Research suggests course of diabetic eye disease influenced by genetic factors

A study including data from about 42,000 eyes found diabetic retinopathy (DR) severity is a risk factor for the progression of diabetic eye disease. Other findings support the idea that genetic factors influence the development of proliferative DR versus diabetic macular edema.

A study analyzing data from real-world patients with diabetes provided further evidence that the risk of both diabetic retinopathy (DR) progression and diabetic macular edema (DME) development increase with higher DR severity.

The research also identified the existence of three distinct clinical subtypes among eyes with DR comprised of a group at increased risk of clinically significant macular edema (CSME), a second group at increased risk of proliferative DR (PDR), and a third but smaller group at increased risk of developing both CSME and PDR.

Geeta Lalwani, MD, Rocky Mountain Retina Associates, Boulder, Colorado, presented the findings at the 2020 virtual meeting of the American Academy of Ophthalmology.

“In addition to DR severity, diabetes duration, hyperglycemia, hyperlipidemia, and hypertension are major drivers of DR progression. However, these factors account for only about 10% of the risk of DR prevalence, which points to the potential involvement of other risk factors,” Lalwani said. “Our finding of different clinical subtypes among eyes with DR suggests that PDR and DME may represent two distinct disease processes potentially driven by distinct genetic factors.

Several candidate genes have been associated with DR pathogenesis, including those associated with angiogenesis and inflammatory pathways, and these appear to result in different phenotypes. More research is needed on the clinical and genetic factors responsible for these distinct risks of DME versus PDR development in patients with type 2 diabetes.”

The study was conducted by reviewing data and 7-field color fundus photograph images collected between 1999 and 2016 in the Inoveon database of patients with diabetes who participated in a retina screening program at primary clinical centers. Eligible patients had at least two gradable images in either eye from two different time points. The severity of DR was graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) DR Severity Scale (DRSS) and presence of CSME were assessed by professional graders at a centralized reading center.

The analyses included approximately 42,000 eyes of 22,000 patients. The patients were predominantly male (83%) and had type 2 diabetes (94%). Nearly 50% of the population was Caucasian, and Native Americans comprised 41% of the group.

Outcomes data

A Kaplan-Meier analysis of data from the entire population showed that 2.7% of eyes developed a ≥2-step worsening of DRSS by year 2, and the rate increased to just under 10% by year 5.

“Consistent with previous literature showing that baseline DR severity is an important predictor of DR progression, we found distinctly higher proportions of patients with higher DR severity at baseline developed a ≥2-step worsening over time,” Lalwani said.

At year 2, the rates of ≥2-step DR progression were 3.1% among eyes with mild NPDR at baseline and 8.4% to 12.9% for those with moderate to severe NPDR. At 5 years, >35% of eyes with moderate-to-severe NPDR at baseline experienced a ≥2-step DR worsening.

Analyses of time to first development of CSME and/or PDR showed that more eyes developed either CSME or PDR alone versus both conditions together. By year 5, the risk of developing CSME alone was just under 1.5%, the risk of developing PDR was just under 0.5%, and the risk of developing both CSME and PDR was 0.1%.

The trend for distinct clinical progression subtypes was also observed in an analysis focused on eyes with moderate to severe NPDR at baseline. The rates of development of CSME and PDR were much greater in the eyes with moderate to severe NPDR severity than in the overall population. By year 4, the risk of developing CSME alone was just over 25% in this group, and the risk of developing PDR alone was just under 19%.

However, an analysis investigating the hypothesis that the majority of eyes with severe NPDR at baseline would develop PDR found that these patients also developed either CSME or PDR with relatively few developing both PDR and CSME.

“Interestingly, these trends were also observed in the sham arm of the PANORAMA study where after 100 weeks of follow-up, the majority of patients developed vision-threatening complications of PDR/anterior segment neovascularization or center-involved DME alone, but not both events simultaneously,” Lalwani said. “This trend is also consistent with retrospective claims-based analyses data.”

Lalwani observed that because of its nature, the INOVEON study had several limitations. These included heterogeneous screening frequencies and variable analysis of the progression to PDR and/or CSME due to variable follow-up.

“Our study might underestimate the progression rate to PDR and/or CSME because patients might not return for follow-up after progression to vision-threatening disease,” Lalwani said. “Unfortunately as well, clinical factor data, including diabetes control, were not collected from the patients.”

Lalwani mentioned that a retrospective cross-sectional study by Hobbs et al. found that the majority of eyes with newly diagnosed PDR did not have concurrent DME, and the majority of eyes with newly diagnosed DME did not have concurrent PDR. In addition, Hobbs et al. reported that several systemic risk factors, including, sex, age, type of diabetes, HBA1c, blood pressure, and LDL cholesterol control, had no significant effect on the development of DME in eyes with PDR or vice versa.

“These findings also suggest that PDR and DME may present two distinct disease processes potentially driven by distinct genetic risk factors,” she said. “Further research is warranted focusing on the clinical and genetic factors responsible for distinct risks of DME versus PDR development in patients with type 2 diabetes.”

Geeta Lalwani, MD
E: glalwani23@gmail.com
Lalwani has no relevant financial interests to disclose.