GLP-1RAs may provide migraine relief independent of weight loss

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have the potential to reduce the frequency of migraines even in patients who do not lose weight—an effect that may be related to a reduction in intracranial pressure, according to a pilot prospective observational study.

In a small Italian cohort of migraine patients with obesity (BMI ≥30 kg/m²), the number of headache days per month dropped by approximately half after 12 weeks of treatment with liraglutide, from 19.8 days at baseline to 10.7 days (mean difference, 9.1 days, 95 percent confidence interval [CI], 5.41–12.84; p<0.001). [Headache 2025;doi:10.1111/head.14991]

Roughly half of patients (48 percent) had at least a 50-percent reduction in monthly headache frequency, and one showed complete resolution of the headache. The severity of migraine-related disability improved, with MIDAS scores decreasing from 60.4 to 28.6 points (mean difference, 31.8, 95 percent CI, 23.72–39.82; p<0.001).

Interestingly, BMI did not significantly change across 12 weeks of liraglutide treatment (from 34 to 33.9 kg/m²; mean difference, 0.1 kg/m², 95 percent CI, −0.004 to 0.153; p=0.060).

Repeated measures analysis suggested that the reduction in headache frequency with liraglutide occurred independently of age, sex, and concomitant medications. Furthermore, in a simple linear regression model, BMI reduction was not a significant predictor of headache frequency reduction.

“These results suggest that the therapeutic effect of GLP-1RAs on migraine is independent of their weight-loss effects, and that the mechanisms driving liraglutide’s effectiveness in migraine prevention may operate independently of the significant metabolic effects GLP-1 RAs have,” said first author Dr Simone Braca from the University of Naples “Federico II”, Naples, Italy, who presented the study at EAN 2025.

Instead, the effect could be due to a reduction in intracranial pressure, Braca continued. This is consistent with recent evidence showing that GLP-1RAs are significantly more effective at reducing intracranial pressure compared with traditional treatments such as acetazolamide or topiramate, an effect that is unrelated to weight loss. [Sci Transl Med 2017;9:eaan0972; Brain 2023;146:1821-1830]

“We think that, by modulating cerebrospinal fluid pressure and reducing intracranial venous sinuses compression, GLP-1RAs suppress the release of calcitonin gene-related peptide (CGRP), a key migraine-promoting peptide,” according to Braca.

“Overall, our finding generates the hypothesis that a derangement in ICP control may play a role in migraine pathogenesis and potentially represent a new promising migraine therapeutic target. If confirmed in further randomized and controlled studies, liraglutide may represent the first migraine treatment aimed at preventing CGRP release rather than blocking its peripheral effects,” he said.

The analysis included 31 patients (mean age 44.9 years, 84 percent female), of which 87 percent had chronic migraine and 13 percent had episodic migraine. Those with papilledema, sixth nerve palsy, or pulsatile tinnitus were excluded from the study.

The patients were treated with liraglutide at 1.2 mg daily for 12 weeks. All of them were receiving background medications such as standard of care (ie, propranolol, amitriptyline, topiramate, flunarizine; 36 percent), anti-CGRP monoclonal antibodies (19 percent), or their combination (45 percent).

During the treatment period, mild adverse events (AEs) occurred in 42 percent of patients. All events were gastrointestinal in nature, including nausea and constipation, and resolved spontaneously. None of the patients discontinued treatments due to the AEs.

When asked why the patients in the study didn’t lose weight, Braca pointed out that the patients might have not made an effort to diet and exercise. While liraglutide is a powerful tool for weight loss, patients must complement it with healthy behaviours for the medication to be effective, he said.