Piecing it together: Does semaglutide fit the NAION puzzle?

When examining the possible connection between semaglutide and NAION, it is essential to differentiate between an association and a causal relationship. A link between 2 factors does not necessarily mean one causes the other. Here is why:

1. Confounding variables

Diabetes and obesity are known risk factors for NAION.^5,6 This means that a person taking semaglutide might already have underlying conditions predisposing them to vision problems. These confounding variables make it challenging to determine whether the medication is to blame.

2. Biologically plausible mechanisms

For any drug to be causally linked to a condition, there must be a plausible mechanism explaining how it could lead to that condition. In the case of semaglutide and NAION, we need to consider how the drug might affect blood flow to the optic nerve. Interestingly, tight blood glucose control in patients with diabetes can sometimes worsen diabetic retinopathy.⁷ This phenomenon, although paradoxical, suggests that a more stringent control of glucose levels might have unintended adverse effects on the retina and the optic nerve. This mechanism could explain why semaglutide, which impacts metabolic control, might lead to a similar paradoxical effect in some patients.

3. Temporal relationship

One key factor in assessing causality is whether the condition’s onset follows a predictable timeline after the drug is introduced. The temporal relationship between semaglutide administration and the devel­opment of NAION has not been clearly defined. It is not entirely clear whether the vision loss occurs immediately after starting the medication or after prolonged use.

4. Class effect and specificity

Semaglutide belongs to the GLP-1 class of drugs. If other medications in this class showed a similar link to NAION, it would strengthen the case for a class-wide effect. However, studies on other GLP-1 analogues have not demonstrated the same association with NAION. Additionally, NAION is a relatively nonspecific condition; many factors can contribute to its development, including other drugs, diabetes control, and underlying vascular issues. This lack of specificity makes it difficult to pin the condition solely on semaglutide.

5. Dose-response relationship

Typically, if a drug causes an adverse effect, there is often a dose-response relationship, meaning the more of the drug a person takes, the more likely they are to experience the adverse effect. So far, no clear dose-response relationship has been observed between semaglutide use and NAION, which raises questions about whether the medication is truly responsible.

6. Dechallenge and rechallenge

One of the gold standards in proving causality is observing how a patient’s condition responds to stopping (dechallenge) and then restarting (rechallenge) the drug. Unfortunately, rechallenge studies with semaglutide are unlikely to occur due to the severity of NAION and the potential risk of further damage to vision.