Semaglutide-associated retinal thickening was fully explained by rapid blood sugar improvement rather than a direct drug effect, with increased time in range linked to increased central retinal thickness across all treatment groups.
P = 0.21 after adjustmentSemaglutide's borderline retinal thickness increase became non-significant when accounting for improved blood sugar control, suggesting glycemia drives the effect
What the researchers found
In 10 semaglutide-treated patients, central retinal thickness (CRT) increased approximately 1% (3.76 μm, 95% CI -0.32 to 7.85, P = 0.065) compared to placebo — borderline non-significant. When adjusted for Time in Range (TIR), this effect was further attenuated (P = 0.21), indicating the retinal change was explained by glycemic improvement rather than a direct semaglutide effect.
Across all four treatment groups (semaglutide, empagliflozin, combination, and placebo), increased TIR was independently associated with increased CRT (0.07 μm per unit increase, 95% CI 0.03–0.12, P = 0.002). This confirms that rapid glycemic improvement — by any mechanism — is the driver of early retinal thickness changes.
Why it matters
The SUSTAIN-6 trial raised a safety signal suggesting semaglutide might worsen diabetic retinopathy, creating concern among patients and prescribers. This study provides mechanistic reassurance: the retinal changes appear to be a well-known consequence of rapid blood sugar improvement (called 'early worsening'), not a unique semaglutide toxicity. This is important for millions of patients taking semaglutide for diabetes and obesity.
How the study worked
This post-hoc analysis drew from a 32-week randomized, placebo-controlled, partly open-label trial of 120 type 2 diabetes patients investigating semaglutide and empagliflozin effects on target organ damage. Forty participants (10 from each of 4 treatment arms) were included. Time in Range (3.9–10.0 mmol/L) was measured using continuous glucose monitoring over 7–8 days. Central retinal thickness was assessed using optical coherence tomography (OCT). Statistical analyses adjusted for TIR to separate drug-specific effects from glycemia-driven changes.
What this study cannot tell us
This is a small post-hoc analysis with only 10 patients per group, severely limiting statistical power. The borderline non-significant retinal thickness increase (P = 0.065) in the semaglutide group means the study cannot definitively rule out a small drug-specific effect. The 32-week follow-up may not capture longer-term retinal changes. OCT measures retinal thickness but does not assess clinical retinopathy outcomes like visual acuity loss. The partly open-label design could introduce bias.
How to read the evidence
This is a small post-hoc analysis (n=40) from a randomized trial, providing low-to-moderate quality evidence. While the randomized trial design is a strength, the small sample size, post-hoc nature, and limited statistical power mean these findings are suggestive rather than definitive. Larger prospective studies are needed to fully characterize the retinal safety of semaglutide.
When this study was published
Published in 2025, this is a very recent study directly addressing an ongoing clinical controversy about GLP-1 agonist safety and diabetic retinopathy.
The bigger picture
As GLP-1 receptor agonists become the most prescribed diabetes and obesity drugs worldwide, understanding their safety profile is critical. The concern about diabetic retinopathy has been a persistent worry since semaglutide's landmark SUSTAIN-6 trial. This study adds to growing evidence that the retinal risk is a class-wide effect of rapid glycemic improvement — previously documented with insulin initiation — rather than something specific to GLP-1 peptide drugs. This distinction is important for clinical decision-making and patient counseling.
Questions still open
- Should diabetic retinopathy screening be intensified whenever any treatment achieves rapid blood sugar improvement, not just with GLP-1 drugs?
- Does the early worsening of retinal thickness with glycemic improvement eventually reverse and lead to better long-term retinal outcomes?
- Would slower semaglutide dose titration reduce the risk of retinal thickness changes while maintaining glycemic benefits?
Common questions
Can semaglutide cause eye problems?
What is 'Time in Range' and why does it matter here?
Read the original research
Semaglutide, central retinal thickness and continuous glucose monitoring in persons with type 2 diabetes: A post-hoc analysis from a randomised trial.
Journal of diabetes and its complications, 39(6), 109039
Citation
Gullaksen, Søren; Vernstrøm, Liv; Sørensen, Steffen Skovgaard; Funck, Kristian Løkke; Petersen, Line; Bek, Toke; Poulsen, Per Løgstrup; Laugesen, Esben. (2025). Semaglutide, central retinal thickness and continuous glucose monitoring in persons with type 2 diabetes: A post-hoc analysis from a randomised trial.. Journal of diabetes and its complications, 39(6), 109039. https://doi.org/10.1016/j.jdiacomp.2025.109039