Miriam E Tucker

September 28, 2017

LISBON, PORTUGAL — Early topical treatment for diabetic retinopathy may be possible in the future, at least for a subset of diabetes patients, new trial results suggest.

Findings from the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) were presented September 13 at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting by Rafael Simó, MD, head of diabetes and metabolism at Vall d'Hebron Research Institute, Barcelona, Spain.

The 2-year randomized trial compared the effects of twice-daily eyedrops containing the neuroprotective agents somatostatin or brimonidine against placebo drops for arresting neurodegeneration and for effects on a variety of retinal and visual outcomes.

Eyedrops were chosen as a way to target early stages of diabetic eye disease noninvasively and without systemic side effects. Neuroprotective agents were studied because prior preclinical and clinical evidence has suggested that neurodegeneration precedes microvascular impairment in diabetic retinopathy, Dr Simó explained.

However, in an unexpected finding, assessment with multifocal electroretinography (mfERG) showed that two-thirds of the 449 patients with type 2 diabetes for at least 5 years actually did not have signs of neurodysfunction at baseline and in them the drugs had no effect at 2 years.

But among the smaller proportion who did, both drugs appeared to significantly slow the progression of the neurodegeneration.

"We have seen two types of patients. In one, neurodegeneration appears at the beginning and perhaps is important in the pathogenesis of diabetic retinopathy.…But in some patients, we just found microangiopathy without neural dysfunction. This was a surprise….We have to understand more about these two phenotypes," Dr Simó told Medscape Medical News in an interview.

But he also said that in the future it might be possible to use eyedrops that target the early microvascular defects as well, opening up the possibility of a combination topical treatment that would allow patients with diabetic retinopathy to avoid the unpleasantness and side effects of laser photocoagulation, injections with antiangiogenic agents, or surgery.

Asked to comment, session moderator Hans-Peter Hammes, MD, section head of endocrinology, Medical Faculty Mannheim, Heidelberg University, Germany, told Medscape Medical News that the study was limited by short duration and also the inability of mfERG to detect early subtle changes in the retina.

"You're looking at a group with neural and vascular lesions. It's not clear whether the vascular lesions might not also have neural lesions on a different level not captured by the measurement and vice versa….We need…to have a complete picture...to develop these technologies further," Dr Hammes said.

High Dropout Rate; Strong Effect Seen Only in a Subgroup

Study subjects were aged 45 to 75 years with a diagnosis of type 2 diabetes with duration of 5 years or longer. At baseline, 50% had an Early Treatment Diabetic Retinopathy Study (ETDRS) score of less than 20 (no microaneurysms), while the other half had ETDRS levels 20 to 35 with presence of at least one microaneurysm in the study eye.

They were randomized to twice-daily drops of brimonidine 0.2% (an approved glaucoma treatment), somatostatin 1%, or placebo for 24 months.

Neurodysfunction was defined as an eye with six or more altered hexagons on implicit time-mfERG retinal response testing (IT-mfERG).  

The dropout rate in the first year was 24%, with the highest rate from the brimonidine group (36%). Dropout rates didn't differ between somatostatin and placebo (17% and 19%, respectively). Most of the adjudicated adverse events overall in the trial were local, including eye pain, ocular hyperemia, conjunctival follicles, and conjunctivitis, with most of these occurring in the brimonidine group as well.

"The high rate of dropouts suggests that specific educational programs and strategies to increase the treatment adherence are needed," Dr Simó commented.

There were no differences at the end of follow-up in the number of new cases of neurodegeneration among the three groups. The proportions of patients without neurodysfunction at baseline and who remained with fewer than six hexagons at 24 months were 79% of 84 placebo patients, 68.5% of 57 brimonidine patients, and 68% of the somatostatin group (= NS).

However, among the total 34.7% (293) who had six or more abnormal hexagons at baseline, those using either of the drugs hadn't changed significantly at 2 years (= .99 for brimonidine and 0.69 for somatostatin), whereas the placebo group had worsened significantly (= .009).

The differences were not due to HbA1c, since those values did not differ among the three groups (7.09% placebo, 7.15% brimonidine, and 7.2% somatostatin), Dr Simó noted.

And there was no overall effect of either drug on an array of secondary end points assessing the prevention or slowing of progression of early diabetic retinopathy stages.

"Further studies with somatostatin with longer follow-up in order to determine whether this beneficial neuroprotective effect results in reduction of microvascular disease are needed," he concluded.

Dr Hammes pointed out that current clinical screening methods look only at vessels and not neuronal damage.

"For the time being we have a group of patients who develop retinal lesions not where we are looking but other places….But we shouldn't run and look for this as a screening method until we identify an efficient treatment" with which there's an improvement in sight preservation. "That hasn't been shown yet. We need a clinical-outcomes study. We're not there yet, but it could come."

EUROCONDOR was funded by BCN Peptides. Dr Simó receives research support from, is on the speaker's bureau for, or is an advisor or board member for Novo Nordisk, Abbott, Lilly, OM-VIFOR, Sanofi, Ferrer, Bayer, and Allergan. Dr Hammes consults for Novartis, Bayer, and Sanofi.

European Association for the Study of Diabetes 2017 Annual Meeting. September 13, 2017; Lisbon, Portugal. Abstract 120

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