From blood sugar to brain relief: GLP-1 therapy slashes migraine frequency

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Researchers at the Headache Centre of the University of Naples “Federico II” gave the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide to 26 adults with obesity and chronic migraine (defined as 15 or more headache days per month). Patients reported an average of 11 fewer headache days per month, while disability scores on the Migraine Disability Assessment Test dropped by 35 points, indicating a clinically meaningful improvement in work, study, and social functioning.

GLP-1 agonists have gained recent widespread attention, reshaping treatment approaches for several diseases, including diabetes and cardiovascular disease.² In the treatment of type 2 diabetes, liraglutide helps lower blood sugar levels and reduce body weight by suppressing appetite and reducing energy intake.^3,4,5

Importantly, while participants’ body mass index declined slightly (from 34.01 to 33.65), this change was not statistically significant. An analysis of covariance confirmed that BMI reduction had no effect on headache frequency, strengthening the hypothesis that pressure modulation, not weight loss, drives the benefit.

“Most patients felt better within the first two weeks and reported quality of life improved significantly”, said lead researcher Dr Simone Braca. “The benefit lasted for the full three-month observation period, even though weight loss was modest and statistically non-significant.”

Patients were screened to exclude papilledema (optic disc swelling resulting from increased intracranial pressure) and sixth nerve palsy, ruling out idiopathic intracranial hypertension (IIH) as a confounding factor. Growing evidence closely links subtle increases in intracranial pressure to migraine attacks.⁶ GLP-1-receptor agonists, such as liraglutide, reduce cerebrospinal fluid secretion and have already proved effective in treating IIH.⁷ Therefore, building on these observations, Dr Braca and colleagues hypothesised that exploiting the same mechanism of action might ultimately dampen cortical and trigeminal sensitisation that underlie migraine.

“We think that, by modulating cerebrospinal fluid pressure and reducing intracranial venous sinuses compression, these drugs produce a decrease in the release of calcitonin gene-related peptide (CGRP), a key migraine-promoting peptide”, Dr Braca explained. “That would pose intracranial pressure control as a brand-new, pharmacologically targetable pathway.”

Mild gastrointestinal side effects (mainly nausea and constipation) occurred in 38% of participants but did not lead to treatment discontinuation.

Following this exploratory 12-week pilot study, a randomised, double-blind trial with direct or indirect intracranial pressure measurement is now being planned by the same research team in Naples, led by Professor Roberto De Simone. “We also want to determine whether other GLP-1 drugs can deliver the same relief, possibly with even fewer gastrointestinal side effects”, Dr Braca noted.

If confirmed, GLP-1-receptor agonists could offer a new treatment option for the estimated one in seven people worldwide who live with migraine,⁸ particularly those who do not respond to current preventives. Given liraglutide’s established use in type 2 diabetes and obesity, it may represent a promising case of drug repurposing in neurology.

References:

1. Braca S, Russo C, et al. GLP-1R Agonists for the Treatment of Migraine: A Pilot Prospective Observational Study. Abstract A-25-13975. Presented at the 11^th EAN Congress (Helsinki, Finland).
2. Zheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther 2024;9(1):234.
3. Lin CH, Shao L, Zhang YM, et al. An evaluation of liraglutide including its efficacy and safety for the treatment of obesity. Expert Opin Pharmacother 2020;21(3):275-85.
4. Moon S, Lee J, Chung HS, et al. Efficacy and safety of the new appetite suppressant, liraglutide: a meta-analysis of randomized controlled trials. Endocrinol Metab (Seoul) 2021;36(3):647-60.
5. Jacobsen LV, Flint A, Olsen AK, Ingwersen SH. Liraglutide in type 2 diabetes mellitus: clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2016;55(6):657-72.
6. De Simone R, Sansone M, Russo C, Miele A, Stornaiuolo A, Braca S. The putative role of trigemino-vascular system in brain perfusion homeostasis and the significance of the migraine attack. Neurol Sci 2022;43(9):5665-72.
7. Mitchell JL, Lyons HS, Walker JK, et al. The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial. Brain 2023;146(5):1821-30.
8. Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z. Lifting The Burden: the Global Campaign against Headache. Migraine remains second among the world's causes of disability, and
   first among young women: findings from GBD2019. J Headache Pain 2020;21(1):137.

Source: News Release
European Academy of Neurology
June 20, 2025