A recent study published in Retina evaluated associations between glucagon-like peptide-1 receptor agonist (GLP-1 RA) use and diabetic retinopathy (DR), diabetic macular edema (DME), and treatment-requiring DR/DME.
Give me some background.
The cardiovascular outcome trials (CVOTs) for GLP-1 RAs demonstrated significant cardiovascular disease benefit and reduced mortality compared with placebo in patients with T2DM.
However: These trials raised concern about potential ophthalmologic adverse events:
- SUSTAIN-6 trial: Significantly increased rate of DR complications for semaglutide
- LEADER trial: Increased, but nonsignificant rate of retinopathy observed in liraglutide
What have we learned about GLP-1 RAs in the meantime?
GLP-1 RAs have been identified as a potential risk factor for DR onset and progression in some clinical research.
However: Other studies have described reduced DR risk or null associations when comparing GLP-1 RAs with insulin or other oral antihyperglycemics.
Now talk about the study.
In this longitudinal, retrospective cohort study, investigators recruited patients from the All of Us (AoU) Research Program and followed participants with type 2 diabetes mellitus (T2DM) for 10 years from initial diagnosis.
- About the AoU: The ongoing program was created in 2015 and seeks to enroll individuals to reflect the diversity of the U.S. population.
Tell me more about the cohort.
Overall: 37,258 participants with T2DM were included in the analysis with the following characteristics:
- GLP-1 RA users: 14.1%
- Race and ethnicity
- Caucasian: 51.8%
- Black: 25.4%
- Hispanic: 2.9%
- Other: 2.9%
- Asian: 1.8%
Compared to individuals who didn’t use GLP-1 RAs, diabetes patients on a GLP-1 RA were more likely to be:
- Younger:
- Users: Mean age of 50.6 years
- Nonusers: Mean age of 54.4 years
- Caucasian:
- Users: 57.1%
- Nonusers: 51.0%
- Female
- Users: 61.9%
- Nonusers: 55.9%
- Income holders of >$50,000
- Users: 40.5%
- Nonusers: 35.8%
Findings?
Compared with never users, GLP-1 RA use was associated with a decreased risk of:
- DME (HR: 0.40, 95% CI: 0.27-0.59, P<0.001)
- DR (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.26-0.37, P<0.001)
- Treatment-requiring DR/DME (HR: 0.18, 95% CI: 0.08-0.40, P<0.001)
Meaning: Initiation of GLP-1 RAs for DM patients may provide a significant protective effect against the ocular complications of diabetes, including the most severe vision-threatening complications which require vitreoretinal intervention.
Anything else?
A statistically significant increased risk of DR was observed for Hispanic or Latino or other race and ethnicity participants.
Black, Hispanic or Latino, and other populations were at an increased risk of developing DME, and Black and Hispanic or Latino populations demonstrated an increased risk of treatment-requiring DR/DME.
Expert opinion?
Prior literature has demonstrated an early paradoxical DR/DME worsening phenomenon, which is believed to be transient and reversible with sustained treatment.
- As such: This study investigated the risk of DR/DME at various time points to identify if early worsening contributed to the increased risk for DR/DME.
“While controlling for the confounding effects of baseline HbA1c and change in A1c, investigators found a decreased risk for DR, DME, and treatment-requiring DR/DME at every time point,” the study authors explained.
Any limitations?
A few, including:
- The AoU Research Program data involved dissociated claims codes; therefore, there is a risk that procedures were undertaken for diagnoses not considered by this study
- Retinal imaging was unavailable in AoU
Take home.
These findings suggest that GLP-1 RA users are at a reduced risk of developing DR, DME, and treatment-requiring DR/DME.
GLP-1 RA agents are also likely protective of poor visual outcomes, although further research is needed to determine whether these medications remain protective when initiated after DR development.
Next steps?
The risk of severe DME requiring a procedure may be decreased compared with mild DME; however, future studies should seek to better distinguish these associations—including potential disparities due to race and ethnicity.
The study authors added: “The results of the ongoing FOCUS clinical trial (NCT03811561), which was designed to directly study the long-term effects of semaglutide on diabetic eye disease end points will be crucial to the discussion of GLP-1 RAs in ophthalmology.”