Safety and Efficacy of Metformin for Idiopathic Intracranial Hypertension: A U.S.-Based Real-World Data Retrospective Multicenter Cohort Study

Introduction

The current standard of care for idiopathic intracranial hypertension (IIH) focuses on reducing intracranial pressure (ICP) and preserving visual function [¹,²]. Weight loss remains the cornerstone of therapy, with studies demonstrating significant improvements in ICP and clinical outcomes following a 5-10% reduction in body weight [³,⁴]. The Idiopathic Intracranial Hypertension Weight Trial (IIH: WT) provided Class I evidence that bariatric surgery is superior to community weight management programs in reducing ICP and improving quality of life [⁵]. Pharmacological management primarily involves acetazolamide, a carbonic anhydrase inhibitor that decreases cerebrospinal fluid (CSF) production. The landmark Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) established acetazolamide’s efficacy in improving visual field function and reducing ICP when combined with a low-sodium weight reduction diet [⁶]. Other therapeutic approaches include topiramate, which offers the dual benefit of ICP reduction and migraine prophylaxis, and surgical interventions such as CSF diversion procedures or optic nerve sheath fenestration for medically refractory cases [⁷].

Despite these interventions, the management of IIH remains challenging, with a considerable proportion of patients experiencing refractory or recurrent disease [⁸]. Refractory IIH is defined as persistent or worsening symptoms and signs (including headaches, papilledema, and visual outcomes) despite maximal medical therapy (usually consisting of weight loss interventions and maximum tolerated doses of acetazolamide) for at least three months. Recurrent disease refers to the return of IIH symptoms and signs after a period of remission, often requiring reinitiation or intensification of therapy [⁸]. Many patients struggle to achieve or maintain weight loss, particularly through non-surgical means. The side effect profile of acetazolamide, including paresthesia, dysgeusia, and fatigue, often limits its long-term use or dose escalation [⁹]. Furthermore, a significant proportion of patients experience a plateau in their clinical improvement or require multiple interventions to maintain remission [¹⁰]. The lack of targeted therapies addressing the underlying pathophysiology of IIH, particularly the complex interplay between adipose dysfunction, CSF dynamics, and metabolic dysregulation, has hindered progress in disease modification and long-term outcomes [¹¹].

The latest evidence from the literature has highlighted the unmet need for novel treatment approaches for IIH. Metformin, a biguanide antidiabetic agent, has demonstrated pleiotropic effects beyond glucose control, including modulation of adipose tissue function and reduction of CSF secretion [¹²]. Preclinical studies have shown that metformin can lower ICP through AMP-activated protein kinase (AMPK)-dependent inhibition of Na+/K+-ATPase at the choroid plexus, suggesting a direct mechanism for CSF production reduction [¹³]. This effect is particularly intriguing given the recent evidence implicating choroid plexus hypersecretion in IIH pathogenesis [¹⁴]. Additionally, metformin’s effects on weight loss, insulin sensitivity, and adipokine profiles may address key pathogenic factors in CSF disorders such as hydrocephalus in rodent models, offering a potential approach to related disease management in certain phenotypes [¹⁵] Figure 1.

The potential of metformin in IIH is further supported by its established safety profile and its ability to mitigate components of metabolic syndrome [¹⁶], which are increasingly recognized as contributors to IIH pathophysiology [¹⁷]. To address this knowledge gap and explore metformin’s potential as a disease-modifying therapy for IIH, we are conducting a multicenter, retrospective cohort study utilizing the TriNetX database. This large-scale, real-world evidence approach allows for assessing metformin’s impact on IIH outcomes across diverse clinical settings in the United States, providing valuable insights into its safety and efficacy in a large patient cohort. Our study aims to evaluate the effects of metformin on IIH-related symptoms, healthcare utilization, and long-term disease progression, offering a robust foundation for future prospective clinical trials. By leveraging this comprehensive dataset, we seek to elucidate metformin’s potential role in expanding the therapeutic armamentarium for IIH, potentially offering a novel, mechanistically targeted approach to this challenging condition.

Methods

Our study utilized data from the expansive TriNetX Research Network, through the global collaborative network database [¹⁸], which contains around 197 million electronic health records aggregated from more than 160 healthcare organizations in the United States. This comprehensive dataset includes a wide range of patient-level information, such as demographic characteristics, diagnoses, treatments, procedures, and outcomes, all coded using standard medical classification systems like the International Classification of Diseases, 10th Revision (ICD-10) and Current Procedural Terminology (CPT). Researchers can access this extensive real-world data through the secure TriNetX platform to conduct observational studies. The dataset is regularly updated, ensuring access to the most current and comprehensive healthcare information available. The Institutional Review Board approved the study protocol at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA (STUDY00008628).

We performed a retrospective analysis of the TriNetX data from 2009 to August 2024 (the timeframe associated with individuals with our inclusion and exclusion criteria in the TriNetX database), focusing on patients diagnosed with IIH. Patients were included if they had a primary diagnosis of IIH (ICD-10 code: G93.2), were 18 years or older, had at least one recorded BMI measurement and had a minimum follow-up period of 1 month. We excluded patients with pre-existing type 1 or type 2 diabetes mellitus (ICD-10 codes: E10., E11.), prediabetes (ICD-10: R73.03), or HbA1c $\ge$ 6.5%. Additional exclusion criteria encompassed other causes of elevated intracranial pressure, including primary brain tumors (ICD-10: C71.*), secondary brain metastases (ICD-10: C79.31), cerebral arteriovenous malformations (ICD-10: Q28.2), and venous sinus thrombosis (ICD-10: I67.6).

The study population was divided into two groups. The metformin group consisted of patients with IIH who received metformin (minimum dose 500mg daily) with no prior history of diabetes or prediabetes, and their first prescription of metformin was initiated after IIH diagnosis. The control group comprised patients with IIH who did not receive metformin at any point during the study period and had no prior history of diabetes or prediabetes. These groups were matched for age, sex, race, ethnicity, baseline body mass index (BMI), and baseline HbA1c using propensity score matching to minimize selection bias.

Primary outcomes were defined as papilledema (ICD-10: H47.1), refractory IIH status (ICD-10: G93.2 with modifier code Z91.82), and therapeutic spinal puncture rate (CPT: 62272). Secondary outcomes included optic atrophy (ICD-10: H47.2), blindness (ICD-10: H54.*), pulsatile tinnitus (ICD-10: H93.A9), diplopia (ICD-10: H53.2), visual field defects (ICD-10: H53.4), and adverse events related to metformin use.

We analyzed the data at different follow-up durations (one month, three months, six months, 12 months, and 24 months). We assessed the following outcomes: papilledema, optic atrophy, blindness, pulsatile tinnitus, diplopia, refractory IIH status, visual discomfort, visual field defects, and therapeutic spinal puncture rate as the primary treatment. For outcome assessment purposes, refractory IIH was defined as persistent or worsening symptoms despite maximum medical therapy for three months or longer. Treatment success was characterized by papilledema’s resolution and visual function improvement, while disease recurrence was defined as a new onset of symptoms after documented resolution. Therapeutic spinal punctures were distinguished from diagnostic procedures, specifically identifying lumbar punctures performed for therapeutic purposes. Visual outcomes encompassed any documented changes in visual acuity or visual fields measured as the change from baseline at specified time points.

Results

Discussion

In our large-scale multicenter retrospective study based on the TriNetX database, we illustrated compelling evidence for the potential efficacy of metformin as a disease-modifying therapy in IIH. Our findings demonstrate significant improvements across multiple IIH-related outcomes in patients treated with metformin compared to those who did not receive the medication.

The marked reduction in papilledema risk observed in the metformin group throughout the study period is particularly striking. This finding aligns with recent research suggesting that metformin may directly affect ICP regulation. Botfield et al. [¹³] Demonstrated that metformin can reduce ICP in rodent models of IIH through AMPK-dependent inhibition of the Na+/K+-ATPase at the choroid plexus, thereby decreasing CSF secretion. Our clinical findings support this preclinical evidence, indicating that metformin’s effects on papilledema may be mediated through direct modulation of CSF dynamics rather than solely through weight loss.

The observed reduction in refractory IIH status among metformin-treated patients is particularly noteworthy. This finding suggests that metformin may address underlying pathophysiological mechanisms contributing to treatment resistance in IIH. Recent evidence has implicated adipose tissue dysfunction and altered adipokine profiles in IIH pathogenesis [¹¹]. Metformin’s known effects on adipose tissue function, including modulation of adipokine secretion and improvement of insulin sensitivity, may contribute to its efficacy in refractory cases. Furthermore, emerging evidence suggests that metformin can influence the gut microbiome, which has been increasingly linked to neurological disorders, including those affecting ICP regulation [¹⁹].

These multifaceted effects of metformin may explain its potential to improve outcomes in patients who have not responded adequately to conventional therapies. The latest evidence has highlighted the importance of metabolic dysfunction in IIH pathogenesis, independent of obesity. For instance, Hornby et al. demonstrated alterations in glucose and lipid metabolism in IIH patients that BMI did not fully explain [²⁰]. Metformin’s pleiotropic effects on metabolism, including improved insulin sensitivity and modulation of lipid profiles, may, therefore, contribute to its efficacy in IIH through mechanisms distinct from weight loss.

The potential endocrinological connections underlying metformin’s efficacy in IIH are particularly interesting. Recent studies have implicated various endocrine factors in IIH pathophysiology, including androgens, glucocorticoids, and growth hormones [²¹]. Metformin has been shown to influence several of these endocrine pathways. For example, metformin can reduce androgen levels and improve insulin sensitivity in polycystic ovary syndrome (PCOS), a condition often comorbid with IIH [²²]. Given that androgen excess has been implicated in IIH pathogenesis, metformin’s androgen-lowering effects may contribute to its therapeutic benefits. Additionally, metformin has been shown to modulate the hypothalamic-pituitary-adrenal (HPA) axis, which could influence CSF dynamics and ICP regulation [²³]These endocrinological effects of metformin may partially explain its apparent disease-modifying properties in IIH observed in our study.

The safety profile of metformin in our IIH cohort was favorable, with no significant differences in adverse events compared to the control group. This is consistent with metformin’s well-established safety record in other clinical contexts and supports its potential as a long-term therapy for IIH. The similar incidence of lactic acidosis between the metformin and control groups is particularly reassuring, given historical concerns about this rare but serious complication [²⁴]. Our findings have important clinical implications. The observed reductions in papilledema and refractory disease status suggest that metformin could address multiple aspects of IIH pathophysiology.

While our results are highly promising, several important limitations of this study warrant careful consideration. First, the retrospective nature of our analysis inherently introduces the potential for selection bias and confounding factors despite our rigorous propensity score matching approach. Electronic health record data use, while providing a good sample size, may be subject to coding errors, missing data, or inconsistent documentation practices across different healthcare institutions within the TriNetX network. A significant limitation is the inability to directly measure intracranial pressure or access detailed CSF dynamics data. The absence of direct ICP measurements and CSF opening/closing pressures limits our ability to quantify the precise physiological effects of metformin on CSF dynamics. Additionally, we could not standardize the methods and timing of ophthalmological assessments across institutions, potentially introducing variability in the evaluation of visual outcomes.

The study’s reliance on ICD-10 codes for diagnosis and outcome measurement may not capture the full spectrum of disease severity or subtle clinical changes. Furthermore, while we controlled for various confounding factors, we cannot completely account for all potential confounders, such as dietary habits, exercise patterns, or concurrent medications that might influence IIH outcomes. The impact of these unmeasured variables on our results remains unknown.

Patient compliance with metformin therapy could not be definitively assessed beyond prescription fills, and we lacked data on medication adherence patterns. The study also cannot account for potential variations in clinical practice patterns across different institutions, including differences in the threshold for therapeutic interventions or the timing of treatment escalation. Another limitation is the potential for immortal time bias, as patients in the metformin group had to survive long enough to receive the prescription. While our matching process attempted to minimize this bias, its influence cannot be completely eliminated. Additionally, the study’s follow-up period, though substantial, may not be sufficient to capture very long-term outcomes or rare adverse events. The generalizability of our findings may be limited by the study population’s characteristics and the participating healthcare institutions’ geographic and demographic distribution. Furthermore, the exclusion of patients with diabetes and pre-diabetes, while necessary for studying metformin’s direct effects on IIH, means our results may not apply to IIH patients with these comorbidities. Finally, as with any observational study, we can demonstrate association but not causation. The precise mechanisms by which metformin influences IIH outcomes remain speculative and require validation through prospective, mechanistic studies. These limitations underscore the need for randomized controlled trials to definitively establish metformin’s role in IIH management and elucidate its therapeutic mechanisms.

Conclusions

Our study provides strong evidence for the potential of metformin as a disease-modifying therapy in IIH, with benefits extending beyond weight loss. These findings open new avenues for IIH management and underscore the need for further research into the complex pathophysiology of this condition. Prospective, randomized controlled trials are warranted to confirm these results and establish optimal treatment protocols. Such studies should include direct measurements of ICP, CSF opening pressure estimations, detailed ophthalmological assessments, and longitudinal investigations into the underlying mechanisms of metformin’s effects in IIH. Additionally, long-term follow-up studies will be crucial to assess the durability of metformin’s benefits and its impact on disease progression. As our understanding of IIH pathophysiology continues to evolve, metformin may represent a promising addition to the therapeutic armamentarium for this challenging condition.