1. 2026;29;75-82Real-World Insights into Dual Calcitonin Gene-Related Peptide (CGRP) Therapies for Chronic Migraine: A Retrospective Review
   Retrospective Study
   Ho Hyun Lee, ., Anita J. Cheung, MPH, Anson Y. Lee, ., Julia R. Jahansooz, MS, Edward J. Weldon, ., Kyle M. Ishikawa, MD, Reyn Yoshioka, ., Man Ian Woo, ., Lana Liquard, ., Eonjung Angeline Kim, MD, Enrique Carrazana, MD, and Kore K. Liow, MD.

BACKGROUND: Patients on regimens of a single calcitonin gene-related peptide (CGRP) may show a delayed response to migraine symptoms. Individuals on such regimens may not even exhibit a reduction of migraine symptoms within a reasonable time frame. Some clinicians have elected to combine small-molecule antagonists (SMAs) and ligand monoclonal antibodies (L-mAbs) to target CGRP molecules and receptors for the purpose of potentially providing increased synergistic relief.

OBJECTIVES: This study aimed to compare the safety and effectiveness of dual-CGRP therapy for patients receiving combined synergistic SMA and L-mAb to the safety and effectiveness of mono-CGRP treatment.

STUDY DESIGN: A retrospective matched cohort study.

SETTING: This study was conducted at a single neurological center in the United States. 

METHODS: A retrospective matched cohort study at a neurological care center analyzed 90 chronic migraine patients who were aged >= 18 years and treated with CGRP inhibitors (L-mAbs: fremanezumab, galcanezumab, eptinezumab; SMAs: ubrogepant, rimegepant, atogepant; or a combination) between May 2018 and February 2024. The study compared 27 patients receiving dual L-mAb and SMA CGRP treatments with 63 patients receiving mono-L-mAb or mono-SMA CGRP treatments, matched by age and gender. Variables included current age, age at diagnosis, gender, onabotulinumtoxinA use, headache frequency, duration, severity, and associated symptoms before the treatment and 3 months after it. Adverse events were recorded for both treatment groups. All hypothesis tests were two-tailed and considered significant at a P-value < 0.05.

RESULTS: Dual-CGRP therapy reduced headache severity by 20%, in contrast to the 10% reduction seen with mono-CGRP therapy (P = 0.039). Patients receiving dual-CGRP therapy also experienced an average reduction of 4 headache days, with some patients experiencing up to 14 fewer days, while mono-CGRP patients showed no change; however, this finding was not statistically significant (P = 0.112). No significant differences in other migraine-associated symptoms were found between the groups. Adverse events in the mono- and dual-CGRP groups were mild, with no serious adverse events or discontinuations reported.

LIMITATIONS: Limitations of our study include a relatively small sample size, the study’s retrospective design, the absence of newer CGRP agents, an inability to control confounders, and the predominant use of a few CGRP inhibitors among patients.

CONCLUSION: Dual-CGRP regimens may enhance migraine symptom control by reducing headache severity without causing significant adverse events. However, these findings need confirmation through randomized, placebo-controlled clinical trials that use larger sample sizes. 

KEY WORDS: Calcitonin gene-related peptide, calcitonin gene-related peptide inhibitors, headache, migraine, monoclonal antibodies, small molecule antagonist