Beyond Neurodegeneration: GLP-1 Receptor Agonists Find Their Footing in Stroke, Sleep, and Intracranial Pressure Disorders

Glucagon-like peptide-1 (GLP-1) receptor agonists have moved decisively beyond diabetes care, emerging as multimodal therapeutics with broad relevance across neurology. Their potent effects on weight, vascular function, inflammation, and appetite regulation have driven interest in applications spanning ischemic stroke prevention, obstructive sleep apnea (OSA), idiopathic intracranial hypertension (IIH), and migraine. These conditions share common pathophysiologic threads including obesity, vascular dysregulation, and altered cerebrospinal fluid (CSF) and neuroinflammatory signaling, that the GLP-1 class is uniquely positioned to modify.

Notably, the most prominent neurodegenerative hypothesis for the class did not survive phase 3 testing. The Exenatide-PD3 trial, published in The Lancet in February 2025, found no benefit of once-weekly extended-release exenatide over placebo on motor, non-motor, cognitive, or imaging end points in patients with moderate Parkinson disease¹, echoing the modest and uncertain phase 2 signal seen earlier with lixisenatide in LIXIPARK.² Together, those results argue that the most reliable neurological indications for current GLP-1 receptor agonists lie outside neurodegeneration. This review summarizes where that case is strongest.

Ischemic Stroke Prevention: The Strongest Non-Glycemic Case

Among non-glycemic indications, ischemic stroke prevention has the most mature evidence base. Cardiovascular outcome trials including LEADER, REWIND, and SUSTAIN-6 first identified reductions in non-fatal stroke incidence independent of glycemic control. A 2024 systematic review and meta-analysis of 11 cardiovascular outcome trials by Adamou and colleagues (n = 82,140) reported a 16% relative risk reduction in stroke (RR, 0.85; 95% CI, 0.77–0.93), with no heterogeneity across daily versus weekly dosing.³ A 2025 meta-analysis incorporating SELECT and FLOW reproduced the signal in mixed diabetic and non-diabetic populations.⁴

Mechanistically, GLP-1 receptors on vascular endothelium and neural tissue appear to influence oxidative stress, mitochondrial function, and neuroinflammation.⁵ Translating that biology into acute neuroprotection has proven harder. The phase 2 TEXAIS trial — the largest published randomized study of exenatide initiated in 9 hours of acute ischemic stroke — did not improve early neurological recovery (61.2% vs 56.7%; adjusted OR, 1.22; 95% CI, 0.79–1.88; P = .38), although it did reduce the frequency of post-stroke hyperglycemia without hypoglycemia.⁶ Whether GLP-1 receptor agonists can deliver acute neuroprotection in a more selected population remains an open question.

Obstructive Sleep Apnea: A Class First in Sleep Medicine

In December 2024, the FDA approved tirzepatide — a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist — for the treatment of moderate-to-severe OSA in adults with obesity, the first pharmacotherapy ever approved for OSA. Approval was supported by the SURMOUNT-OSA 1 and 2 phase 3 trials. Across both trials, tirzepatide reduced the apnea–hypopnea index (AHI) by approximately 25–30 events per hour (treatment difference vs placebo of –20 and –24 events per hour, respectively, at 52 weeks), alongside improvements in body weight, hypoxic burden, systolic blood pressure, and patient-reported sleep quality.⁷

The decision marks a paradigm shift in sleep medicine, providing the first therapy that targets the upstream pathophysiology of OSA — predominantly obesity-driven upper airway collapsibility — rather than its downstream consequences. How tirzepatide should be sequenced with positive airway pressure therapy, and whether benefit is sustained beyond the trial period, will be defined by ongoing real-world studies.

Idiopathic Intracranial Hypertension: Beyond Weight Loss

IIH is strongly linked with obesity, and a weight loss goal of approximately 10% is often disease-modifying. GLP-1 receptor agonists deliver this magnitude of weight reduction for many patients, making them natural candidates for adjunctive therapy. There is also evidence supporting a direct intracranial pressure (ICP)–lowering effect beyond weight loss. Botfield and colleagues demonstrated GLP-1 receptor expression at the rodent choroid plexus and showed that the GLP-1R agonist exendin-4 acutely reduced ICP in a rat model of hydrocephalus, with ICP approximately 35% lower in 30 minutes and the effect sustained over 24 hours.⁸

Translating those findings to patients, the phase 2 PRESSURE trial randomized women with active IIH to subcutaneous exenatide or placebo and reported telemetric ICP reductions of approximately 5.7 cm CSF at 2.5 hours, 6.4 cm CSF at 24 hours, and 5.6 cm CSF at 12 weeks, without serious safety signals.⁹ A retrospective cohort analysis of the TriNetX U.S. Collaborative Network published in JAMA Neurology in 2025 — comparing 555 propensity-matched IIH patients on GLP-1 receptor agonists with non-users, reported significant reductions in symptom burden, medication use, and procedural intervention rates,¹⁰ supporting a clinically meaningful real-world effect.

Migraine: An Emerging CGRP and Neuroinflammation Signal

Headache is a major comorbidity in IIH, and more than half of patients experience concurrent migraine. Early translational and clinical work suggests GLP-1 receptor agonists may modulate migraine pathways directly. In a nitroglycerin-induced chronic migraine mouse model, Jing and colleagues demonstrated that liraglutide downregulated calcitonin gene-related peptide (CGRP), c-fos, and PI3K/p-Akt expression in the trigeminal nucleus caudalis and reduced microglial activation.¹¹

Clinically, a 2025 prospective open-label pilot study of liraglutide as add-on therapy in 31 patients with obesity and high-frequency or chronic migraine reported a reduction in mean monthly headache days from 19.8 to 10.7 over 12 weeks (P <.001) — a nearly 50% reduction that was independent of changes in BMI.¹² If confirmed in randomized controlled trials, this would position the class alongside CGRP-targeted therapies in obesity-associated migraine.

Safety, Access, and Practical Considerations

The GLP-1 class safety profile is by now well established. Gastrointestinal effects like nausea, diarrhea, constipation, and dyspepsia are dose-dependent and most prominent at initiation, and pancreatitis remains a recognized but uncommon adverse event.¹³ Hypoglycemia risk is minimal in the absence of insulin or sulfonylurea co-therapy. Thyroid C-cell tumors observed in rodent models have not been replicated in primates, where GLP-1 receptor expression in C-cells is markedly lower.¹⁴ Ongoing pharmacovigilance has raised, but not confirmed, signals around non-arteritic anterior ischemic optic neuropathy and gallbladder disease that warrant continued surveillance. Cost, variable insurance coverage for off-label indications, and the need for sustained therapy to maintain benefit remain practical barriers.

Conclusion and Future Directions

GLP-1 receptor agonists represent an expanding class of therapeutics with significant non-neurodegenerative potential across vascular, sleep-related, intracranial pressure, and headache disorders. Strong evidence supports their role in ischemic stroke prevention and OSA, and promising early data point to meaningful benefits in IIH and migraine. Their ability to modulate weight, inflammation, vascular function, and CSF physiology provides a biologically plausible framework for broad neurological application.

Research priorities include adequately powered randomized trials of acute stroke neuroprotection in selected populations; controlled IIH and migraine studies with intracranial-pressure and headache-day end points; comparative effectiveness studies of mono-agonist versus dual GIP/GLP-1 strategies; and long-term real-world data on durability of benefit, adherence, and cost.

Disclosures

The authors report no relevant financial relationships.

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