‘Clear Advantage' of GLP-1s for IIH vs Conventional Therapy
These outcomes were achieved without a significant change in BMI, which suggests GLP-1 RAs have therapeutic benefits aside from weight loss alone.
The results reflect 'clear advantages' of GLP-1 RAs over current IIH management strategies, including surgical interventions and medications like acetazolamide, study investigator Dennis J. Rivet II, MD, professor, Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, told Medscape Medical News .
'These therapies belong in the armamentarium of medications used in IIH, and they should be considered prior to surgery,' he said.
The findings were published online on July 14, 2025, in JAMA Neurology .
Unknown Mechanism
IIH is characterized by elevated intracranial pressure (ICP) without an identifiable cause. Obesity is present in about 90% of IIH cases, with the highest incidence in women with overweight of childbearing age.
The exact mechanism linking obesity to IIH is unknown, but weight loss appears to be beneficial. Bariatric surgery, such as a gastric bypass or sleeve gastrectomy, can be an effective means of weight loss, which then may reduce the risk for IIH.
Other treatments of IIH include pharmacological agents such as acetazolamide or procedural interventions such as cerebrospinal fluid (CSF) diversion to increase CSF drainage, optic nerve sheath fenestration, and venous sinus stenting (VSS).
GLP-1 RAs, which have been around for more than a decade now, are gaining popularity for weight loss as well as type 2 diabetes. However, they're proving beneficial in other 'less obvious' disease states, including heart failure with preserved ejection fraction and liver cirrhosis. Rivet noted there's also growing interest in exploring them for addiction.
These agents are also under investigation for IIH, but efficacy data are limited.
The retrospective study analyzed deidentified electronic health records (EHRs) from adults with IIH who had not used GLP-1 RAs, using data from 67 healthcare organizations in the TriNetX US Collaborative Network.
Researchers established two cohorts: patients who initiated a GLP-1 RA within 6 months of an IIH diagnosis and a control group who started conventional therapies without GLP-1 RAs.
After propensity score matching, each group included 555 patients. Baseline characteristics were well balanced (mean age, approximately 43 years; 86% women; 54% White; about two thirds with overweight or obesity), with comparable rates of symptoms, signs, and medication use.
Outcomes included the use of medications other than GLP-1 RAs; symptoms and signs such as headache, visual disturbances or blindness, dizziness, papilledema, tinnitus, and optic atrophy; procedures, including spinal puncture, shunt placement, VSS, optic nerve decompression, and bariatric surgery; and mortality. Both groups had a median follow-up of 365 days.
Patients in the GLP-1 RA group were significantly less likely to require any medication than those in the control group (29.7% vs 56.4%; P < .001). Notable reductions were observed in the use of tricyclic antidepressants (6.8% vs 12.3%; P = .002), topiramate (11.2% vs 19.6%; P < .001), furosemide (6.8% vs 14.4%; P < .001), and acetazolamide (8.6% vs 24.0%; P < .001). Use of valproate did not differ significantly between the groups (2.7% vs 3.4%; P = .49).
The GLP-1 group also had fewer headache symptoms (12.3% vs 27.4%; P < .001), visual disturbances or blindness (7.0% vs 11.7%; P = .007), and papilledema (2.2% vs 11.5%; P < .001).
In addition, GLP-1 RA users had fewer procedures overall (6.8% vs 15.7%; P < .001). Bariatric surgery (5.4% vs 10.1%; P = .004) and CSF shunt procedures (≤ 1.8% vs 5.2%; P = .002) were significantly less frequently performed in the GLP-1 RA group. Mortality was significantly lower in the GLP-1 RA group (≤ 2.0% vs 5.0%; P = .003).
Statistical comparisons could not be made for tinnitus, optic atrophy, spinal puncture, and VSS because of small sample sizes.
'Pleasantly Surprised'
Rivet said he was 'pleasantly surprised' that the benefits of GLP-1 RAs were seen across the board.
'If you told me that it was only beneficial in reducing surgeries or only beneficial in reducing medications, that would still be important and it would be a victory, but it was beneficial for both,' he said.
He was particularly encouraged by the reduction in symptoms among GLP-1 RA users. Patients are mostly concerned about feeling better and getting their headaches under control, he said.
While it's too early to routinely recommend GLP-1 RAs for IIH without randomized controlled trials, as a surgeon Rivet said he would discuss these agents as a viable alternative to surgery with patients.
Interestingly, mean BMI remained similar between treated and control groups, suggesting benefits beyond weight loss, which appears to suggest there are alternative mechanisms for GLP-1 RA therapy.
Rivet referenced a pilot study showing a rapid reduction in ICP within 2.5 hours of GLP-1 RA administration, indicating mechanisms other than weight loss. Potential effects may include metabolic actions on the choroid plexus or hypothalamic appetite control.
GLP-1 RAs have relatively milder side effects, mainly gastrointestinal effects, than bariatric surgery. Economically, GLP-1 RAs may be less costly upfront than surgery, and prices could decrease as newer medications emerge and older agents go off-label, he noted.
Limitations of the study included potential diagnostic coding errors, lack of blinding, no differentiation among GLP-1 RA types or doses, and limited generalizability. Additionally, the study did not address whether patients discontinued GLP-1 RAs due to side effects.
Need for Further Validation
In an accompanying editorial, Nancy J. Newman, MD, of the Departments of Neurology and Neurological Surgery at Emory University School of Medicine in Atlanta, and colleagues described the findings as 'encouraging' but emphasized that well-designed studies are 'essential' given the limited data on GLP-1 RAs as monotherapy or in combination regimens for IIH.
'It is time for industry to recognize that the IIH patient population is unfortunately rapidly growing and a market worth testing with an appropriately designed clinical trial of GLP-1 RAs for IIH treatment,' they noted.
IIH is particularly challenging to study retrospectively using EHR data because it is frequently misdiagnosed — especially in women with obesity and chronic headaches, the editorialist added.
The 'extremely low' reported prevalence of papilledema among study participants raises concerns that a significant proportion of included patients may not have had true IIH. However, the editorialists acknowledged that this finding could also reflect the undercoding of papilledema, as well as IIH itself.
They expressed similar concerns about the reporting of headaches and visual disturbances, noting that systematic or consistent documentation of such symptoms in EHR data is unlikely.
The fact that participants experienced beneficial effects without a change in BMI is remarkable and supports the premise that GLP-1 RAs may offer greater therapeutic benefits beyond weight loss, Newman and colleagues noted.
They also addressed cost considerations, noting that other medications used for IIH — as well as surgical procedures, many of which fail and require repetition — are often as expensive, if not more so, than GLP-1 RAs. Moreover, these alternatives generally carry a higher risk for serious complications, they wrote.
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