Introduction: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure, predominantly affecting obese women of reproductive age. While GLP-1 receptor agonists have shown promise in IIH management, the potential of dual GIP/GLP-1 receptor activation through tirzepatide remains unexplored. This study aimed to evaluate tirzepatide's efficacy as an adjunctive therapy in IIH management. Methods: We conducted a retrospective cohort analysis using the TriNetX Global Health Research Network, analyzing data through November 2024. Through propensity score matching, we compared 193 tirzepatide-exposed IIH patients with 193 controls receiving standard care. Primary outcomes included papilledema severity, visual function, headache frequency, and treatment resistance, monitored at multiple follow-up timepoints. Results: Our analysis revealed significant improvements across all measured outcomes in the tirzepatide group. At 24 months, we observed a 68% reduction in papilledema risk (RR 0.320, 95% CI 0.189-0.542, p<0.001), a 73.9% reduction in visual disturbance and blindness risk (RR 0.261, 95% CI 0.143-0.477, p<0.001), and a 19.7% reduction in headache risk (RR 0.803, 95% CI 0.668-0.966, p=0.019). The tirzepatide group demonstrated significant body-mass index reductions, reaching -1.147 kg/m^2 (95% CI [-1.415, -0.879], p<0.001) at 24 months compared to controls. Conclusions: Our results demonstrate that tirzepatide, when used as an adjunctive therapy, provides significant therapeutic benefits in IIH management, particularly in improving papilledema and visual outcomes. Our findings suggest that dual GIP/GLP-1 receptor activation may offer advantages over traditional single-receptor therapies, potentially through enhanced metabolic regulation and direct effects on intracranial pressure dynamics.

The project described was supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through CTSA award number: UM1TR004400. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

The project described was supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through CTSA award number: UM1TR004400. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All used data is available within TriNetX database platform.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All used data is available within TriNetX database platform.