Moving Beyond Monotherapy

As in other complex diseases, combination treatment is likely to become an important approach for DME.

BY SHREE K. KURUP, MD

Perhaps even more so than other retinal vascular diseases, diabetic eye disease is multifactorial. Its pathogenesis involves many mediators, including vascular endothelial growth factor (VEGF)¹ and inflammatory cytokines.^2,3 Thanks to several recent FDA approvals and indication expansions, we have more options than ever for targeting the causes of diabetic macular edema (DME). Clinical trials have shown anti-VEGF agents and steroids to be effective for improving retinal anatomy and vision in patients who have DME.^4-7

Given the results they’re capable of producing, anti-VEGF agents are first-line therapy in most cases of DME. However, achieving favorable outcomes requires frequent injections, with monthly injections leading to the best results.^4-5,8-9 This level of treatment can be difficult to sustain for patients with diabetes. Often, they’re seeing several other doctors who monitor the systemic aspects of the disease; many develop DME at a relatively young age, and the disease is often bilateral. Furthermore, anti-VEGF agents don’t produce the desired result in every patient. For example, in a study by the Diabetic Retinopathy Clinical Research Network (DRCR.net Protocol I, prn re-treatment criteria, average number of injections was 8 to 9 in year 1, 2 to 3 in year 2 and 2 in year 3), 27% of the patients who received ranibizumab (Lucentis, Genentech) treatment had macular thickness >300 µm at 1 year, and 40% had residual fluid at 2 years.⁸ At the 3-year visit, the percentage of Lucentis-treated eyes with central subfield thickness ≥250 μm was 36%. Similarly, in DRCR.net Protocol T study, after receiving an average of 10 injections in a year, 34% of aflibercept (Eylea, Regeneron) patients, 42% of Lucentis patients and 64% of bevacizumab (Avastin, Genentech) patients had >250-µm macular thickness.⁹ (For more on Protocol T, see page 9.)

My Approach to Treating DME

Most DME cases in my practice are severe, so it’s rare that a patient needs only a few anti-VEGF injections over a year’s time. More often, I recommend combination therapy as a means to potentially increase efficacy by taking advantage of more than one mechanism of action and simultaneously limiting the treatment burden by achieving a more lasting therapeutic effect. If we attempt to use only monotherapy — i.e., address only one factor contributing to a multifactor disease — invariably, we’ll have patients who will fail that treatment approach. Addressing more than one component of the disease makes the treatment more scientific and more in line with the current thinking on diabetes both systemically and in the eye. While combination therapy makes solid theoretical sense, only a small number of prospective studies of this approach have been conducted. (See “Recent Evaluations of Combination Therapy,” on page 14.) More research is needed to determine the precise effects of combination therapy and to compare options. In the meantime, we must rely on our clinical acumen to provide each patient with the best possible care.

When I examine a diabetic eye, I evaluate the global picture of the therapeutic need based on the severity of the retinal disease as indicated by clinical exam and imaging, history of treatment, pattern of recurrence, pattern of chronicity and underlying control of glucose. If the therapeutic need is significant, I know intense and prolonged treatment will be required. This also presents a high likelihood of noncompliance. Therefore, when I see this scenario, I immediately consider combination therapy, and most of my patients prefer it. I also consider combination therapy for patients with less substantial disease who are high functioning and want to have as few office visits as possible.

For patients with mild disease, anti-VEGF treatment alone could be enough to improve and sustain visual acuity and restore the macular anatomy. Based on the results of the Protocol T trial, and if conditions permit, I start with Eylea. However, if the response isn’t as predictable as I’d like, I quickly shift to combination therapy. In my opinion, there is no rationale for giving a certain number of injections before considering additional therapy. My additional therapy of choice is the dexamethasone intravitreal implant (Ozurdex, Allergan). In my experience, this implant is longer lasting and doesn’t carry the risk of intractable glaucoma or pseudoendophthalmitis that I’ve seen with triamcinolone. None of my Ozurdex patients has required any treatment beyond drops for IOP, and a vitrectomy would enable removal, if needed. Now that the fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) has been approved for DME, it is an option as well, although its side-effect profile appears to be a challenge.

Understanding the Limits of Monotherapy

As our scientific knowledge grows, we see that diseases have myriad reasons for coming to exist and we need to combat them on that playing field. For example, the more we understand about oncogenesis, the more we understand the way retinal diseases manifest. As in cancer, anti-VEGF represents only one branch of therapy for DME. At this point, it is inconceivable that monotherapy will be all we need for successful treatment of the ocular effects of diabetes. ■

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