With Sobha Sivaprasad, FRCOphth and J. Michael Gonzalez-Campoy, MD, PhD
Injections of the monoclonal antibody, aflibercept, outperformed the current first-line treatment with panretinal photocoagulation for proliferative diabetic retinopathy,1 according to findings published in the Lancet, and is intended for use in conjunction with standard treatment for the management of both type 1 and type 2 diabetes.
Findings from the head-to-head trial,1 conducted by a team of researchers in the United Kingdom, demonstrated that a one-year course of injections of aflibercept (Eylea, Regeneron) was superior to photocoagulation at improving visual acuity, including gains in binocular vision that could mean the difference between retaining or losing a driver’s license.
“This one-year, phase 2b study showed early effectiveness of aflibercept over [standard] laser treatment,” said Sobha Sivaprasad, FRCOphth, a professor at the National Institute for Health Research, in London, who led the trial. Panretinal laser photocoagulation (PRP) has been the standard of care for proliferative diabetic retinopathy for more than 4 decades.
“Longer term studies will help us understand the uptake of the intervention by patients, or whether patient compliance may alter this outcome,” Dr. Sivaprasad told EndocrineWeb.
An estimated 1/3 of people over age 40 with diabetes develop diabetic retinopathy, according to the US Food and Drug Administration.2 Roughly 7.7 million Americans were diagnosed with diabetic retinopathy in 2010, up from about 4 million in 2000, and the incidence is projected to double by 2050, according to the National Eye Institute. The condition is more common in Hispanics, for whom rates are rising much faster than for other ethnic groups.
Aflibercept blocks a variety of growth-promoting molecules, including vascular endothelial growth factor, placental growth factor 1 and 2 and galectin-1.1 The FDA approved the drug—along with two related agents, bevacizumab and ranibizumab--for the treatment of several eye conditions, including the wet form of age-related macular degeneration, macular edema, and diabetic retinopathy. 2
However, the latest study is believed to be the first randomized controlled trial to examine the efficacy of intravitreal injections of aflibercept against PLP for the treatment of proliferative diabetic retinopathy.
Although generally safe, the PRP surgery, which cauterizes leaky vessels in the retina, carries potential side effects, including bleeding in the eye, retinal detachment, and severe burning of the fovea that can lead to blindness.
People who received the injections were significantly more likely to report being satisfied with the procedure than those who underwent surgery—a surprising finding, according to the investigators, but one that “highlighted patients’ preference for this therapy.”
Laser therapy traditionally has been associated with partial blindness, although modern lasers are thought to reduce this risk. However, the new study found that intravitreal injections were linked to a lower risk of such vision loss at the one-year mark than were modern laser treatments,
Some clinicians might be reluctant to offer intravitreal injections over photocoagulation because the laser procedure is considered a more permanent solution. But, she added, 65% of people in the laser group required supplemental photocoagulation, and a previous study of the anti-VEGF agent ranibizumab found that 45% of patients undergoing laser treatment required additional interventions over a two-year period.
Dr. Sivaprasad said she was surprised to see how effective the injections proved to be. “I expected non-inferiority of aflibercept and not a superiority, as co-existent macular edema was an exclusion criterion for the study,” she told EndocrineWeb.
“Macular edema determines the central visual outcome and so we excluded this group to ensure the superior effects of aflibercept on the macular edema did not confound the primary outcome. Furthermore, the DRCR Protocol S study on ranibizumab in proliferative diabetic retinopathy showed a non-inferiority of ranibizumab over [laser therapy],3 so I expected similar results.”
The Lancet study was a single-blinded, non-inferiority trial of 232 men and women age 18 years and older with either type 1 or type 2 diabetes.1 No participants had macular edema, an exclusion criterion for the trial, although some had been treated previously with photocoagulation.
Patients in the aflibercept group received three intravitreal injections of the drug at the start of the trial and at weeks 4 and 8, and as needed after week 12. The others received laser surgery.1 Patients received an average of 4.4 injections, including three loading doses, during the study.
The primary outcome of the trial was a change in best-corrected vision at week 52. Secondary outcomes included improvements in visual acuity after 12 weeks and other vision-related gains.1
Of the total study population, the researchers conducted a modified intention-to-treat analysis of 221 people and a per-protocol analysis on 210 trial participants. For the primary outcome, patients who received the injections experienced a mean gain of 3.9 letters over those who underwent photocoagulation,1 according to Dr. Sivaprasad. The improvement was similar in the per-protocol analysis (P<0.0001).
Binocular vision improved in the patients who received injections, on average, but worsened over time for those who underwent surgery,1 the study authors found.
Aflibercept also was more likely than laser surgery to lead to an elimination of macular edema and total regression of new vessels in the retina after a year of treatment.1
“The results provide substantial evidence that the visual outcome of active proliferative diabetic retinopathy at 1 year with aflibercept therapy is superior to” laser photocoagulation, Dr. Sivaprasda and team reported. “This study is also the first to show a superior visual acuity outcome with an anti-VEGF agent in eyes with proliferative diabetic retinopathy with no baseline macular edema compared with” the surgical intervention.1
J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism, and Endocrinology, in Eagan, told EndocrineWeb, the new results “are very promising.”
“This will provide a viable alternative to panretinal photocoagulation,” Dr. Gonzalez-Campoy said, “Although it is emerging science, it is exciting to have more treatments to prevent blindness in patients with diabetes mellitus. The upside, preserving vision, makes any possible drawbacks--particularly intraocular injections--worth enduring.”