Effectiveness and tolerability of liraglutide as add-on treatment in patients with obesity and high-frequency or chronic migraine: A prospective pilot study

Abstract

Objective: To assess whether glucagon-like-peptide-1 receptor (GLP-1R) agonists could serve as a novel prophylactic treatment for migraine in patients with obesity.

Background: Increased intracranial pressure (ICP) is speculated to play a role in migraine mechanisms, as chronic migraine and idiopathic intracranial hypertension without papilledema (IIWHOP) are often clinically indistinguishable. These striking similarities suggest a deep pathogenetic link between the two conditions posing the hypothesis that control of ICP may be helpful in migraine treatment. The GLP-1R agonists have been shown to greatly reduce ICP. Notably, they have also been demonstrated to decrease calcitonin gene-related peptide expression in chronic migraine models.

Methods: This was a prospective, interventional, open-label, pilot cohort study, evaluating the effectiveness of liraglutide as an add-on treatment of unresponsive migraine in patients with obesity. We consecutively enrolled patients with high-frequency or chronic migraine and a body mass index (BMI) of >30 kg/m², and unresponsive to at least two preventive treatments. We excluded patients with papilledema, sixth nerve palsy, or pulsatile tinnitus, to rule out patients in which idiopathic intracranial hypertension could be clinically suspected. Liraglutide was administered 1.2 mg daily. The study was conducted from January to July 2024, with a 12-week follow-up period. The primary outcome of this study was the reduction of monthly days with headache after 12 weeks of treatment with liraglutide compared to baseline.

Results: We enrolled 31 patients (26 females, five males, with a mean [standard deviation, SD] age of 44.9 [14.6] years). The mean (SD) monthly days with headache decreased from 19.8 (6.7) to 10.7 (7.7) days post-treatment. This change was significant with a mean difference of 9.1 days (95% confidence interval [CI] 5.41-12.84, p < 0.001, Cohen's d: 0.90). Conversely, BMI decreased slightly from a mean (SD) of 34.0 (2.3) to 33.9 (2.3) kg/m², and this change was not significant (mean difference = 0.1 kg/m², 95% CI -0.004 to 0.153 kg/m², p = 0.060, Cohen's d: 0.34). Analysis of covariance indicated that age, sex, and concomitant medications did not significantly influence headache frequency reduction (all p > 0.050). Simple linear regression analysis showed that BMI reduction did not significantly predict headache frequency reduction (β = -1.448, 95% CI -19.390 to 16.495, p = 0.870, R² = 0.001), indicating no meaningful relationship between the two variables.

Conclusion: Our findings show that liraglutide may be effective in the treatment of unresponsive high-frequency or chronic migraine in patients with obesity, and that this effect is independent from weight loss. Although further studies are needed to clarify this topic, these findings generate the hypothesis that a derangement in ICP control may play a role in migraine pathogenesis and potentially represent a novel therapeutic target.

Keywords: calcitonin gene‐related peptide; chronic migraine; glucagon‐like‐peptide‐1 receptor; intracranial pressure; liraglutide; migraine.