Numerous advances in diabetic eye disease, but many questions remain

With all the technological and medical advances for the treatment of diabetic eye diseases, retinal specialists still have an ongoing therapy issue because patients require continual and constant monitoring and maintenance, said Rishi P. Singh, MD.

"Unfortunately for our patients, vision gains are limited and in a minority of patients," said Dr. Singh, of the Cole Eye Institute.

Dr. Singh is this year's ASRS President's Retina Young Investigators Award recipient. Dr. Singh concentrated his lecture on the outstanding questions in diabetic eye disease researchers attempted to answer last year.

For instance, what can imaging tell clinicians about the cause of vascular diseases, in particular, diabetic retinopathy (DR)?

"Is DR truly just a retinal disease or is it a disease of the entire eye?" Dr. Singh asked. "What affect do baseline factors have on the progression of the disease and treatment outcomes? How can we best prevent complications in these patients who now need cataract surgery?"

Lessons learned from imaging

Clinicians often think of diabetic eye disease as limited to the retina, but Dr. Singh and colleagues have found that is not necessarily the case.

In one study on choroidopathy using optical coherence tomography (OCT) angiography,¹ eyes with nonproliferative DR and proliferative DR (PDR) showed significantly decreased choriocapillaris capillary perfusion density (CPD), whereas those without DR did not show a significant change. Compared with controls, only those eyes with PDR showed significantly decreased retinal CPD and significantly increased foveal avascular zone area.

"Proliferative patients manifest decreased in CPD, especially in the parafoveal region," he said. "It's important to think about the patient as a whole, and realize that diabetes is a retinal disorder, but may also be a choroidal disorder as well. The vessels below the retina may also contribute to the ischemia and changes that we see in diabetic eye disease."

Lessons learned from intensive management of diabetes

The DCCT Research Group² found patients on "really intensive medical therapy actually worsen for a short period of time, usually the first 2 years," Dr. Singh said. "Their DR gets worse as a result of being under really tight control and this has been found in numerous clinical trials since."

In the STAMPEDE study,³ researchers looked at patients who underwent bariatric surgery and found a "dramatic and rapid reduction in A1c mostly in the first 6 months with a net reduction of nearly 3% at 12 months with persistent effects of 2.5% at 36 months," Dr. Singh said, adding that at both 2 and 5 years, there was no significant difference in retinopathy scores or step progression within the treatment groups from baseline across cohorts. "That's a very different finding from what the DCCT group found."

Lessons learned from baseline characteristics

Previously published data from Dr. Singh⁴ found that patients with an A1c of <7 had more robust visual acuity and OCT improvements following anti-VEGF therapy for diabetic macular edema.

In a follow-up study utilizing data from a phase III clinical trial,[5] VA improvement with ranibizumab was independent of systemic factors (including glycemic control, body mass index, and blood pressure).

"That's reassuring because we tend to evaluate patients taking into account their systemic complications. We found there were significant visual gains despite baseline factors being poor," Dr. Singh said. "As a result, the clinician who is about to treat a patient does not need to have the patient 'medically optimized' before initiating therapy." 

Dr. Singh also analyzed the data from VIVID/VISTA trials on aflibercept found vision gains were similar between the laser and anti-VEGF group, but "the gain of vision from laser alone eroded as the hbgA1c value rose in the patient."

Thus, when a clinician is deciding between laser and anti-VEGF for macular edema, only when considering laser should a clinician be concerned about baseline A1c values. 

Lessons learned from diabetics and cataract surgery

Macular edema is the most common complication in patients with diabetes undergoing cataract surgery.  There is an approximate 3% to 30% incidence of macular edema post-cataract surgery; rates increase to 32% if a patient has diabetes and to 81% if a patient has background retinopathy.

"We wanted to determine how patients should be treated; what preventative drugs or options can we give our diabetic patients to avoid post-cataract complications," he said.

In their large phase III study evaluating nepafenac and steroids,[6] the combination provided "a huge differential. In the pooled response, more patients achieved a 15-letter gain in VA," he said. "Before this study, there was little guidance on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in cataract surgery. This study helps clinician by advising treatment with NSAIDs in only those with diabetic retinopathy."

Questions still remain

As far as research has helped understanding pathogenesis of diabetic eye disease and treatments, Dr. Singh said there are still unanswered questions.

"While we can address proliferative retinopathy and diabetic macular edema, we still don't have a good sense of how to reverse ischemia, which is becoming a more significant reason for vision loss," he said.

An outstanding issue facing all ophthalmologists is getting patients with diabetes to be screened and evaluated for visual complications earlier.

"We do not have good remote technology to be able to accomplish this yet," he said.
Finally, "we need a sustained delivery drug or device since some of our patients travel a far distance; taking time off from work can be burdensome."

References:

References
1. Conti FF, Qin VL, Rodrigues EB, et al. Choriocapillaris and retinal vascular plexus density in diabetic eyes using split-spectrum amplitude decorrelation spectral-domain optical coherence tomography angiography. 2018 May 23. pii: bjophthalmol-2018-311903. doi: 10.1136/bjophthalmol-2018-311903. [Epub ahead of print]
2. DCCT Research Group. The Relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes. 1995;44:968-983.
3. Schauer PR, Bhatt DL, Kirwan JP et al. for the STAMPEDE Investigators. Bariatric Surgery versus Intensive Medical Therapy for Diabetes-5-Year Outcomes. N Engl J Med. 2017;376:641-651. Doi: 10.1056/NEJMoa1600869
4. Matsuda S, Tam T, Singh RP, et al. The impact of metabolic parameters on clinical response to VEGF inhibitors for diabetic macular edema. J Diabetes Complications. 2014;28:166-170. doi: 10.1016/j.jdiacomp.2013.11.009
5. Singh RP, Habbu K, Ehlers JP, Lansang MC, Hill L, Stoilov I. The impact of systemic factors on clinical response to ranibizumab for diabetic macular edema. Ophthalmology. 2016;123:1581-1587. doi: 10.1016/j.ophtha.2016.03.038
6. Singh RP, Lehmann R, Mantel J, et al. Nepafenac 0.3% after cataract surgery in patients with diabetic retinopathy. Results of 2 randomized phase 3 studies. Ophthalmology. 2017;124:776-785.