PHARMACOLOGICAL ASSOCIATION OF ATOGEPANT AND TIRZEPATIDE: PRELIMINARY CLINICAL SAFETY PROFILE IN A CASE SERIES

S. Sorrenti¹, M. Ciuffreda¹, E. Pisello¹, C. Pellegrino², A. Monacelli², G. Cucè³, C. Piangatelli¹, D. Galante⁴ | ¹U.O.C. Anestesia Rianimazione Terapia del Dolore, AST Ancona, Fabriano (AN), Italy; ²Scuola di Specializzazione in Anestesia Rianimazione, Terapia Intensiva e del Dolore, Università Politecnica delle Marche, Ancona, Italy; ³Scuola di Specializzazione in Igiene e Medicina Preventiva, Università degli Studi di Messina, Italy; ⁴U.O.C. Anestesia e Rianimazione, ASL Foggia, Cerignola (FG), Italy

Introduction. Tirzepatide is indicated, in combination with calorie restriction and physical activity, for the treatment of obesity and overweight with weight-related comorbidities. It is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for the preventive treatment of migraine in adults with at least four migraine days per month (1,2). Evidence regarding the safety of the concomitant use of these two drugs is currently scarce.
Methods. We conducted a preliminary observational case series including five non-diabetic women aged 35–45 years with migraine without aura and obesity (BMI 30–32 kg/m²). All patients had been receiving atogepant 60 mg once daily for at least one month before starting tirzepatide. Tirzepatide was initiated at 2.5 mg subcutaneously once weekly and increased to 5 mg weekly after four weeks according to routine clinical practice. Patients were followed jointly by a Headache Center and a dietitian while adhering to a hypocaloric diet and regular physical activity. The primary endpoint was the clinical safety of the drug combination. Secondary outcomes included changes in migraine-related disability assessed using the MIDAS questionnaire.
Results. No clinically relevant adverse events attributable to the concomitant administration of atogepant and tirzepatide were observed during follow-up. No patient discontinued treatment because of adverse events. The combination was well tolerated in all five patients. Progressive body weight reduction was observed in all subjects. Migraine-related disability improved or remained stable after tirzepatide initiation, with MIDAS grades improving from baseline in all patients. No clinical findings suggested pharmacological interactions between the two therapies.
Conclusions. In this preliminary case series, the concomitant administration of atogepant and tirzepatide showed a favorable short-term safety profile, with no emerging safety signals or treatment-limiting adverse events. Both therapies maintained their expected clinical effectiveness during combined administration. Although these findings are encouraging, the small sample size, short follow-up, and absence of a control group preclude definitive conclusions. Larger prospective studies are warranted to better define the safety profile of this pharmacological association.