Metabolic Syndrome, GLP-1 Use, and NAION

A 59-year-old Caucasian male presented for an emergency visit, complaining of an intermittent obstruction to his left eye’s superior visual field, along with associated blurry vision. He stated the episode began 2 days prior and had not changed. The patient denied any associated ocular pain, new onset of floaters, or flashes of light.

AN UNHEALTHY COMBINATION

The patient’s ocular history was unremarkable, with no active use of ocular medications.

His medical history was positive for hypertension, hyperlipidemia, and type 2 diabetes. Current medications were glimepiride 4 mg BID, metformin ER 500 mg BID, empagliflozin 25 mg QD, and a semaglutide 2 mg injection QW, all for his type 2 diabetes. Additionally, he reported using lisinopril 10 mg QD and carvedilol 6.25 mg BID for high blood pressure, rosuvastatin 40 mg QD for hyperlipidemia, and aspirin 81 mg QD to preserve his cardiovascular health.

The patient’s blood pressure was 118/72 mm Hg at this visit, and he reported that his last hemoglobin A1C and fasting blood sugar were around 10% and 202 mg/dL, respectively, with the latter signaling poorly controlled diabetes.

STANDARD TESTING

Ocular examination revealed uncorrected VA of 20/40 OD and OS, normal extraocular motilities, a grade 1 afferent pupillary defect OS, and confrontation visual fields that were full-to-finger counting OD and constricted superiorly OS. Additionally, the patient’s IOPs were 13 mm Hg OD and 11 mm Hg OS.

Anterior segment examination showed 2+ nuclear sclerosis OU and 2+ cortical cataract OU.

OPTIC NERVE DAMAGE

Posterior segment evaluation showed an inferior sectoral optic disc edema with a small flame-shaped hemorrhage overlying it in the optic nerve OS. Also, inferior sectoral thickening of the retinal nerve fiber layer (RNFL) OS was noted (Figure 1). A dense but incomplete superior altitudinal defect was also seen OS (Figure 2).

DIAGNOSTIC DETECTIVE WORK

Based on the patient’s age and clinical findings, he was questioned about symptoms of giant cell arteritis (GCA) caused by arteritic anterior ischemic optic neuropathy (AAION). The symptoms of GCA include, but are not limited to, fever, headache, anorexia/weight loss, neck pain, jaw claudication, scalp pain, ear pain, fatigue, myalgia, and general malaise.¹

AAION is an acute optic neuropathy characterized by optic nerve infarction, where the short posterior ciliary arteries supplying the optic nerve are inflamed and lead to local thrombosis.¹ It is one of many visual manifestations of GCA and is an ophthalmic medical emergency that must be ruled out in patients older than 50 years of age, as it can lead to permanent vision loss and death.¹

Palpation of the superficial temporal arteries was performed to see whether they were bulbous, enlarged, or tortuous, had a diminished pulse, or caused the patient pain, as these can be clinical signs of GCA. The patient denied GCA symptoms, and palpation revealed no GCA clinical signs, suggesting that the patient had non-arteritic anterior ischemic optic neuropathy (NAION).

NAION is characterized as unilateral sectoral disc edema, secondary to poor perfusion to the optic nerve, causing local ischemia.^2,3 The condition is purely a diagnosis of exclusion, so AAION must always be ruled out.^2,3

To rule out AAION, the patient was referred to the ER for bloodwork, including erythrocyte sedimentation rate, C-reactive protein, and cell blood count with differential. Discussion with the ER doctors was also had regarding the potential need for a temporal artery biopsy or color doppler ultrasound to confirm GCA, if indicated with bloodwork or patient symptoms. The results from the ER supported a NAION diagnosis.

THE INS AND OUTS OF NAION

NAION remains a poorly understood condition that has an unclear pathophysiology. Its main risk factor is poor metabolic control through conditions such as hypertension, hypercholesterolemia, and diabetes.^2,3 Furthermore, research has linked NAION to certain medication classes, including, but not limited to, interferons, PDE-5 inhibitors, and GLP-1s.^2,3

Additionally, NAION is linked with small optic nerve heads with small/absent cupping (≤ 0.2), optic disc drusen, sleep apnea, nocturnal arterial hypotension, and smoking.^2,3 That said, all these risk factors are currently regarded as associative rather than causative.^2,3

The condition mainly affects Caucasian individuals over 50 years of age, with a prevalence between 2.3 and 10.3 people per 100,000 individuals per year.³ NAION has no sex predilection.³ Currently, there is no effective treatment for NAION. This emphasizes the importance of prevention through good metabolic health and limitation/avoidance of other risk factors.

In addition to AAION, diabetic papillitis should be part of the differential diagnosis. This is a rare condition usually found in younger patients who have diabetes.⁴ Research suggests rapid glycemic control can lead to it, causing unilateral, rarely bilateral, optic disc edema.^4,5 Diabetic papillitis is typically not visually destructive and has a good visual prognosis after its self-limiting resolution.^4,5 This condition will generally not have visual field defects other than an enlarged blind spot consistent with the optic nerve edema and is a diagnosis of exclusion.^4,5 It also may or may not present with concurrent macular edema and/or diabetic retinopathy.^4,5

Our patient’s medical history revealed significant metabolic dysregulation, strongly supporting the notion that metabolic syndrome was a major contributing factor to his NAION. In fact, a growing body of research supports a strong correlation between metabolic syndrome and NAION.^2,3 Nevertheless, he was also using semaglutide injections. Research shows a temporal relationship between semaglutide use and NAION onset.^6-8 A 5-year longitudinal study reveals that weekly semaglutide injections were associated with a doubled risk of developing NAION.^2,3

While a definitive causal link has not been established, this emerging data underscores the need for continued investigation into this potential connection.

CASE CONCLUSION

The patient’s visual acuity was stable during the term of his NAION. He returned to our clinic for a follow-up the next week for an updated visual field and an OCT of the RNFL. The visual field showed significant improvement, with the RNFL remaining unchanged. The improvement in the visual field defect was unique, considering research into NAION suggests defects may last weeks, months, or even years.^2,3 

The patient was educated on his NAION diagnosis, as well as the potential link between his metabolic issues and semaglutide use. Additionally, the importance of maintaining strict control of his blood sugar and blood pressure and regularly following up with his primary care physician for the assessment of both was stressed. The patient was also informed that the fellow eye has a 15% to 24% risk of developing NAION over 5 years.^2,3 Unfortunately, research has suggested the use of preventative measures does not stop the development of NAION in the fellow eye.³ At his last visit, there was marked improvement in both the RNFL and the visual field (Figure 3 and Figure 4). The patient informed us he had discontinued his semaglutide injections and was in communication with his primary care provider regarding any alternative medications. The patient continues to be monitored for any visual field changes. 

Recent literature shows that spontaneous NAION history may lead to increased incidence of NAION or postcataract surgery optic neuropathy in the fellow eye following cataract surgery.⁹ We mention this, as the patient did present with a cataract. The current hypothesis is that a perioperative rise in IOP can lead to decreased perfusion to the optic nerve head, leading to NAION.⁹ Although there is no causal relationship, and the incidence is low, it is imperative to educate and counsel patients on this potential risk.⁹ Further research is indicated on this relationship, as current research is conflicting.

This case emphasizes the importance of taking a thorough and individualized approach to patient care, one that considers not only well-established risk factors, but also newer, less-defined associations that may contribute to disease onset.