Weighing the Side Effects of Treatments for DME

In my experience, saving sight is usually our patients’ biggest concern.

BY GAURAV K. SHAH, MD

The recently completed round of clinical trials evaluating treatments for DME has led to FDA approval of several new options. While retina specialists can look to these trials for guidance on how to use the options in practice, we must also use our clinical acumen to determine what treatment strategy is best for each patient. Educating patients on the potential side effects of anti-VEGF agents and sustained-release steroid implants, and how we can manage them, so they’re active participants in their care, is a cornerstone of the approach employed in my practice.

Anti-VEGF Agents

The RISE/RIDE¹ and VIVID/VISTA² Phase III clinical trials confirmed the safety and efficacy of the anti-VEGF drugs Lucentis 0.3 mg and Eylea for the treatment of DME. With regard to safety, in RISE/RIDE there was a trend, which did not reach statistical significance, for a higher incidence of serious adverse events potentially related to systemic VEGF inhibition with the 0.5-mg dose of Lucentis compared with the 0.3-mg dose (the dose ultimately approved by the FDA). Also, when Lucentis and Avastin were compared for the treatment of age-related macular degeneration in the CATT trial,³ there was a signal, not statistically significant, for more serious systemic adverse events with the use of Avastin 1.25 mg.

I’ve found that when my patients weigh the potential yet largely theoretical systemic side effects of the anti-VEGF agents with the ability of these medications to save their vision, more often than not, they choose to proceed with anti-VEGF therapy as first-line. I discuss this option even with patients who have had a stroke. However, because vision doesn’t worsen in DME as quickly as it does in AMD, initial treatment with a steroid implant is a reasonable alternative for patients who suffered a stroke as recently as a few weeks ago if they are averse to any systemic risk. If necessary, we can supplement with anti-VEGF treatment in a few months.

Sustained-Release Steroid Implants

Two sustained-release steroid implants have also been cleared by the FDA for use in patients with DME. The MEAD⁴ and FAME⁵ clinical trials confirmed the safety and efficacy of Ozurdex and Iluvien for this indication. Cataract and glaucoma are the side effects of greatest concern with these treatment options. Cataracts, which are easily treated, tend to be less of a concern for me and my patients than the development of glaucoma. While an increase in IOP may occur with Ozurdex, it tends to be very predictable and the effect peaks in about 60 days. It’s reasonable to use Ozurdex in patients whether or not they have ocular hypertension if it is the only treatment that will save vision. For patients with ocular hypertension, I test their level of response to steroids with topical difluprednate ophthalmic emulsion 0.05% (Durezol, Alcon) prior to implanting Ozurdex. An increase of 1-2 mmHg does not concern me, while an increase of 4-5 mmHg may. I also consult with a glaucoma specialist to determine what IOP the patient can tolerate and I’m certain to measure IOP consistently at the same time of day.

It is not yet clear to me what role Iluvien will play in my practice, although I suspect I will recommend it for a very small minority of patients, perhaps those who have failed all other therapies and have a post-vitrectomized eye. The implant’s predicted 3-year duration of action is good, but we want to avoid the need for incisional glaucoma surgery that was noted in the clinical trial. This is especially true for young patients, in whom glaucoma surgery would alter the dynamics of the eye and potentially quality of life going forward. Also, it is difficult to predict which patients would actually require steroid treatment of a long duration such as 3 years. Finally, it remains to be seen whether commercial insurance carriers may be hesitant to cover a long-term steroid device in younger patients, which may lead to policies that curtail access to Iluvien.

Can Combination Therapy Enhance Safety?

We do have a strong rationale for utilizing combination therapy in patients with DME (See “Moving Beyond Monotherapy,” on page 7), although at this point, we don’t have supporting evidence from prospective clinical trials. That said, it’s not unreasonable to expect that if adding a drug to a treatment regimen allows us to use less of another drug that it would be beneficial with regard to safety.

In my practice, I combine anti-VEGF agents with a steroid implant or intravitreal triamcinolone (Triesence, Alcon) and/or laser when it’s necessary to achieve the desired treatment effect. I also may switch back and forth between different treatments, such as starting with an anti-VEGF agent, switching to Ozurdex, which may “break the cycle” of the disease, and then returning to anti-VEGF injections. In recalcitrant cases, I check for mechanical traction on the retina as well as consider systemic fluid overload and impaired kidney function as sources of macular edema. It is paramount to treat those issues before considering treatment for macular edema because not addressing them would only lead to treatment failure. It is helpful to work with internists and endocrinologists to aggressively manage systemic issues.

Focus on the Individual

From any perspective, having additional treatment options for our patients with DME has been a welcome development. As far as using them in the most effective and safe manner, I’ve found it works best to avoid fixed treatment protocols and see each patient as an individual, to follow the patient’s lead with regard to tolerance of side effects, and to take a direct role in helping patients to maintain solid control of the many systemic problems that accompany diabetes. ■

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