Safety and Efficacy of Metformin for Idiopathic Intracranial Hypertension. A U.S-Based Real-World Data Retrospective Multicenter Cohort Study.
Keywords:
Idiopathic Intracranial Hypertension, Pseudotumor Cerebri, Intracranial Pressure, Metformin, Metabolic SyndromeAbstract
Introduction: Idiopathic intracranial hypertension (IIH) remains a challenging condition to manage, with limited therapeutic options. This study investigated the potential of metformin as a novel treatment for IIH, exploring its effects on disease outcomes and safety profile.
Methods: We conducted a retrospective cohort study using the TriNetX database, analyzing data from 2009 to August 2024. Patients diagnosed with IIH were included, with exclusions for other causes of elevated intracranial pressure and pre-existing diabetes. Propensity score matching was employed to balance cohorts according to age, sex, race, ethnicity, Hemoglobin A1C, and baseline body mass index (BMI) at the time of metformin initiation. Outcomes were assessed at various follow-up points up to 24 months.
Results: Our study initially comprised 1,268 patients in the metformin group and 49,262 in the control group, with notable disparities in several parameters. Post-matching, both cohorts were refined to 1,267 patients each after matching with metformin group. Metformin-treated patients showed significantly lower risks of papilledema, headache, and refractory IIH status at all follow-up points (p<0.0001). The metformin group also had reduced rates of therapeutic spinal punctures and acetazolamide continuation. BMI reductions were more pronounced in the metformin group, with significant differences observed from 6 months onward (p<0.0001). Notably, metformin's beneficial effects persisted independently of BMI changes. The safety profile of metformin was favorable, with no significant differences in adverse events compared to the control group which did not receive metformin during the study timeframe.
Conclusions: Our study provides evidence for metformin's potential as a disease-modifying therapeutic approach in IIH, demonstrating improvements across multiple outcomes. The benefits appear to extend beyond weight loss, suggesting complex mechanisms of action. These findings warrant further investigation through prospective clinical trials to establish metformin's role in IIH management and explore its underlying therapeutic mechanisms.
References
1. Mollan SP, Davies B, Silver NC, Shaw S, Mallucci CL, Wakerley BR, Krishnan A, Chavda SV, Ramalingam S, Edwards JJJoN, Neurosurgery, Psychiatry. Idiopathic intracranial hypertension: consensus guidelines on management2018: 1088
2. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013: 1159 [PMID: 23966248 10.1212/WNL.0b013e3182a55f17: 10.1212/WNL.0b013e3182a55f17]
3. Sinclair AJ, Burdon MA, Nightingale PG, Ball AK, Good P, Matthews TD, Jacks A, Lawden M, Clarke CE, Stewart PM, Walker EA, Tomlinson JW, Rauz S. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ (Clinical research ed). 2010: c2701 [PMID: 20610512 10.1136/bmj.c2701: 10.1136/bmj.c2701]
4. Manfield JH, Yu KK, Efthimiou E, Darzi A, Athanasiou T, Ashrafian H. Bariatric Surgery or Non-surgical Weight Loss for Idiopathic Intracranial Hypertension? A Systematic Review and Comparison of Meta-analyses. Obesity surgery. 2017: 513 [PMID: 27981458 10.1007/s11695-016-2467-7: 10.1007/s11695-016-2467-7]
5. Ottridge R, Mollan SP, Botfield H, Frew E, Ives NJ, Matthews T, Mitchell J, Rick C, Singhal R, Woolley R, Sinclair AJ. Randomised controlled trial of bariatric surgery versus a community weight loss programme for the sustained treatment of idiopathic intracranial hypertension: the Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) protocol. BMJ open. 2017: e017426 [PMID: 28963303 10.1136/bmjopen-2017-017426: 10.1136/bmjopen-2017-017426]
6. Wall M, McDermott MP, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, Kupersmith MJJJ. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial2014: 1641
7. Mollan SP, Aguiar M, Evison F, Frew E, Sinclair AJ. The expanding burden of idiopathic intracranial hypertension. Eye (London, England). 2019: 478 [PMID: 30356129 10.1038/s41433-018-0238-5: 10.1038/s41433-018-0238-5]
8. Mulla Y, Markey KA, Woolley RL, Patel S, Mollan SP, Sinclair AJ. Headache determines quality of life in idiopathic intracranial hypertension. The journal of headache and pain. 2015: 521 [PMID: 25982204 10.1186/s10194-015-0521-9: 10.1186/s10194-015-0521-9]
9. Schmickl CN, Owens RL, Orr JE, Edwards BA, Malhotra A. Side effects of acetazolamide: a systematic review and meta-analysis assessing overall risk and dose dependence. BMJ open respiratory research. 2020: [PMID: 32332024 10.1136/bmjresp-2020-000557: 10.1136/bmjresp-2020-000557]
10. Yri HM, Wegener M, Sander B, Jensen R. Idiopathic intracranial hypertension is not benign: a long-term outcome study. Journal of neurology. 2012: 886 [PMID: 22008872 10.1007/s00415-011-6273-9: 10.1007/s00415-011-6273-9]
11. Hornby C, Mollan SP, Botfield H, OʼReilly MW, Sinclair AJ. Metabolic Concepts in Idiopathic Intracranial Hypertension and Their Potential for Therapeutic Intervention. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2018: 522 [PMID: 29985799 10.1097/wno.0000000000000684: 10.1097/wno.0000000000000684]
12. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clinical science (London, England : 1979). 2012: 253 [PMID: 22117616 10.1042/cs20110386: 10.1042/cs20110386]
13. Botfield HF, Uldall MS, Westgate CSJ, Mitchell JL, Hagen SM, Gonzalez AM, Hodson DJ, Jensen RH, Sinclair AJ. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus. Science translational medicine. 2017: [PMID: 28835515 10.1126/scitranslmed.aan0972: 10.1126/scitranslmed.aan0972]
14. Karimy JK, Reeves BC, Damisah E, Duy PQ, Antwi P, David W, Wang K, Schiff SJ, Limbrick DD, Jr., Alper SL, Warf BC, Nedergaard M, Simard JM, Kahle KT. Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets. Nature reviews Neurology. 2020: 285 [PMID: 32152460 10.1038/s41582-020-0321-y: 10.1038/s41582-020-0321-y]
15. Łabuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopień B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacological reports : PR. 2010: 956 [PMID: 21098880 10.1016/s1734-1140(10)70357-1: 10.1016/s1734-1140(10)70357-1]
16. Lin Z, Sun L. Research advances in the therapy of metabolic syndrome. Frontiers in pharmacology. 2024: 1364881 [PMID: 39139641 10.3389/fphar.2024.1364881: 10.3389/fphar.2024.1364881]
17. Wardman JH, Andreassen SN, Toft-Bertelsen TL, Jensen MN, Wilhjelm JE, Styrishave B, Hamann S, Heegaard S, Sinclair AJ, MacAulay N. CSF hyperdynamics in rats mimicking the obesity and androgen excess characteristic of patients with idiopathic intracranial hypertension. Fluids and barriers of the CNS. 2024: 10 [PMID: 38273331 10.1186/s12987-024-00511-1: 10.1186/s12987-024-00511-1]
18. Palchuk MB, London JW, Perez-Rey D, Drebert ZJ, Winer-Jones JP, Thompson CN, Esposito J, Claerhout B. A global federated real-world data and analytics platform for research. JAMIA open. 2023: ooad035 [PMID: 37193038 10.1093/jamiaopen/ooad035: 10.1093/jamiaopen/ooad035]
19. Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, Liu J, Deng Y, Xia J, Chen B, Zhang S, Yun C, Lian G, Zhang X, Zhang H, Bisson WH, Shi J, Gao X, Ge P, Liu C, Krausz KW, Nichols RG, Cai J, Rimal B, Patterson AD, Wang X, Gonzalez FJ, Jiang C. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nature medicine. 2018: 1919 [PMID: 30397356 10.1038/s41591-018-0222-4: 10.1038/s41591-018-0222-4]
20. Hornby C, Mollan SP, Mitchell J, Markey KA, Yangou A, Wright BLC, O'Reilly MW, Sinclair AJ. What Do Transgender Patients Teach Us About Idiopathic Intracranial Hypertension? Neuro-ophthalmology (Aeolus Press). 2017: 326 [PMID: 29238388 10.1080/01658107.2017.1316744: 10.1080/01658107.2017.1316744]
21. O'Reilly MW, Westgate CS, Hornby C, Botfield H, Taylor AE, Markey K, Mitchell JL, Scotton WJ, Mollan SP, Yiangou A, Jenkinson C, Gilligan LC, Sherlock M, Gibney J, Tomlinson JW, Lavery GG, Hodson DJ, Arlt W, Sinclair AJ. A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics. JCI insight. 2019: [PMID: 30753168 10.1172/jci.insight.125348: 10.1172/jci.insight.125348]
22. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Therapeutic advances in endocrinology and metabolism. 2010: 117 [PMID: 23148156 10.1177/2042018810380215: 10.1177/2042018810380215]
23. Lv WS, Wen JP, Li L, Sun RX, Wang J, Xian YX, Cao CX, Wang YL, Gao YY. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain research. 2012: 11 [PMID: 22325091 10.1016/j.brainres.2012.01.028: 10.1016/j.brainres.2012.01.028]
24. DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism: clinical and experimental. 2016: 20 [PMID: 26773926 10.1016/j.metabol.2015.10.014: 10.1016/j.metabol.2015.10.014
Downloads
Published
Issue
Section
License
Copyright (c) 2024 ASIDE Internal Medicine
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
