On this episode of Ready, Set, Retina, Daniel Epshtein, OD, FAAO, is joined by A. Paul Chous, MA, OD, FAAO, to discuss a case report of diabetic re-entry retinopathy.
Dr. Chous owns a private optometry practice called Chous EyeCare Associates in Tacoma, Washington, that specializes in diabetes eyecare and is an Adjunct Professor of Optometry at Western University of Health Sciences in Pomona, California.
What is diabetic re-entry retinopathy?
Diabetic re-entry retinopathy refers to the phenomenon of diabetic retinopathy (DR) worsening after a patient’s blood glucose level quickly drops and reenters a normal range, typically occurring after a decrease of 2 or more points in HbA1c level.1
This drop is usually caused by the initiation of both intensive insulin therapy and potent glucagon-like peptide-1 (GLP-1) agonist treatment, noted Dr. Chous.
A brief refresher on GLP-1 agonists
Of note, GLP-1 agonists stimulate insulin production via the pancreas and reduce glucagon secretion to slow gastric emptying and reduce appetite for weight loss and improved glycemic control.2
In recent years, semaglutide (a GLP-1 agonist) has become a powerful tool for treating type 2 diabetes mellitus (T2DM) and evolved into a popular off-label weight-loss medication for non-diabetic patients as well.
There are currently three FDA-approved semaglutide medications on the market:2
- Ozempic (0.5mg, 1mg, or 2mg weekly semaglutide injections, Novo Nordisk)
- Rybelsus (7mg or 14mg daily semaglutide tablets, Novo Nordisk)
- Wegovy (2.4mg weekly semaglutide injection, Novo Nordisk)
To hear the results of a survey Dr. Chous conducted at the Academy of Optometry 2024 on how often and for which conditions optometrists refer patients to retina specialists, watch the full interview!
Diabetic re-entry retinopathy case report
Baseline
A 60-year-old female Asian American patient whom Dr. Chous had treated for the past 15 years presented to the clinic for a follow-up visit. She had T2DM for the past 14 years and received a diagnosis of stage 2 chronic kidney disease (CKD) more recently. The patient’s hemoglobin A1C (HbA1c) levels ranged from 9 to 12% since her T2DM diagnosis.
Studies have found that HbA1c <6% significantly increases mortality, and HbA1c >8% is considered poor glucose control,3 noted Dr. Chous, indicating that this patient required further intervention to achieve healthier blood glucose control. The patient’s body mass index (BMI) was 34 kg/m2, which is considered obese by BMI metrics.
At the time of assessment, she was taking a range of medications, including:
- Metformin (anti-diabetic medication)
- Lantus (insulin glargine injection, Sanofi)
- Lisinopril (angiotensin-converting enzyme [ACE] inhibitor)
- Rosuvastatin (statin)
- Levothyroxine (hypothyroidism medication)
- Dr. Chous added that hypothyroidism has been shown to be a risk factor for severe nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR)4
At the baseline visit, the patient had mild nonproliferative diabetic retinopathy (NPDR) in both eyes (OU) and mild epiretinal membrane (ERM) in the right eye (OD). Her best-corrected visual acuity (BCVA) was 20/20 OU.
Figure 1: Fundus image OD taken at baseline demonstrating mild NPDR and ERM; microaneurysms can be visualized.
Figure 1: Courtesy of Paul Chous, MA, OD, FAAO.
Figure 2: OCT image OD taken at baseline.
Figure 2: Courtesy of Paul Chous, MA, OD, FAAO.
Figure 3: Fundus image OS taken at baseline showing mild NPDR, normal foveal architecture, and the presence of microaneurysms.
Figure 3: Courtesy of Paul Chous, MA, OD, FAAO.
Figure 4: OCT image OS taken at baseline.
Figure 4: Courtesy of Paul Chous, MA, OD, FAAO.
Treatment with semaglutide
Subsequently, the patient was prescribed weekly 2.4mg semaglutide injections (Wegovy) to improve glucose control and assist with weight loss. Dr. Chous explained that Wegovy is a higher-dose semaglutide medication; its weaker cousins are Ozempic and Rybelsus.2
After treatment with Wegovy, the patient demonstrated:
- 22-pound weight loss (BMI dropped from 34 kg/m2 to 31.2kg/m2)
- HbA1c dropped from 12 to 6.6% over 8 months
- Significant worsening in NPDR
- Worsening cataracts
To learn more about the ophthalmic effects of semaglutide and other GLP-1 agonists, check out Semaglutides: A Guide to Ocular Effects and Surgical Considerations.
Figure 5: Fundus image OD from a 1-year follow-up appointment demonstrating mild NPDR and intraretinal hemorrhage in the nasal quadrant.
Figure 5: Courtesy of Paul Chous, MA, OD, FAAO.
Figure 6: OCT image OD from the 1-year follow-up appointment, the scan looks relatively unchanged from baseline.
Figure 6: Courtesy of Paul Chous, MA, OD, FAAO.
Figure 7: Fundus image OS from the 1-year follow-up appointment showing mild NPDR and intraretinal hemorrhage.
Figure 7: Courtesy of Paul Chous, MA, OD, FAAO.
Figure 8: OCT image OS from the 1-year follow-up appointment, the scan looks relatively unchanged from baseline.
Figure 8: Courtesy of Paul Chous, MA, OD, FAAO.
Dr. Chous added that he put the previous images through an artificial intelligence (AI) algorithm loaned to him by the University of Southern California (USC), which reported that the patient had more than mild NPDR based on the fundus images alone.
1.5-year follow-up visit
At a previous appointment, Dr. Chous performed a full-field flicker electroretinogram (ffERG) and found that her retinal function was reduced. There was a decreased amplitude of the b-wave ERG and reduced latency, and when he repeated the ERG at the most recent appointment, the results were even worse.
This, along with results from the clinical examination, demonstrated that the patient’s NPDR had worsened after beginning intensive insulin therapy.
Figure 9: Fundus image OD from the most recent visit, an increased number of retinal hemorrhages can be visualized.
Figure 9: Courtesy of Paul Chous, MA, OD, FAAO.
Figure 10: Fundus image OD taken at the most recent appointment, more retinal hemorrhages than previously are shown on the scan.
Figure 10: Courtesy of Paul Chous, MA, OD, FAAO.
The intersection of hypoglycemia, diabetic retinopathy, and GLP-1 agonists
Dr. Chous noted that in his experience, patients who are prescribed potent GLP-1 agonists, such as Wegovy, potentially Ozempic, and the combination GLP-1/GIP agonist tirzepatide in the form of Mounjaro (tirzepatide injection, Eli Lilly and Company), or Zepbound (tirzepatide injection, Eli Lilly and Company) have a potentially higher risk of diabetic re-entry retinopathy.
This is because these drugs can rapidly lower blood glucose levels, especially when they are prescribed in tandem with insulin therapy. As a result, paradoxically, the diabetic retinopathy status tends to worsen in these patients, and the effect may be modulated by hypoglycemia, explained Dr. Chous.5
This hypothesis is based on the findings from different studies:
- A retrospective study that evaluated the incidence and predictors of visual acuity (VA) loss in 882 T2DM patients found that a key risk factor for experiencing 2 lines or more of vision loss was acute hypoglycemia that required hospitalization or a paramedic to come to the house.6
- Another study found that in T2DM patients on insulin therapy who go on to develop diabetic retinopathy, after 5 years, the biggest risk factors for developing proliferative diabetic retinopathy were having been on insulin and having experienced hypoglycemia.
- A review of in vitro models of diabetic retinopathy that were cultured in various blood glucose concentrations demonstrated that spending 15 minutes in a 70mg/deciliter blood glucose solution (which is considered hypoglycemic in humans) resulted in a 100-fold increase in hypoxia-inducible factor (HIF).7
Of note, HIF is closely associated with vascular endothelial growth factor (VEGF) production.8 Consequently, this provides a plausible biological explanation for why hypoglycemia may accelerate retinopathy.
With this in mind, Dr. Chous’ current working hypothesis is that hyperglycemia initiates diabetic retinopathy, but when you take a hypoxic or ischemic retina and subject it to hypoglycemia, it causes a massive increase in VEGF levels and reactive oxygen species that can worsen retinopathy.
Treating diabetic patients on GLP-1 agonists
A recent meta-analysis of randomized clinical trials that compared GLP-1 agonists to placebo, insulin, or oral anti-diabetic medications found that GLP-1 agonists as a class overall didn’t worsen diabetic retinopathy, and ocular adverse events may have been influenced by the potency of the GLP-1 agonist and patient demographic and clinical characteristics.9
Ultimately, optometrists need to be mindful of how they discuss blood glucose control with diabetic patients and mention that a rapid drop in HbA1c may worsen their diabetic retinopathy due to hypoglycemia.
As such, Dr. Chous’ approach to preventing severe hypoglycemia is recommending that patients get a continuous glucose monitoring device that alerts them if their blood sugar levels are low. In addition, he mentions that eating a low glycemic index diet (ex., Mediterranean diet) has been shown to help blood glucose levels from getting too high or too low.10
Monitoring diabetic retinopathy in patients on GLP-1 agonist medications
Dr. Chous explained that he generally decides when to follow up with a patient depending on the level of DR at the initiation of GLP-1 agonist treatment and the potency of the medication.
For example, if a patient has mild NPDR and will start a less potent GLP-1 agonist, he will likely recommend that they return after 6 months to determine if they are experiencing progression. He also likes to perform ERG on these patients to gain insight into their objective retina function.
Conclusion
When treating diabetic patients who are considering starting a GLP-1 agonist medication, optometrists should consider:
- GLP-1 agonists are not linked to worsening DR as a whole class of drug, but it is important to keep in mind the potency of the drug and how quickly the patient’s HbA1c level drops
- Continuous glucose monitoring is helpful to ensure that patients are not hypoglycemic
- ERG can be helpful for determining the patient’s objective retinal function
- Clinicians can titrate the clinical follow-up for patients with a higher risk of DR progression due to concurrent insulin therapy and GLP-1 agonist medication
