What impact do GLP-1 agonists have on migraine?

What impact do GLP-1 agonists have on migraine?

Comment by InpharmD Researcher

The effect GLP-1 receptor agonists have on migraine is unclear. Scant data, primarily from small trials and animal models, suggest GLP-1 RAs may have a potential to reduce monthly migraine incidence (Table 1). However, case reports have described migraine as a possible rare adverse event.

Background

Experimental evidence from animal models and clinical trials suggests an analgesic potential of GLP-1 receptor activation in modulating pain pathways. In headache disorders, GLP-1 receptor agonists demonstrated efficacy in reducing migraine-associated trigeminovascular sensitization and lowering intracranial pressure in patients with idiopathic intracranial hypertension, with clinical trials reporting significant reductions in monthly headache days independent of weight loss. In animal models, liraglutide was shown to reduce pain mediators and inflammation linked to migraine, while GLP-1R expression was observed in the trigeminocervical complex. In a rat model, liraglutide suppressed pro-inflammatory molecules and promoted the release of anti-inflammatory cytokines, notably IL-10, alleviating migraine-associated pain. GLP-1R analogs have been investigated for their potential in weight loss and headache reduction in IIH. In a case-control pilot study [Table 1] involving 39 participants with a BMI ≥ 30 kg/m², those treated with semaglutide or liraglutide, along with standard weight management, achieved greater weight loss and fewer headache days compared to those on standard management alone. [1]

A double-blind trial reported significant reductions in intracranial pressure and headache frequency in the exenatide group compared to placebo. Notably, exenatide's effect on intracranial pressure appeared independent of weight changes, suggesting a direct action on the choroid plexus. An exploratory study found no cognitive impact from exenatide in IIH patients. However, discontinuation of GLP-1R agonists in those with metabolic disorders might lead to adverse effects, as illustrated by a case of idiopathic intracranial hypertension post-therapy cessation. Additionally, in healthy volunteers, GLP-1's vasodilatory and headache-inducing properties were deemed insignificant compared to placebo. These findings explore the therapeutic potential of GLP-1R agonists in headache disorders, although more research is needed to corroborate these effects and mechanisms. While findings suggest analgesic applications beyond metabolic disorders, further research is required to delineate the mechanistic pathways involved and assess long-term clinical safety/efficacy. [1]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What impact do GLP-1 agonists have on migraine?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-3 for your response.

Treatment with GLP-1 receptor agonists is associated with significant weight loss and favorable headache outcomes in idiopathic intracranial hypertension
Design	Open-label, single-center, case-control pilot study N= 39
Objective	To study the effect of GLP-1-RAs on weight management, headache, and visual outcomes in patients with idiopathic intracranial hypertension (IIH)
Study Groups	GLP-1-RA (n= 13) UCWM (n= 26)
Inclusion Criteria	Definite IIH according to the modified Friedman criteria, BMI ≥30 kg/m², and a follow-up of ≥ 6 months
Exclusion Criteria	Not explicitly stated
Methods	Patients with IIH and BMI ≥30 kg/m² were offered GLP-1-RA (semaglutide or liraglutide) in addition to usual care weight management (UCWM). Semaglutide was initiated at 0.25 mg per week and escalated to 2 mg per week over 16 weeks. Liraglutide was initiated at 0.6 mg per day and escalated to 3.0 mg per day over 4 weeks. Patients who did not elect to receive GLP-1 therapy served as age-, sex-, and weight-matched controls; these patients underwent UCWM consisting of dietary counselling and non-supervised physical exercise.
Duration	March 2022 to September 2022
Outcome Measures	Primary: Percentage weight loss at 6 months compared to baseline Secondary: Rate of patients with ≥ 10% weight loss, monthly headache days (MHD), rate of patients with ≥ 30% and ≥ 50% reduction in MHD, visual outcome parameters, adverse events (AEs)
Baseline Characteristics		GLP-1-RA (n= 13)	UCWM (n= 26)	p-value
	Age, years	35.1 ± 7.9	32.9 ± 8.1	0.435
	Female	12 (92.3%)	24 (92.3%)	>0.999
	Disease duration, weeks (IQR)	40.9 (11.9–105.0)	4.0 (1.0–23.0)	0.003
	CSF opening pressure, cmH2O (IQR)	28.6 ± 7.9	32.6 ± 6.1	0.129
	BMI, kg/m² (IQR)	33.5 (31.8–39.3)	35.0 (30.4–38.1)	0.803
	IQR: interquartile range
Results		GLP-1-RA (n= 13)	UCWM (n= 26)	p-value
	Mean percentage weight loss after 6 months	-12.0% ± 3.3%	-2.8% ± 4.7%	<0.001
	Weight loss ≥10% after 6 months	69.2%	4.0%	<0.001
	Median reduction in MHD after 6 months (IQR)	-4 (-10.5 to 0.5)	0 (-3 to 1)	0.02
	50% responder rate after 6 months	76.9%	40.0%	0.04
	Reduction in acetazolamide dosage after 6 months	-16.5 (-50 to 0)	0 (-25 to 50)	0.04
Adverse Events	AEs were mild or moderate and attributed to gastrointestinal symptoms in 9/13 patients. None of the AEs led to premature treatment discontinuation.
Study Author Conclusions	GLP-1-RAs are an effective and safe treatment option for achieving significant weight loss with a favorable effect on headache, leading to reduced acetazolamide dosage in patients with idiopathic intracranial hypertension.
Critique	The study suggests that GLP-1-RAs are effective for weight loss and headache improvement in IIH, but the small sample size and short follow-up period limit the generalizability of the findings. The non-randomized, open-label design may introduce bias, and differences in disease duration between groups could affect results. Longer-term studies with larger cohorts are needed to confirm these findings and assess visual outcomes.

References:

Krajnc N, Itariu B, Macher S, et al. Treatment with GLP-1 receptor agonists is associated with significant weight loss and favorable headache outcomes in idiopathic intracranial hypertension. J Headache Pain. 2023;24(1):89. Published 2023 Jul 18. doi:10.1186/s10194-023-01631-z

Hemiplegic Migraines Exacerbated using an Injectable GLP-1 Agonist for Weight Loss
Design	Case report
Case presentation	The patient was a male in his early 50s from the northeastern United States with a complex medical history including adult ADHD, narcolepsy with cataplexy, and major depressive disorder (in remission); he was managed with methylphenidate, clonidine, and fluoxetine. For the past 12 years, he experienced annual attacks characterized by heart palpitations, hemiplegic paralysis, migraines, and aura (lasting up to 24 hours), leading him to believe they were transient ischemic attacks related to an undiagnosed arrhythmia. Extensive cardiac evaluation, including 30-day heart monitoring and echocardiography, revealed a single episode of non-sustained ventricular tachycardia but otherwise normal cardiac function. Referred to a neurologist, he was diagnosed with migraine aura without headache, non-familial hemiplegic migraine, and balance impairment. Neuroimaging showed moderate cerebral white matter hyperintensities, mild cerebral atrophy, and nonspecific white matter gliosis, consistent with chronic migraine sufferers. He was prescribed ubrogepant for migraine management. The patient's dedication to health was marked by an intense exercise and diet regimen, resulting in an 85-pound weight loss, much of which was regained, likely due to "metabolic adaptation" as confirmed by a bariatric physician. He started treatment with liraglutide (Saxenda), coinciding with an increase in hemiplegic migraines to almost daily occurrences, which were mitigated with ubrogepant. After discontinuing Saxenda, migraine frequency reduced significantly to once every few months. Concerns about metabolic adaptation and side effects influenced ongoing management decisions.
Study Author Conclusions	The reported case highlights an important pharmacovigilance concern regarding GLP-1 receptor agonists, particularly for patients with preexisting neurologic conditions. In line with these findings, a phase IV clinical study utilizing FDA data on Saxenda highlighted migraines as a side effect, underscoring the intricate nature of GLP-1 agonist effects and the importance of personalized therapeutic approaches. Given the emerging evidence of neuropsychiatric and vascular adverse effects associated with these agents, the publication underscores the necessity for clinicians to consider patient-specific risk factors when prescribing GLP-1 receptor agonists, advocating for a more personalized approach to obesity and metabolic disorder management.

References:

Modestino EJ, Bowirrat A, Lewandrowski KU, et al. Hemiplegic Migraines Exacerbated using an Injectable GLP-1 Agonist for Weight Loss. Acta Sci Neurol. 2024;7(5):12-18. doi:10.31080/asne.2024.07.0731

Investigating GLP-1 Injections: Potential Mitochondrial Dysfunction in Non-Diabetic Patients Presenting with Migraines and Hypoglycemia: A Case Report
Design	Case report
Case presentation	A 43-year-old female patient with a BMI of 32 kg/m² and normal glucose levels, reflective of obesity without diabetes, sought nutritional guidance to manage energy levels and adverse effects from her semaglutide (Ozempic) prescription, including nausea and hypoglycemia. The patient’s medical history included weight gain post-pregnancy and occasional migraines with aura. Her medications included escitalopram, levothyroxine, gabapentin, and pantoprazole. Initially prescribed 0.5 mg of Ozempic, her dosage was later reduced to 0.25 mg due to side effects, and a continuous glucose monitor was recommended to track hypoglycemia. Nutritional interventions included increasing protein intake to 90 grams daily and eating frequent small meals, which stabilized her blood glucose within two weeks, eliminating the need for nighttime glucose monitoring. Despite these interventions, chronic nausea persisted, leading to a switch to 0.15 mg of Mounjaro six months later. New migraine symptoms developed after starting tirzepatide (Mounjaro); no imaging or workup was done for the migraine presentation. Due to suspected mitochondrial dysfunction, the nutritionist recommended supplements (CoQ10, D-ribose, methylated vitamin B complex, and acetyl-L-carnitine). The patient discontinued acetyl-L-carnitine due to nausea but reported significant improvement in migraine symptoms within 48 hours of beginning the other supplements, with no recurrence noted. Following dietary changes and supplement therapy, both hypoglycemia and migraine issues were effectively managed, showcasing the positive outcomes of tailored nutritional and supplemental interventions in this patient's care.
Study Author Conclusions	This case study highlighted a patient who experienced a decrease in hypoglycemic symptoms by consuming nutrient-dense meals, despite not being on GLP-1 medications. Protein intake, particularly in the evening, was crucial for maintaining stable blood sugar levels. The authors speculate that GLP-1 agonists, like exendin-4 and those derived from Gila monster saliva (i.e., exenatide), may cause mitochondrial uncoupling, altering energy metabolism by increasing resting energy expenditure and potentially triggering migraines through enhanced sirtuin enzyme activity. GLP-1 receptor activation in the medulla and hypothalamus might disrupt mitochondrial function, possibly increasing ATP synthesis and oxidative stress, leading to migraines. Although migraines are not typical side effects of these medications, increased reactive oxygen species and impaired mitochondrial function are potential causative factors. Supplementation with CoQ10, vitamin B complex, and D-ribose showed improvement in mitochondrial function and relief from migraines in the case study, suggesting these micronutrients support the electron transport chain and mitigate oxidative stress. Evidence also points to GLP-1 medications affecting cholesterol metabolism, with likely reductions in HMG-CoA reductase and SREBP-1C enzyme activity, impacting CoQ10 synthesis. This reduction could disrupt energy production, while D-ribose might help bypass enzymatic pathways to enhance ATP generation. Human studies are needed to further elucidate how GLP-1 medications affect mitochondrial activity in the central nervous system and CoQ10 metabolism.

References:

Jamail J, Knowles R, Fuller L. Investigating GLP-1 Injections: Potential Mitochondrial Dysfunction in Non-Diabetic Patients Presenting with Migraines and Hypoglycemia: A Case Report. Integr Med (Encinitas). 2024;23(6):21-25.