Edward J Modestino¹*, Abdalla Bowirrat², Kai-Uwe Lewandrowski^3,4, Alireza Sharafshah⁵, Rajendra D Badgaiyan⁶, Panayotis K Thanos⁷, David Baron⁸, Catherine A Dennen⁹, Igor Elman¹⁰, Keerthy Sunder¹¹, Kevin T Murphy¹² and Kenneth Blum^2,4,8,12,13

¹Department of Psychology, Curry College, Milton, MA, USA
²Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel
³Department of Orthopaedics, Fundación Universitaria Sanitas, Bogotá, DC, Colombia
⁴Division of Personalized Pain Therapy and Education, Center for Advanced Spine Care of Southern Arizona, Tucson, AZ, USA
⁵Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
⁶Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA
⁷Behavioral Neuropharmacology and Neuroimaging Laboratory, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Clinical Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA
⁸Center for Sports, Exercise, Global Mental Health, Western University Health Sciences, Pomona, CA, USA
⁹Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA
¹⁰Department of Psychiatry, Harvard University School of Medicine, Cambridge, MA., USA
¹¹Department of Medicine, University of California, Riverside School of Medicine, Riverside, CA, USA
¹²Karma Doctors & Karma TMS, and Suder Foundation, Palm Springs, CA, USA
¹³Division of Personalized Neuromodulation, PeakLogic, LLC., Del MAR, CA., USA

*Corresponding Author: Edward J Modestino, Department of Psychology, Curry College, Milton, MA, USA.

Received: February 22, 2024; Published: April 19, 2024

Abstract

The widespread adoption of Glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity and diabetes has raised concerns about their potential adverse effects, including the induction of depression and suicide ideation. We report on a male patient in his early 50s with a complex medical history, including adult Attention-Deficit/Hyperactive Disorder, narcolepsy with cataplexy, and major depressive disorder in remission, who experienced exacerbated hemiplegic migraines after initiating treatment with an injectable GLP-1 agonist (Saxenda) for weight loss. Despite a previous history of experiencing hemiplegic migraines once or twice a year, the patient reported daily occurrences of migraines, many of which were hemiplegic, during the 60 days of GLP-1 agonist treatment. The migraines abated only upon discontinuation of the medication. This case underscores the need to carefully consider patient history and potential genetic predispositions when prescribing GLP-1 agonists, highlighting the complex interactions between these medications, existing comorbidities, and the dopaminergic and calcitonin gene-related peptide pathways. Our findings suggest that GLP-1 agonists, while beneficial for some, may pose significant risks for patients with specific genetic backgrounds or neurological conditions, calling for personalized approaches to treatment and increased awareness of potential adverse effects.

 Keywords: Hemiplegic Migraines; Injectable Glp1; Weight Loss; Adverse Effects

References

1. Li JR., et al. “Case Report: Semaglutide-associated depression: a report of two cases”. Frontiers in Psychiatry 14 (2023):
2. Blum K., et al. “Dopamine Lifespan Neuromodulation Wanted Across Brain Reward Circuitry: GWAS Meta And Pharmacogenomic Analyses; 21^ST Annual World Congress SMBT, March 15^th, (2024).
3. Trujillo J. “Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes”. Journal of Clinical Pharmacy and Therapeutics 1.1 (2020): 43-60.
4. Ard J., et al. “Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists”. Advances in Therapy 38.6 (2021): 2821-2839.
5. Shyangdan DS., et al. “Glucagon-like peptide analogues for type 2 diabetes mellitus”. Cochrane Database of Systematic Reviews 2011.10 (2011): CD006423.
6. Zheng SL., et al. “Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors with All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis”. JAMA 319.15 (2018): 1580-1591.
7. Elashoff M., et al. “Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies”. Gastroenterology 141.1 (2011): 150-156.
8. Questions and Answers-Safety Requirements for Victoza (liraglutide) [Internet]. U.S. Food and Drug Administration. FDA (2018).
9. Sodhi M., et al. “Risk of Gastrointestinal Adverse Events Associated with Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss”. JAMA 330.18 (2023): 1795-1797.
10. He L., et al. “Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials”. JAMA Internal Medicine 182.5 (2022): 513-519.
11. Woronow D., et al. “Acute Cholecystitis Associated With the Use of Glucagon-Like Peptide-1 Receptor Agonists Reported to the US Food and Drug Administration”. JAMA Internal Medicine 182.10 (2022): 1104-1106.
12. Singh S., et al. “Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study”. JAMA Internal Medicine 173.7 (2013): 534-539.
13. Sodhi M., et al. “Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss”. JAMA (2023).
14. Halfdanarson TR and Pannala R. “Incretins and risk of neoplasia”. BMJ 346 (2013): f3750.
15. Cohen D. “Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?” BMJ 346 (2013): f3680.
16. Butler AE., et al. “Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors”. Diabetes 62.7 (2013): 2595-2604.
17. Egan AG., et al. “Pancreatic safety of incretin-based drugs--FDA and EMA assessment”. The New England Journal of Medicine 370.9 (2014): 794-797.
18. Brooks M. “FDA Sides with EMA on Incretin Diabetes Drugs” (2013).
19. Boess F., et al. “Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man”. Journal of Molecular Endocrinology 50.3 (2013): 325-336.
20. Bjerre Knudsen L., et al. “Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation”. Endocrinology 151.4 (2010): 1473-1486.
21. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OZEMPIC^® safely and effectively. See full prescribing information for OZEMPIC. OZEMPIC (semaglutide) injection, for subcutaneous use Initial U.S. Approval: 2017 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning (2023).
22. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TRULICITY safely and effectively. See full prescribing information for TRULICITY. TRULICITY (dulaglutide) injection, for subcutaneous use (2023).
23. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VICTOZA safely and effectively. See full prescribing information for VICTOZA. VICTOZA^® (liraglutide) injection, for subcutaneous use Initial U.S. Approval: 2010 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning (2023).
24. Pradhan R., et al. “Exendin-based glucagon-like peptide-1 receptor agonists and anaphylactic reactions: a pharmacovigilance analysis”. The Lancet Diabetes and Endocrinology 8.1 (2020): 13-14.
25. Bjerre Knudsen L., et al. “Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation”. Endocrinology 151.4 (2010): 1473-1486.
26. Filippatos TD and Elisaf MS. “Effects of glucagon-like peptide-1 receptor agonists on renal function”. World Journal of Diabetes 4.5 (2013): 190-201.
27. Johansen OE and Whitfield R. “Exenatide may aggravate moderate diabetic renal impairment: a case report”. British Journal of Clinical Pharmacology 66.4 (2008): 568-569.
28. López-Ruiz A., et al. “Acute renal failure when exenatide is co-administered with diuretics and angiotensin II blockers”. Pharmacy World and Science 32.5 (2010): 559-561.
29. Leehey DJ., et al. “Acute Kidney Injury Associated With Semaglutide”. Kidney Medicine 3.2 (2021): 282-285.
30. Kaakeh Y., et al. “Liraglutide-induced acute kidney injury”. Pharmacotherapy 32.1 (2012): e7-11.
31. Vallatharasu Y., et al. “Severe, prolonged thrombocytopenia in a patient sensitive to exenatide”. American Journal of Hematology 94.3 (2019): E78-E80.
32. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BYETTA safely and effectively. See full prescribing information for BYETTA. BYETTA ® (exenatide) injection, for subcutaneous use Initial U.S. (2005).
33. EMA statement on ongoing review of GLP-1 receptor agonists (2023).
34. Robin Respaut CT. “Wegovy. Other weight-loss drugs scrutinized over reports of suicidal thoughts” (2023).
35. Tobaiqy M and Elkout H. “Psychiatric adverse events associated with semaglutide, liraglutide and tirzepatide: a pharmacovigilance analysis of individual case safety reports submitted to the EudraVigilance database”. International Journal of Clinical Pharmacy (2024).
36. Blum KE and Kozlowski GP. “Ethanol and neuromodulator interactions: a cascade model of reward”. Alcohol and Social Behavior (1990): 131-149.
37. Perez-Montes DE Oca A., et al. “Obesity and GLP-1”. Minerva Endocrinology (Torino) 46.2 (2021): 168-176.
38. Andreadis P., et al. “Semaglutide for type 2 diabetes mellitus: A systematic review and meta-analysis”. Diabetes, Obesity and Metabolism 20.9 (2018): 2255-2263.
39. Htike ZZ., et al. “Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis”. Diabetes, Obesity and Metabolism 19.4 (2021): 524-536.
40. Gerstein HC., et al. “REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial”. Lancet 394.10193 (2019): 121-130.
41. Marso SP., et al. “SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes”. The New England Journal of Medicine 375.19 (2016): 1834-1844.
42. Marso SP., et al. “LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes”. The New England Journal of Medicine 375.4 (2016): 311-322.
43. Kanie T., et al. “Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis”. Cochrane Database of Systematic Reviews 10.10 (2021): CD013650.
44. Suchankova P., et al. “The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence”. Translational Psychiatry 5.6 (2015): e583.
45. Hernandez NS., et al. “GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA”. Molecular Psychiatry 26.8 (2021): 4394-4408.
46. Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, Brychta R, Chen KY, Skarulis MC, Walter M, Walter PJ, Hall KD. Persistent metabolic adaptation 6 years after "The Biggest Loser" competition. Obesity (Silver Spring). 2016 Aug;24(8):1612-9. doi: 10.1002/oby.21538. Epub 2016 May 2. PMID: 27136388; PMCID: PMC4989512
47. Saxenda and Migraine - A phase IV clinical study of FDA Data. eHealthMe. (n.d.-b).

Citation

Citation: Edward J Modestino., et al. “Hemiplegic Migraines Exacerbated using an Injectable GLP-1 Agonist for Weight Loss”. Acta Scientific Neurology 7.5 (2024): 12-18.

Copyright

Copyright: © 2024 Edward J Modestino., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.