Anti-VEGF Agents for Diabetic Macular Edema

Nancy Holekamp, MD: Historically, laser was the mainstay of therapy, but we’ve had a paradigm shift, and while we still use laser, it’s no longer the mainstay. It has shifted toward what we call anti-VEGF agents. Dr Leng, can you discuss the mechanism of action of anti-VEGF agents and discuss which ones are available and the data to support their use?

Theodore Leng, MD, FACS: The revolution happened around 2005 with anti-VEGF. That was when we moved…to intravitreal injections for the treatment of neovascular AMD [age-related macular degeneration] and subsequently used similar agents for the treatment of diabetic macular edema [DME]. Anti-VEGFs are proteins and antibodies that bind this signal that we have been discussing, the vascular endothelial growth factor, which promotes new blood vessel formation and vascular leakage; vascular leakage is the primary driver in diabetic macular edema. When we inject these medications into the eye, the molecules of the drugs soak up the free VEGF molecules, quenching their ability to act on the M target, which are VEGF receptors on the cells in the retinal vessels.

There are several agents that we currently use: ranibizumab, which was the first FDA-cleared agent to treat diabetic macular edema; aflibercept, which is a fusion protein; and bevacizumab in an off-label fashion to treat diabetic macular edema. The DRCR.net [Diabetic Retinopathy Clinical Research Network] did a comparison trial, Protocol T, several years ago [and] compared 3 agents head-to-head to see what the safety and efficacy were for those drugs. The main takeaways were that these drugs were effective at improving vision and preventing vision loss, which is the goal for these patients.

On average, patients were between 10 and 13 letters after the first and second year in this 2-year study. The study tried to mimic what we do in the real world as far as how we treat these patients. They received monthly injections for the first 6 months unless their vision was essentially perfect, 20/20 vision, and the thickness of their retinas and OCT [optical coherence tomography] were fairly normal, around 250 microns or less. If that criterion was met, they could defer the injections in the first 6 months. Most people received the first 6 injections and moved to a strategy where the patients were treated if they were continuing to improve or if they were worsening. If they maintained different statistics—such as their vision didn’t decrease by over 5 letters or one line of vision or their macular edema didn’t worsen by more than 10%—they were observed.

The study showed that all 3 agents were effective. There are areas of discussion that we’ve had in our field to see which agent is more effective than another. We saw subgroup analyses with people who have [a] worse version, meaning 20/50 or worse, where aflibercept was superior to the other 2 agents for improving vision in the first year, but by year 2, there was no difference in vision. This leads to another discussion about area under the curve, or vision under the curve, and whether you want that first-year visual gain maintained by using one agent over another or if the results may be the same after 2 years and any of the agents would be adequate for treating these patients. In patients with good vision, any of the 3 agents were adequate at maintaining and improving vision.

Nancy Holekamp, MD: You mentioned that there are 3 agents: ranibizumab, aflibercept, and off-label bevacizumab. What factors do you consider when selecting a therapy for patients?

Theodore Leng, MD, FACS: Based on the trial data, if patients have 20/50 or worse vision with center-involved DME, I would start with aflibercept because we should give everyone the best chance for the best vision for the longest amount of time. Although at 2 years there was no difference, in the first year there was, and if it were me or my family member, I would want to have great vision the first year. A lot of our care is often dictated by external factors. There are insurance concerns, step therapy we must deal with, I care for patients in a managed Medicaid HMO [health maintenance organization], and some plans don’t have a lot of funds and they would prefer us using a more cost-effective medication. Larger managed health care systems also make similar suggestions to the physicians as far as their practice patterns. The practice in medicine is complex in many ways, and this is something that we must help our patients navigate.

Nancy Holekamp, MD: Thanks to all of you for this rich and informative discussion, and thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

Transcript edited for clarity.