Jimena Tatiana Hathaway recently published an original investigation Ophthalmology in JAMA entitled “Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide,“. As their main finding, they addressed the potential ocular risks associated with semaglutide, the medication commonly prescribed for type 2 diabetes and weight management. The study’s findings raise important issues about the potential role of semaglutide in Non-arteritic anterior ischemic optic neuropathy (NAION) [1].

It develops a crucial discussion about the challenge of identifying causal factors in adverse medical events. While the study raises awareness about possible risks, it is essential to approach the issue with a comprehensive evaluation of all relevant risk factors, highlighting the role of precision medicine and omics analysis in reaching accurate conclusions.

NAION is the most prevalent type of ischemic optic neuropathy [2]. NAION can lead to sudden, painless vision loss and is the second most prevalent cause of persistent optic nerve-related vision loss in individuals after glaucoma [2]. The disease is significantly more common among Caucasians compared to African-Americans or Hispanics [3]. The precise pathophysiology of NAION is not fully understood, but it is generally thought to involve a combination of structural and vascular factors.

The JAMA Ophthalmology study’s association of NAION with semaglutide use adds a new dimension to our understanding of the disease, emphasizing the need for a deeper investigation into patient susceptibility. Semaglutide, a GLP-1 receptor agonist, has been implicated due to its potential effects on significant weight loss, hyperglycaemia, blood pressure, and vascular regulation [4]. However, it is critical to consider that this association does not imply NAION causation without further research to establish a direct mechanistic relation.

The causative landscape of NAION

NAION usually occurs when the blood supply to the optic nerve head is disrupted [5]. Nearly all patients who develop NAION possess a ‘disc-at-risk’ [6]. Risk factors must be carefully considered when offering precautions and treatments for NAION.

NAION has been associated with various cardiac and cerebral vascular diseases, including hypertension, diabetes mellitus (DM), hyperlipidemia, stroke, and prothrombotic disorders, among others [7]. Additionally, various specific genetic polymorphisms including ACE I/D, MTHFR c.C677T, and Factor V Leiden were examined for their association with NAION [8].

Understanding causality beyond semaglutide

NAION is a multifactorial condition influenced by various systemic and ocular factors. Semaglutide, as a GLP-1 receptor agonist, may theoretically influence vascular dynamics, potentially contributing to NAION in susceptible individuals. However, determining a causal relationship between Semaglutide and NAION necessitates thorough investigation beyond observational studies.

Personalized medicine: a path to personalized risk assessment

The concept of personalized medicine involves tailoring medical treatment to the individual characteristics of each patient, including genetic makeup, lifestyle, and environment [9]. In the context of NAION, personalized medicine could revolutionize how we identify and manage at-risk individuals. The JAMA study underscores the importance of identifying patients who might be genetically predisposed to adverse reactions when prescribed medications like semaglutide.

Personalized medicine offers a promising framework for dissecting common disease mechanisms and individualizing treatment approaches. In the context of NAION and its potential associations with medications like semaglutide, omics analysis become invaluable tools for tackling obesity in a personalized fashion. Omics technologies, including genomics, metabolomics, and proteomics, enable scientists to explore genetic signatures that may predispose individuals to NAION or influence their response to medications.

Genetic variations play a significant role in determining susceptibility to various diseases, including NAION. Polymorphisms in genes related to vascular regulation, inflammation, and optic nerve structure could influence an individual’s risk of developing NAION. For example, genetic variants in the PON1 gene, which is involved in oxidative stress response, have been associated with an increased risk of NAION [10]. Genetic variations in the NOS3 gene, which encodes endothelial nitric oxide synthase, can affect vascular tone and blood flow [11]. Additionally, variants in the MT-ND1 gene, part of the mitochondrial genome, have been associated with mitochondrial dysfunction and increased susceptibility to optic nerve damage [12].

Understanding these genetic factors allows for a more precise approach to patient care. Genetic testing could identify individuals at higher risk for NAION, enabling clinicians to make more informed decisions regarding prescribing medications that could potentially worsen the risk (Fig. 1).

Fig. 1
figure 1

This figure illustrates NAION as a multifactorial condition influenced by genetic predisposition and other risk factors. The central diagram represents NAION, influenced by genetic factors and environmental and pharmacological influences. The genetic factors section highlights variations implicated in NAION susceptibility, underscoring the role of precision medicine in identifying at-risk individuals. The environmental and pharmacological factors section shows potential triggers, such as medication use like semaglutide, that may interact with genetic predispositions

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Importance of post-marketing surveillance

Post-marketing surveillance plays an important role in monitoring the safety profile of medications once they are available to the broader population. It allows for the detection of rare adverse reactions that may not have been evident in pre-market clinical trials. In the case of semaglutide, ongoing surveillance should systematically collect and analyze data on NAION cases, considering individual patient characteristics, concurrent medications, medical histories, and other relevant factors [13, 14].

Conclusions

The JAMA article on the risk of NAION in patients prescribed semaglutide highlights the need for a comprehensive approach to understanding and managing this complex condition. While the association between semaglutide and NAION provides the need for further investigations.

Male gender, hypertension, hyperlipidemia, diabetes mellitus, coronary heart disease, sleep apnea, a history of cardiovascular medications, and being heterozygous for Factor V Leiden risk factors were associated with NAION. A deeper understanding of these risk factors in NAION can guide future research and treatment strategies. Emphasizing a systematic evaluation of all risk factors, including but not limited to medication use, is critical in post-marketing surveillance.

As we advance into the era of personalized medicine, integrating genetic insights into clinical practice will be crucial. By identifying genetic risk factors, polygenic risk scores and personalized treatment plans by pharmacogenomics accordingly, we can move towards a future where adverse drug reactions are minimized, and patient outcomes are optimized. The exploration of genetic variations in NAION serves as a reminder of the complex interaction between genetic makeup and health, so guiding towards more personalized and effective healthcare solutions. Personalized medicine approaches, coupled with advanced omics analyses, hold promise in solving the complex mechanisms underlying NAION and refining therapeutic strategies. By adopting a holistic and personalized-based approach, we can ensure that patient safety remains a top priority while advancing our understanding of complex medical conditions.