4.8) mmHg to 24.0 (3.8) mmHg, p=0.028). There was no significant difference in ICP measurements at any point during the daytime, or between short standing or supine recordings and prolonged daytime and end of night recordings respectively. However, ICP increased progressively in conjunction with lying supine position from 23:00hrs to 07:00hrs by 34% (5.2 (1.9) mmHg, p=0.026).
The IIH Pressure Med study followed, it was a randomised, sequential, open label trial in women with active IIH. Participants were treated for 2 weeks with acetazolamide, amiloride, furosemide, spironolactone and topiramate. Order of treatment was randomised, minimum 1 week drug washout between rounds. ICP was recorded before and after with telemetric, ICP monitors. Cognitive function was tested with the NIH Toolbox Cognition Battery.
14 participants were recruited, at baseline BMI 38.1(6.2) kg/m2and ICP 30.6(5.1) cmCSF. ICP fell significantly with 4 drugs (mean mmHg(SE), p=) acetazolamide -3.31mmHg(0.95), 0.0009, furosemide -3.03(0.88), 0.0011, spironolactone -2.71(0.88), 0.0033, topiramate -2.29(0.85), 0.0095. There was no significant effect between those drugs. Executive function (T Score change(SE), p=) worsened with acetazolamide -10.3(3.2), 0.002 and topiramate -7.0(2.7), 0.012.
IIH Pressure demonstrated that Exenatide reduced ICP acutely and after chronic dosing and improvements in headache and visual function were recorded. GLP-1R agonists represent a new approach to treat IIH. The physiology study demonstrated that ICP does not appear to have a diurnal variation in IIH, but varies by position and duration in that position. ICP rose at night whilst the patient was continuously supine. This knowledge gives reassurance that ICP can be accurately measured and compared at any time of day. The IIH Pressure Med Study assessed Acetazolamide, furosemide, spironolactone and topiramate; all reduced ICP significantly, but there was no statistical difference between any treatment. Cognitive side-effects were common with acetazolamide and topiramate and detailed cognitive assessment demonstrated significantly worse performance following treatment.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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