SAFE-CGRP Study: multicenter retrospective evaluation of the safety of CGRP pathway–targeting monoclonal antibodies in migraine with relevant comorbidities or conditions excluded from trials

Cristina Sanabria Gago¹Iris Fernández Lázaro¹Patricia Heredia¹Antonio Sanchez Soblechero²Alberto Lozano Ros²Elisa Luque Buzo²Yesica González Osorio³Angel Guerrero-Peral³Alicia Gonzalez-Martinez⁴David García-Azorín⁵Germán Latorre⁶Carlos Calle⁶Daniel Toledo-Alfocea⁷Javier Casas Limón⁸Sarai Urtiaga Valle⁹Marta González Salaices⁹Guillermo Martín Ávila¹⁰Rodrigo Terrero Carpio¹⁰Julio Pascual¹¹Vicente González-Quintanilla¹¹Jorge Madera¹¹Marcos Polanco¹²Jaime Rodriguez Vico¹³Alex Jaimes¹³Andrea Gómez García¹³María Luz Cuadrado^14,15Ana Beatriz Gago-Veiga^1*

• ¹Headache Unit. Neurology Department. Hospital Universitario La Princesa, Madrid, Spain
• ²Headache Unit, Department of Neurology, Hospital General Universitario Gregorio Marañón, Madrid, Spain., Madrid, Spain
• ³Headache Unit, Department of Neurology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain, Valladolid, Spain
• ⁴Departments of Neurology and Immunology, Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Madrid, Spain., Madrid, Spain
• ⁵Headache Unit, Department of Neurology, Hospital Universitario Río Hortega de Valladolid, Valladolid, Spain., Valladolid, Spain
• ⁶Headache Unit, Department of Neurology, Hospital Universitario de Fuenlabrada,, Fuenlabrada, Spain
• ⁷Headache Unit, Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain, Madrid, Spain
• ⁸Headache Unit, Department of Neurology, Hospital Universitario Fundación Alcorcón, Alcorcón, Spain
• ⁹Headache Unit, Department of Neurology, Hospital de Torrejón, Torrejón, Spain
• ¹⁰Headache Unit, Department of Neurology, Hospital Universitario de Getafe,, Getafe, Spain
• ¹¹Headache Unit, Department of Neurology, Hospital Universitario Marqués de Valdecilla, Santander, Spain
• ¹²Headache Unit, Department of Neurology, Hospital Universitario Marqués de Valdecilla, Madrid, Spain
• ¹³Headache Unit, Department of Neurology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain., Madrid, Spain
• ¹⁴Headache Unit, Department of Neurology, Hospital Universitario Clínico San Carlos,, Madrid, Spain
• ¹⁵Complutense University of Madrid,, Madrid, Spain

Introduction: Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) have shown efficacy in the treatment of migraine. However, certain comorbidities have been excluded from clinical trials or may pose potential risks, despite not being formal contraindications. This study aimed to assess the safety of anti-CGRP or anti-CGRP receptor mAbs in real-world patients with such conditions. Methods: A retrospective multicenter study was conducted across 11 headache units in Spain. Patients with relevant or trial-excluded comorbidities who received at least one anti-CGRP or anti-CGRP receptor mAb were included. Results: Of 2,042 evaluated patients, 353 had at least one comorbidity. The mean treatment duration was 12.7 months (standard deviation [SD] = 8 months). A total of 53 conditions were included: 202 had autoimmune diseases, 163 presented vascular risk factors or diseases (body mass index [BMI] >30: 15.2%, diabetes: 5.38%, stroke/transient ischemic attack (TIA): 3.08%, cardiac ischaemic disease: 1.44%), of which 23 had moderate-to-high cardiovascular risk (Framingham scale); 23 had pulmonary diseases, 71 had a history of cancer, 12 were immunosuppressed, and 16 had other conditions. In 12% of cases, disease control was suboptimal after treatment initiation, without a causal relationship to the mAb. A possible treatment-related worsening was observed in 14 cases: four with arterial hypertension worsening, seven with Raynaud’s syndrome, two with arthritis flares, and one hereditary angioedema. No severe adverse events were reported. Discussion: In this study, treatment with monoclonal antibodies acting on the CGRP pathway showed a favorable safety profile in patients with complex clinical conditions not represented in clinical trials, with no serious adverse events observed during extended follow-up. These findings support their use in real-world clinical settings, although further studies are needed to confirm their long-term safety.