Semaglutide was linked to a 75% increased risk of diabetic retinopathy worsening in the SUSTAIN-6 trial, though the absolute risk was small.
~75% increased relative riskSUSTAIN-6 showed higher retinopathy worsening with semaglutide, but this was a secondary endpoint with small absolute numbers
What the researchers found
In the SUSTAIN-6 cardiovascular outcome trial, semaglutide was associated with approximately 75% increased risk of diabetic retinopathy (DR) worsening. This was a secondary endpoint, not the trial's primary focus. Cases were rare in absolute terms.
Insulin icodec (a novel once-weekly insulin) also showed increased DR worsening compared to daily insulin. No other recent antihyperglycemic agent (SGLT2 inhibitors, DPP-4 inhibitors, other GLP-1 drugs) was associated with DR worsening.
Importantly, after the SUSTAIN-6 finding, nearly all subsequent trials excluded patients with pre-existing diabetic retinopathy. This means the true risk in the most vulnerable population remains unclear. Dedicated semaglutide eye safety studies were underway at the time of publication.
The most at-risk patients are those with pre-existing high-risk DR, poor baseline blood sugar (where rapid improvement could trigger worsening), and those using insulin.
Why it matters
Millions of people take semaglutide for diabetes and weight loss. Understanding eye safety is critical because diabetic retinopathy is the leading cause of blindness in working-age adults. The finding that rapid blood sugar improvement may worsen eye disease is not new (it was known with insulin), but semaglutide's powerful glucose-lowering effect makes this concern more relevant.
The numbers in context
- SUSTAIN-6: ~75% increased risk of DR worsening with semaglutide
- Cases were rare in absolute terms
- Insulin icodec: increased DR worsening vs daily insulin
- Most vulnerable: pre-existing high-risk DR, poor baseline glucose, insulin users
- Nearly all subsequent trials excluded patients with pre-existing DR
How the study worked
Literature review of clinical trial data for novel antihyperglycemic agents, with focus on diabetic retinopathy as a secondary endpoint or safety outcome. Covers incretin mimetics, SGLT2 inhibitors, long-acting insulins, and insulin delivery systems.
Who was studied
Review of diabetic retinopathy outcomes across clinical trials of novel diabetes drugs
What this study cannot tell us
DR worsening was a secondary endpoint in SUSTAIN-6, not a primary outcome. The 75% relative risk increase translates to a small absolute risk because DR events were rare. After SUSTAIN-6, trial design changed to exclude DR patients, making it impossible to assess risk in the most vulnerable group. The review does not provide pooled analysis. Long-term eye outcomes on semaglutide are unknown.
How to read the evidence
Rated moderate: based on a large randomized trial (SUSTAIN-6), but retinopathy was a secondary endpoint and the mechanism is debated.
When this study was published
Published in 2024, reviewing data from SUSTAIN-6 and other trials. The retinopathy question has been discussed since semaglutide's approval.
The bigger picture
Millions take semaglutide for diabetes and weight loss. Diabetic retinopathy is the leading cause of blindness in working-age adults. Understanding eye safety is critical even when the absolute risk is low.
Questions still open
- Is the retinopathy worsening caused by rapid blood sugar drops or a direct drug effect?
- Should patients with advanced retinopathy avoid rapid-acting blood sugar drugs?
Common questions
Can semaglutide damage your eyes?
Why might blood sugar drugs worsen eye disease?
Read the original research
NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.
Retina (Philadelphia, Pa.), 44(11), 1851-1859
Citation
Rajagopal, Rithwick; McGill, Janet B. (2024). NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.. Retina (Philadelphia, Pa.), 44(11), 1851-1859. https://doi.org/10.1097/IAE.0000000000004252