Beyond weight loss: a case study and narrative review of the potential role of glucagon-like peptide-1 receptor agonists for the treatment of idiopathic intracranial hypertension

Introduction

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a disorder characterized by elevated intracranial pressure (ICP) with no identifiable structural cause, such as a mass lesion or obstructive hydrocephalus. The condition predominantly affects obese women of childbearing age, with pathogenesis linked to metabolic and hormonal dysregulation. Common symptoms include headache, transient visual obscurations, and papilledema, which can lead to visual impairment or blindness if left untreated (1,2).

Treatment for IIH focuses on weight reduction, lifestyle changes, and pharmacological management with medications such as acetazolamide or topiramate. Surgical intervention is typically reserved for fulminant cases or where maximum medical therapy fails. Recent advances in the understanding of the role of weight and metabolic dysregulation in IIH have sparked interest in exploring medications initially developed for diabetes and obesity management (3). A class of medications targeting glucagon-like peptide-1 (GLP-1) receptors have shown significant efficacy in weight reduction (4). Semaglutide and other drugs in this class, such as exenatide and liraglutide, have shown promising results in promoting weight loss and improving symptoms in patients with IIH.

There are currently limited articles reviewing the use of GLP-1 receptor agonists (GLP-1RAs) specifically for the treatment of IIH. A review article in 2021 discussed the utility of GLP-1RA for the treatment of IIH, with a particular focus on weight management (5). The role of GLP-1RAs in pain modulation, including IIH related headache, has also been explored (6). However, a systematic review in 2023 found only one phase 2 randomized controlled trial of exenatide versus placebo for IIH, which did demonstrate a significant reduction in ICP at all time points, as well as improved headache and visual acuity (7,8). The purpose of this article is to synthesize the current literature regarding IIH and the emerging role of GLP-1RA as a potential therapeutic option for this condition. An illustrative case in which GLP1-RAs were instrumental in patient treatment is also provided to help understand the clinical relevance of this topic. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-24-42/rc).

Methods

A search of the literature was conducted on OVID (1947–May 2025) using the terms [papilledema OR intracranial hypertension OR idiopathic intracranial hypertension OR brain pseudotumor] AND [glucagon like peptide 1 OR glucagon like peptide 1 receptor agonist OR semaglutide OR exendin 4 OR liraglutide OR tirzepatide]. Studies of both humans and animals were considered. A total of 86 articles were retrieved. The authors screened title and abstract for relevance and included further studies found through examining references (Table 1).

Illustrative case report

A 23-year-old man presented with a 2-month history of seeing a discoloured area in both eyes, on a background of longstanding intermittent headache and at least 5 years of pulsatile tinnitus. Past medical history was significant for morbid obesity (current weight 286 kg), pulmonary embolism and deep vein thrombosis 4 years prior, previously treated with warfarin. On examination, visual acuity was 20/50 in each eye, colour vision was 16/16 Ishihara colour plates in the right eye and 12/16 plates in the left eye. There was no relative afferent pupillary defect. Extraocular movements were full with no ocular misalignment. Fundus examination revealed massive bilateral optic disc edema. Humphrey visual fields demonstrated grossly enlarged blind spots in each eye (Figure 1).

Figure 1 Baseline images showing severe bilateral papilledema and enlarged blind spots. Top row: fundus photos from initial presentation. Bottom row: 24-2 Humphrey visual fields grey scale and pattern deviation from initial presentation.

A computed tomography (CT) head and CT venogram showed an empty sella and bilateral narrowing of the venous sinuses. Due to body habitus, neither magnetic resonance imaging (MRI) nor lumbar puncture was possible to obtain. Based on the risk factor of morbid obesity in a young patient with papilledema and imaging features suggestive of intracranial hypertension, a diagnosis of IIH was made. He was rapidly titrated up to 4 g daily of acetazolamide and 20 mg of furosemide, but was deemed not to be a good surgical candidate for ventriculoperitoneal shunting or optic nerve sheath fenestration. Diagnostic cranial venous manometry was performed by interventional radiology, and revealed raised venous pressure throughout and a pressure gradient of 16 mmHg across the left sigmoid sinus without stenosis. Due to the lack of alternate treatment options, a stent was deployed into the left sigmoid sinus despite the lack of stenosis.

One month post-venous sinus stenting, there was no improvement in optic disc edema or visual fields, and visual acuity was further reduced to 20/70 in both eyes. As there were no other surgical options, and he was on a maximum dose of acetazolamide, a decision was made to treat with a GLP-1RA as a non-invasive option, based on recent emerging evidence for efficacy in IIH. Although weight was likely a significant contributor to the disease pathogenesis, the time required for weight loss through diet or even bariatric surgery would not have been rapid enough to address the severity of the papilledema and risk to vision.

The patient was referred to endocrinology and started on tirzepatide 2.5 mg subcutaneous once weekly for 4 weeks, then increased to 5 mg once weekly as per standard dosing protocol. Two months later, visual acuity had improved to 20/20 in both eyes with significant improvement in papilledema and a reduction in the size of the blind spots. Both headache and pulsatile tinnitus were also markedly improved. At this time, due to supply issues, he was switched to semaglutide 0.5 mg subcutaneous once weekly. Both medications were well tolerated with no reported side effects. At 1-year follow-up, he remained on semaglutide, and his weight was measured at 251.8 kg, representing a 12% reduction in body mass. Visual acuity was 20/20 in both eyes with optic disc gliosis and atrophy but no persistent edema. Visual fields showed a mildly enlarged blind spot in each eye (Figure 2). The furosemide was discontinued, and the acetazolamide tapered down to 500 mg TID, but he remains on semaglutide indefinitely.

Figure 2 One-year follow-up demonstrating resolution of papilledema and improved visual function. Top row: fundus photos from 1-year follow-up. Bottom row: 24-2 Humphrey visual fields grey scale and pattern deviation from 1-year follow-up.

Pathophysiology of IIH

Although the precise cause of IIH remains unclear, the frequent association with obesity implicates metabolic disturbances as a crucial risk factor, particularly those linked to excess adipose tissue. The risk of developing IIH increases significantly with increasing body mass index (BMI), or following recent weight gain (3) and can go into remission with weight loss (5). Hormonal factors, such as elevated estrogen levels, may explain the female predominance in IIH (2). The increased ICP in IIH is thought to stem from impaired cerebrospinal fluid (CSF) absorption, possibly due to elevated venous sinus pressure. Obesity-associated intra-abdominal pressure may also contribute, influencing CSF dynamics.

Mechanism of action of GLP-1 receptor agonists

GLP-1 is a hormone released by the small intestine in response to food intake. GLP-1RAs mimic GLP-1 and have primarily been used for glycemic control in type 2 diabetes and for weight reduction in obese patients (8,9). The mechanism of action for diabetes management involves slowing gastric emptying, enhancing glucose-induced insulin secretion and inhibiting glucagon secretion. Through its action on neurons projecting from the nucleus tractus solitarius to the hypothalamus, GLP-1 also promotes satiety. This pathway has been beautifully illustrated by Krajnc et al. 2023 (10). In obesity management, GLP-1RAs in general, and semaglutide in particular, have been shown to induce significant and sustained weight loss in clinical trials (4).

GLP-1 receptors are found throughout the central nervous system including the choroid plexus epithelium. Stimulation by GLP-1RAs directly reduces CSF production through activation of cyclic adenosine monophosphate protein and subsequent phosphorylation of protein kinase A, which in turn inhibits sodium/potassium adenosine triphosphatase dependent secretion of CSF (11). Recent studies have indicated that GLP-1RAs may possess neuroprotective properties (12) and directly reduce ICP. In a rat model of hydrocephalus, exenatide significantly lowered ICP, suggesting similar potential benefits in IIH (11).

Current evidence for GLP-1RAs in IIH

GLP-1RAs and weight reduction

Weight management remains the primary intervention for IIH. Loss of approximately 3–15% of body weight can result in remission of IIH (5), while weight gain of 5–15% can result in recurrence of IIH (3). Typical diet and lifestyle modification strategies achieve around 5% weight loss, but maintenance of weight loss is often unsuccessful, with a return to baseline within 2–5 years (4,13,14). Bariatric surgery has been more successful, attaining 25–30% weight loss, with associated improvement in cardiovascular health and remission of IIH in affected patients (14,15). The weight-reducing and appetite-suppressing effects of GLP-1RAs may also offer an important tool for managing IIH patients who struggle with weight loss through lifestyle changes alone (1). Conversely, the first line treatment for IIH, acetazolamide, has little to no effect on weight loss (Table 2) (16). In a pilot study of 39 patients with IIH and BMI greater than 30 kg/m², patients treated with semaglutide or liraglutide in addition to counselling on diet and exercise achieved significantly greater weight loss (−12%) after 6 months than those offered counselling alone (−2.8%) (10). Furthermore, 100% of patients treated with GLP-1RAs lost more than 5% of body weight, compared to 36% with conventional weight loss strategies (10). A large population based cohort utilizing the TriNetX research database found a mean reduction in BMI of −1.635 kg/m² at 1 year in 4,968 IIH patients prescribed GLP-1RAs compared to −0.758 kg/m² in controls (17). Another cohort study of the same TriNetX database found that 193 IIH patients taking tirzepatide had a reduction in BMI of 1.147 mm/kg² greater than 193 controls (18).

Headache and symptom improvement

The majority of patients with IIH suffer disabling headache, which significantly impacts quality of life (19). Obesity alone increases the risk of headache and migraine by 27%, suggesting that weight loss itself is an important goal in the symptomatic treatment of IIH (20). In addition to greater weight loss, Krajnc et al. [2023] observed a reduction in median monthly headache days at 6 months in those treated with GLP-1RAs [−4; 95% confidence interval (CI): −10.5, 0.5] compared to conventional weight management (0; 95% CI: −3, 1; P=0.02) (10). IIH patients treated with GLP-1Ras also required lower doses of acetazolamide compared to controls (10). Another study of 15 IIH patients treated with exenatide or placebo also found a favourable headache outcome in those treated with exenatide, with a significant reduction in monthly headache days [−7.7, standard deviation (SD) 9.2] compared to placebo (−1.5, SD 4.8) (Table 3) (8). Animal studies investigating liraglutide in a rat model of migraine led to reduced expression of calcitonin gene-related peptide and other pro-inflammatory molecules involved in pain mediation, as well as upregulation of interleukin-10 which can improve migraine-associated pain (6,25). These small studies support the potential for this class of medications to alleviate one of the most debilitating IIH symptoms.

Neuroprotective effects

In addition to headache and vision loss, IIH has been documented to cause impairments in executive function and attention (26). To compound this dysfunction, the most commonly used medications to treat IIH, acetazolamide and topiramate, may further worsen cognitive function (21). In contrast, Grech et al. [2024] found no difference in cognitive performance in 7 IIH patients treated with exenatide compared to 8 patients treated with placebo (Table 3). Furthermore, treated patients showed improvement in cognition after 12 weeks (21). Animal and preliminary human studies indicate that GLP-1RAs may also have neuroprotective properties that could mitigate optic nerve damage (12).

Direct ICP reduction

The putative goal of IIH treatment is to address the underlying abnormality of raised ICP. The IIH treatment trial assessed 165 patients with IIH, treated either with acetazolamide or placebo in addition to a low sodium weight reduction diet. Among the 85 patients with a repeat lumbar puncture at 6 months, acetazolamide lowered ICP by 112.3 mmH₂O compared to 52.4 mmH₂O in the placebo group (27). Experimental studies have also pointed to a direct ICP-lowering effect of GLP-1RAs. Botfield et al. [2017] demonstrated that exenatide effectively reduced ICP in healthy rats within 10 minutes of subcutaneous administration. After 30 minutes, ICP was 35% lower and this reduction was sustained over 24 hours. Repeated administration resulted in sustained lowering of ICP between doses. A similar response was demonstrated in a rat model of hydrocephalus, with rapid and sustained lowering of ICP by 44% (11). In humans, a study of 16 IIH patients monitored through an implanted telemetric ICP catheter were treated with exenatide or placebo for 12 weeks. ICP was 4.2 cmH₂O lower than the placebo group within 2.5 hours, and this difference was maintained through to 12 weeks (8). Although exenatide was the focus of these studies, similar mechanisms may apply to other GLP-1RAs.

Adverse effects

GLP-1RAs are generally well tolerated, but with a common set of side effects, typically affecting the gastrointestinal system. Symptoms include nausea, diarrhea, vomiting and constipation, occurring twice as often as patients treated with placebo. These symptoms tend to be mild to moderate and resolve or improve even with continued medication use (9,28,29). In clinical trials, serious adverse effects requiring discontinuation were reported in less than 2% (9,28,29). However, a database analysis of nearly 200,000 individuals treated with GLP-1RAs for diabetes, obesity or both identified a discontinuation rate of 36.5% at 12 months (30). Continued treatment is important for maintenance of weight loss, as multiple studies have now demonstrated significant weight regain within 1 year after cessation of GLP-1RAs (9,28,29,31). In patients with IIH, abrupt cessation of GLP-1RA therapy has been reported to lead to a return of symptoms or new onset IIH in two separate case reports, highlighting the requirement of continuous therapy (22,24).

Strengths, limitations and future directions

This narrative review has several strengths, including the timely synthesis of emerging evidence on the potential role of GLP-1 receptor agonists in the management of IIH. By integrating data from preclinical studies, early-phase clinical trials, and real-world reports, as well as presenting an illustrative case, we provide a clinically relevant overview of this novel therapeutic approach. However, limitations must be acknowledged. This review is based on studies that are either small or non-randomized, and have involved multiple different GLP-1RAs. Despite this, the growing body of evidence supporting GLP-1RAs for weight reduction, headache relief, and direct ICP modulation in IIH highlights their potential as adjunctive therapy (Table 3). Large-scale clinical trials are needed to fully understand the effects of GLP-1RAs on ICP, headache outcomes, visual prognosis and quality of life in IIH patients. The possibility of direct action on CSF dynamics by GLP-1 receptor activation is an area that warrants further exploration. In particular, the rapid and sustained reduction in ICP (8,11) may be useful for the immediate treatment of fulminant IIH while awaiting surgical intervention.

While these agents are not yet formally approved for IIH, their potential dual benefit of weight loss and ICP reduction could substantially enhance the current management of IIH. There is also preclinical evidence that GLP-1RAs may directly modulate pain through reduction of central sensitization, suggesting the possibility of additional symptomatic improvement for IIH patients with headache (32). Careful consideration of patient selection criteria and possible side effects, such as gastrointestinal discomfort and hypoglycemia, will be important when using GLP-1RAs for the treatment of IIH.

Future research is required to determine the optimal GLP-1RA and dosing strategies for IIH. Evaluating the long-term outcomes of GLP-1RA therapy on ICP and vision could solidify their role in IIH management, potentially establishing them as first-line or adjunctive therapies in selected patients.

Conclusions

GLP-1 receptor agonists, including semaglutide, exenatide, and liraglutide, show potential as adjunctive therapies for IIH, especially in patients where lifestyle modifications have been insufficient. These drugs not only aid in weight loss but also appear to provide neuroprotective benefits and direct reduction of ICP. While further research is needed to confirm these effects, the current literature supports the potential utility of GLP-1RAs in IIH management.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-24-42/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-24-42/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-24-42/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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