Keeping up with the latest diabetic eye disease research

I was fortunate to attend the Association for Research in Vision and Ophthalmology (ARVO) Diabetic Retinopathy this past August.

Esteemed researchers and clinicians from all over the world presented myriad talks on subjects ranging from the epidemiology of diabetic eye disease to novel biochemical and epigenetic pathways underlying retinopathy to emerging preventive strategies and treatments. The two-day program also featured a number of interesting scientific posters including a summary of the work several colleagues and I have been doing for the last five years.

All in all, it was jam packed with information that may significantly impact the way we manage patients in coming years, and I’ll share with you here some of the topics that especially piqued my interest.

Related: Improve and protect the next patient with diabetes

Research of note

Renu Kowluru, PhD, from Wayne State University presented new work on the epigenetics of diabetic retinopathy (DR)-that is, environmental factors independent of gene DNA sequence that determine the activation or suppression of genes resulting in disease. In particular, damage to mitochondrial DNA (mtDNA) is characteristic of DR and results from over-methylation of that DNA, causing apoptosis of retinal capillary endothelial cells.¹ As such, blocking enzymes responsible for excess methylation of mtDNA may offer great therapeutic promise. Research in this area is ongoing.

Alexander Lbujmov, PhD, from UCLA presented work on the use of adult stem cell therapy to prevent vascular hyperpermeability and retinal capillary closure in early DR,² as well as efforts to use gene therapy to treat corneal complications of diabetes like recurrent erosion, loss of corneal sensitivity, edema, and ulceration, abnormalities which are reported to affect 50 to 75 percent of patients having diabetes.³

More from Dr. Chous: The importance of multidisciplinary care for diabetes

Gregg Semenza, MD, PhD, from Johns Hopkins presented evidence showing that hypoxia inducible factor (HIF) is the master regulator of normal and pathologic vascularization and is necessary for activation of multiple genes producing multiple angiogenic factors like vascular endothelial growth factor (VEGF), angiopoetin-like 4 (ANGPTL4), and others.⁴ Further, he and other speakers showed evidence that half of all eyes with diabetic macular edema (DME) do not have elevated VEGF and that existing HIF inhibitors-such as digoxin-may better block all angiogenic molecules. This may be especially useful for patients who have a poor response to Avastin (bevacizumab, Genentech), Lucentis (ranibizumab, Genentech), and/or Eylea (aflibercept, Regeneron).

Next: More research

Clinically, poor VA response to anti-VEGF injections for fovea-involved DME was underscored in a talk by Jennifer K. Sun, MD, from Harvard, who showed that disorganization of retinal internal layers within the central 1 mm (what her team calls “DRIL”) on spectral domain OCT (sdOCT) predicted precisely which patients are unlikely to have a good response to anti-VEGF therapy.⁵ DRIL is typified by loss of distinct boundaries among the ganglion cell, inner plexiform, inner nuclear, outer plexiform, and outer nuclear layers.

Speaking of imaging advancements, Steve Burns, PhD, from Indiana University’s School of Optometry presented mind-blowing images of early diabetes-induced retinal capillary and blood flow changes using adaptive optics, changes which may precede clinical diagnosis of diabetes.⁶

On the prevention front, Emily Chew, MD, PhD, from the National Eye Institute (NEI) reviewed data from the ACCORD-Eye and FIELD studies, both of which showed that use of the triglyceride-lowering agent, fenofibrate significantly lowers the risk of worsening diabetic retinopathy and the need for photocoagulation. She argued that this agent should be considered in addition to tight metabolic control for patients with type 2 diabetes and early DR, a sentiment echoed by former NEI Chair Robert N. Frank, MD, PhD, in his review of controlled clinical trials for diabetic retinopathy. Dr. Frank also suggested an AREDS2-type trial to determine the effects of a multi-component nutritional supplement on the development and progression of DR.

Related: Why communication is the key to diabetes success

Michael Brownlee, MD, PhD, from the Albert Einstein College of Medicine presented evidence that duration of hyperglycemia may be more predictive of retinopathy risk than mean blood glucose (as reflected by HbA1c). Specifically, he displayed animal data showing that a mere six-hour exposure to blood glucose >180 mg/dl results in a two-week, massive overproduction of free radical molecules (reactive oxygen species [ROS]) that cause vascular diabetes complications, despite immediate normalization of blood glucose after that six-hour exposure.⁷ Dr. Brownlee showed data from the Diabetes Control and Complications Trial (DCCT) that HbA1c accounts for a mere six to 11 percent of total individual risk for DR and its progression, and that HbA1c may not reflect these short-term spikes which appear to “massively increase risk."

Other notable presentations included data showing that green and blue-green wavelengths emitted by an LED sleep mask (through closed eyelids) may mitigate retinal hypoxia in diabetes by down-regulating rod photoreceptor metabolism during sleep (rods account for 90+ percent of retinal oxygen consumption) and a small series of patients with DME who benefited from this therapy. Disturbingly, data from the Chicago HealthLNK Repository of nearly 2 million patients from Chicago area academic medical centers, federally-qualified health centers, and community hospitals showed that Medicaid and uninsured patients with diabetes were significantly less likely to be diagnosed with DR/DME and treated for these conditions than were patients with Medicare or private health insurance; this despite evidence that these patients are no less likely to be affected by eye disease.

Oh yeah-the poster I presented showed evidence that a novel, multi-component nutritional supplement significantly improved visual function in patients with diabetes and early DR.⁸ The same formula also prevented mtDNA damage, ROS over-production and capillary apoptosis characteristic of DR in an animal model.⁹ Check out the results of our human trial at http://www.ncbi.nlm.nih.gov/pubmed/26089210. More on this next time.

References

1. Mishra M, Kowluru RA. Epigenetic Modification of Mitochondrial DNA in the Development of Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2015 Aug;56(9):5133-42.

2. Kramerov AA, Ljubimov AV. Stem cell therapies in the treatment of diabetic retinopathy and keratopathy. Exp Biol Med (Maywood). 2015 Oct 9.

3. Saghizadeh M, Dib CM, Brunken WJ, et al. Normalization of wound healing and stem cell marker patterns in organ-cultured human diabetic corneas by gene therapy of limbal cells. Exp Eye Res. 2014 Dec;129:66-73.

4. Hubbi ME, Semenza GL.Regulation of cell proliferation by hypoxia-inducible factors. Am J Physiol Cell Physiol. 2015 Dec 15;309(12):C775-82.

5. Sun JK, Radwan SH, Soliman AZ, et al. Neural Retinal Disorganization as a Robust Marker of Visual Acuity in Current and Resolved Diabetic Macular Edema. Diabetes. 2015 Jul;64(7):2560-70.

6. Burns SA, Elsner AE, Chui TY, et al. In vivo adaptive optics microvascular imaging in diabetic patients without clinically severe diabetic retinopathy. Biomed Opt Express. 2014 Feb 27;5(3):961-74.

7. Giacco F, Du X, Carratú A, et al. GLP-1 Cleavage Product Reverses Persistent ROS Generation After Transient Hyperglycemia by Disrupting an ROS-Generating Feedback Loop. Diabetes. 2015 Sep;64(9):3273-84.

8. Chous AP, Richer SP, Gerson JD, et al. The Diabetes Visual Function Supplement Study (DiVFuSS). Br J Ophthalmol. 2016 Feb;100(2):227-34

9. Kowluru RA, Zhong Q, Santos JM, et al. Beneficial effects of the nutritional supplements on the development of diabetic retinopathy. Nutr Metab (Lond). 2014 Jan 30;11(1):8