Migraine is a neurological disorder characterised by recurrent headache attacks of moderate-to-severe pain intensity lasting 4 to 72 h when untreated. It is often accompanied by increased sensitivity to light, noise, and odours or gastrointestinal disorders such as nausea or vomiting (1).

Migraine affects over 1 billion people worldwide, with a higher prevalence in women (3:1 ratio to men), often beginning at puberty and mostly affecting those aged 35–39 years old (2). Depending on the monthly frequency of the attacks, episodic migraine (EM) is defined as a headache occurring <15 days per month, while chronic migraine (CM) is defined as a headache occurring ≥15 days per month, of which at least 8 days meet the criteria for a migraine attack and/or respond to acute migraine-specific medication (3, 4).

Migraine therapy can be acute and/or preventive treatments. The acute therapy restores patient’s functional status by aborting the headache stage and associated symptoms of migraine (5). On the other hand, the preventive therapy aims to decrease the frequency, severity, and duration of migraine attacks (6–8). The decision to start with preventive treatment must be individualised, and is indicated when the attacks are frequent and disabling, the patients’ quality of life is impaired or when acute treatments are not sufficiently effective or not well tolerated (5). In this context, the insufficient efficacy and tolerability of traditional treatments for migraine has prompted the search for new therapeutic strategies for the preventive treatment of migraine such as monoclonal antibodies (mAb) against the calcitonin gene-related peptide (CGRP) receptor (erenumab) or against CGRP ligand (eptinezumab, fremanezumab and galcanezumab) or gepants (9–16). The recent commercialization by the Spanish authorities of anti-CGRP therapies, including galcanezumab, has allowing many investigators and industry to collect data in real-world settings.

The latest update of the European Headache Federation (EHF) guidelines as well as the American Headache Society position statement update suggest using mAb against the CGRP pathway and gepants as a first line treatment option for those patients who require a preventive treatment (15, 17). In Spain, preventive treatments such as anti-CGRP mAbs are recommended in patients who suffer ≥4 migraine attacks per month and previous treatment failures (18, 19).

Galcanezumab was authorised in the European Union in November 2018 indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month (20). However, the Spanish National Health System (NHS) decided full reimbursement would be for those patients with >8 or more monthly migraine days (MMDs) and > 3 or more failures of previous treatments used with sufficient doses for at least 3 months (including botulin toxin; onabotulinumtoxin A [OnabotA] in patients with CM) (21).

Even though there is a growing body of real-world data examining galcanezumab’s effectiveness and safety in migraine prevention, a comprehensive analysis of its utilisation within the Spanish population remains a notable gap in the literature. The purpose of this systematic literature review is to provide an in-depth analysis of the available evidence regarding galcanezumab’s use for migraine prevention, including effectiveness, safety, treatment patterns, and patient-reported outcomes. Through this review, we seek to facilitate evidence-based decision-making and enhance understanding of galcanezumab’s potential role in preventing the burden of migraine within the Spanish adult population.

A systematic review of the literature was conducted following the recommendations included in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane guidelines (22, 23).

In the present study, we systematically and comprehensively reviewed the existing real-world evidence on the use of galcanezumab in Spain. Since 2020, a total of 29 publications were identified encompassing a population of 2,592 Spanish patients with migraine. Notably, studies from the Galca-Only consortium are contributing to the understanding of the use of galcanezumab in our country as more than one third of these patients were enrolled in this study.

Our review shows that in Spain, patients treated with galcanezumab are mostly women with a range of a mean age of 43.6–56.0 years and who present mostly CM, which reflect the sociodemographic characteristics previously reported for the worldwide population with migraine, except for the higher prevalence of CM, reflective of Spanish uptake of this treatment, starting in more severely affected patients (2). The studies frequently described MOH, reported in up to 66% of patients when it was not an inclusion criterion. This is in line with migraine being described as the most common risk factor associated with MOH, affecting 78% of patients (35). Fortunately, recent studies have shown that the use of anti-CGRP mAbs was effective in this subpopulation (36–38).

In the reviewed studies, patients treated with galcanezumab showed a reduction in MMDs, monthly headache days, HIT-6 score and MIDAS score as early as 3 months after treatment initiation. These improvements were generally maintained or further enhance in responsive patients at 6 and 12 months. These findings indicate that the outcomes of galcanezumab in Spanish clinical practice are consistent with those observed in clinical trials and align with the results reported in previous real-world studies conducted in other countries (39–45). This demonstrates the effectiveness of galcanezumab in a variety of patients with CM and EM.

In an international context, it is noteworthy to mention the multicentre prospective cohort GARLIT study, which has reported on the galcanezumab use and its effectiveness in a real-life setting among Italian patients (46–51). While some studies reported the percentage of responders reducing 30% and/or 50% of monthly headache days, it remains challenging to draw definitive conclusions due to variations in patient populations and differing cut-off points (32, 33, 52–58). Summarising the results within a specific range or in a concise manner is particularly difficult.

Nonetheless, recent evidence suggests the need for a paradigm shift in the use of CGRP antagonists, such as galcanezumab, from being last-line treatments to becoming primary options in migraine management. The largest real-world study to date (59) found that patients with fewer migraine days and lower disability at baseline are more likely to respond well to treatment. This underscores the importance of initiating anti-CGRP therapy earlier to improve patient outcomes.

Regarding galcanezumab safety, it was suggested as a well-tolerated therapeutic option for patients with migraine since no serious AEs were reported. Treatment discontinuation due to inadequate tolerability occurred in <7% of cases (60). In our review, constipation was the most reported AE with heterogeneous prevalence ranging from 4 to 44%. Constipation frequency was also heterogeneous in previously published real-world studies; while is commonly reported as the most frequent AEs in some of these studies including all CGRP antagonists (39, 40, 48, 61), the majority of the studies reported injection site reaction as the most common AEs, with a frequency ranging from 8 to 34.6% (42–44). Other mild AEs such as dizziness, fatigue (42, 46, 60, 61) and nausea or vomiting (39) were reported. In general, these events occurred mainly in the first months and then tended to be resolved.

Treatment persistence rate observed in the reviewed studies was up to 59.8% at 12 months, a bit lower than the recent evidence published in Spain that is up to 71.4% (60). Although conclusions should be drawn with caution due to the mandatory discontinuation at 12 months in Spain that could influence this result and the same in other studies. Discontinuation was reported around 20–30%, and mostly due to ineffectiveness or improvement of the disease. Regarding the treatment discontinuation due to the positive disease progression, some studies showed that galcanezumab treatment effect was reduced during the post-treatment suspension period, decreasing over time, but not returning to baseline, in addition to patients not experiencing unexpected AEs (48, 62, 63). This information may be useful when treatment is stopped for a variety of reasons. Discontinuation due to AEs was low, revealing the good tolerability of galcanezumab. Data on discontinuation rates in other countries in the literature are scarce and heterogeneous and vary from approximately 3% (42, 64) at 3 months to 50, 43, and 32% at 6, 9 and 12 months, respectively (64).

In our systematic review, the maximum treatment duration reported was of 1 year, as it was the maximum follow-up time (28). However, it was suggested that patients with a higher baseline MMDs could be considered suitable candidates for continuing treatment for longer (28), which would allow the consolidation of the improvement before discontinuation (17). In line, Núñez-Lozano et al. (27) reported that galcanezumab demonstrated a high level of persistence in patients with severe migraine, particularly in those with CM and a history of multiple prior preventive treatments up to 12 months. Although clinical trials report similar efficacy between the different mAbs available, switching in clinical practice is recorded. Switching between erenumab and galcanezumab appeared to be slightly more frequent, although this may be due to the fact that they were marketed first in Spain, and therefore most data refer to this change in mechanism. Moreover, switching between mAb anti-CGRP in selected patients may be an option, although more studies would be required to establish the effectiveness of switching these treatments (65, 66).

Regarding concomitant treatments, OnabotA is the most frequently reported treatment, in line with previously published studies (67). A synergistic benefit of the two treatments is displayed, although evidence does not clearly state whether the concomitant preventive treatment is slowly titrated out or whether they are regular migraine therapies (67). The EHF (17) and SEN (68) guidelines recommend considering combination therapy for each individual situation.

Finally, Spanish patients reported increased global satisfaction with galcanezumab as well as decreased levels of anxiety and depression symptoms at 12 and 24 weeks after treatment initiation (31). These results are similar to those reported by Guerzoni et al., observing that HADS-A and HADS-D scores were significantly reduced in Italian patients with CM treated with galcanezumab (48). This might be due to the effect of galcanezumab on migraine relief, as has already been suggested by these authors, and the enhancement of the overall well-being and quality of life in individuals with migraines (69).

However, none of the studies in this review report health related quality of life using either generic or disease-specific questionnaires, such as the MSQ (Migraine Specific Quality of Life) questionnaire. While the exact cause remains unclear, this could be due to several factors, including the limited routine use of these measures in clinical practice or the lack of full integration of these assessments in observational research studies. Another possibility, as suggested by previous studies (70), is that current scales do not fully capture the multifaceted experience of living with migraine. Tools such as MIDAS and HIT-6, among others, has its advantages, but also significant limitations. These scores are often used as benchmarks for headache frequency or severity but do not consider other important aspects, such as the inter-ictal periods during which patients may still experience the broader impacts of the disease. This makes it challenging to accurately measure the full burden of migraine, especially given the irregular and variable nature of the condition. Therefore, it would be helpful to develop more comprehensive tools to better assess migraine-related disability, as well as to emphasise the collection of disease-specific health related quality of life data in future studies. Our review presents some limitations. First, a large number of conference abstracts were reviewed, and the information provided in them was reduced. In addition, most included studies were single-centre representing specific Spanish regions. However, considering that most of the Spanish regions were covered and multicentre national studies were also reviewed, the results may reflect the current situation of Spanish patients with migraine treated with galcanezumab. Additionally, although there are a few studies assessing the effectiveness of galcanezumab against other mAb anti-CGRP, these studies have a descriptive design, and therefore the comparative data are still missing.

In conclusion, this systematic literature review of real-world studies in Spanish patients with migraine treated with galcanezumab highlights the effectiveness of this treatment while being a well-tolerated therapeutic option.