Large-Scale Study Highlights Therapeutic Benefits of GLP-1 Receptor Agonists in Idiopathic Intracranial Hypertension

Dennis Rivet, MD

A recently published study of more than 44,000 patients with idiopathic intracranial hypertension (IIH) showed that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) offer therapeutic benefits including lowered medication use, procedures, and improved symptoms. While more prospective studies are needed to confirm these findings, the data support the potential of these medications as a management strategy.

The retrospective study identified 44,373 patients with IIH from the TriNetX US Collaborative Network who started GLP-1 RAs within 6 months of diagnosis (n = 603) and compared them with nonusers (n = 43,770) on various outcomes. After matching, the analysis included 550 patients for each group, with the GLP-1 group using the following medications: lixisenatide, albiglutide, dulaglutide, semaglutide, liraglutide, and exenatide.

Published in JAMA Neurology, results showed that those on GLP-1s were less likely to require any medication compared with the control group (29.7% vs 56.4%; P <.001), and demonstrated significantly lower mortality (≤2.0% vs 5.0%; P = .003). In addition, those on these medications had a lower prevalence of IIH symptoms such as headache (12.3% vs 27.4%; P <.001), visual disturbances/blindness (7.0% vs 11.7%; P = .007), and papilledema (2.2% vs 11.5%; P <.001).

"We know every guideline for IIH emphasizes weight loss, but getting patients to achieve it is incredibly difficult," senior author Dennis Rivet, MD, told NeurologyLive. "GLP-1 agonists are very effective for weight loss, and there’s already evidence they work on multiple systems, including the brain. Receptors in the choroid plexus, which helps regulate spinal fluid, suggest a possible direct mechanism beyond just weight loss, making them especially interesting for this disease."

Rivet, the Harold I. Nemuth Chair in Neurological Disorders at Virginia Commonweath University, believes these data hold significant implications for the use of GLP-1 RAs, which have gained attention in other areas of neurodegenerative disorders, sleep disorders, and weight loss.

In the study, those on GLP-1 RAs had fewer procedures overall (6.8% vs 15.7%; P <.001), including bariatric surgery (5.4% vs 10.1%; P = .004) and cerebrospinal fluid shunt procedures (≤1.8% vs 5.2%; P = .002) than nonusers. In terms of specific medications, investigators noticed a significant decline in use of tricyclic antidepressants (6.8% vs 12.3%; P = .002), furosemide (6.8% vs 14.4%; P <.001), and acetazolamide (8.6% vs 24.0%; P <.001). There was no change in the use of valproate (GLP-1: 2.7% vs nonusers: 3.4%; P = .49).

READ MORE: Real-World Data Points to Greater Impact of Semaglutide Over Tirzepatide in Reducing Heart Attack, Stroke Risk

"Bariatric surgery is effective in IIH, but it carries significant morbidity," Rivet noted. "What surprised us was that while surgery worked, we didn’t see the same mortality benefit. In contrast, patients on GLP-1 agonists had lower all-cause mortality at one year, which is an intriguing and unexpected finding."

A subgroup analysis stratifying patients based on body mass index (BMI)–using a benchmark of 40–was conducted, with data confirming all significant associations from the primary analysis except for dizziness, which did not differ in GLP-1 RA users and nonusers with a BMI of 40 or greater. When looking at bariatric surgery and conventional management with bariatric surgery, there were some noted differences, with bariatric surgery associated with greater weight loss in both comparisons.

Overall, the subgroup findings revealed that despite lower 1-year BMI in the surgery group, GLP-1 RA users had lower medication use, fewer symptoms/signs, and procedures. Conversely, among GLP-1 RA nonusers, bariatric surgery resulted in lower medication use and fewer symptoms/signs but required more procedures and had higher mortality. Overall, this suggested that while greater weight loss may be achieved through bariatric surgery, GLP-1 RAs may provide better outcomes through other means.

Rivet added, "A retrospective database study is a signal—it’s encouraging, but it’s not definitive. The obvious next step is a placebo-controlled trial, and I think it could be done, even in a rare condition like IIH. But the reality is many of these patients already meet on-label indications for GLP-1 use, so clinical practice may shift before such a trial is ever performed."

In terms of where else GLP-1 agonists might play a role, Rivet noted that secondary stroke prevention is an area of need that holds promise. In addition, he suggested that beyond stroke, the rapid effect of these medications on inflammatory markers could leave for potential in diseases like psoriatic arthritis and other inflammatory conditions.

REFERENCE
1. Sioutas GS, Mualem W, Reavey-Cantwell J, et al. GLP-1 Receptor Agonists in Idiopathic Intracranial Hypertension. JAMA Neurol. Published July 14, 2025. doi:10.1001/jamaneurol.2025.2020