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Retinal Physician

Article

Managing DME

Applying study findings to clinical practice

Retinal Physician March 1, 2016

The pathogenesis of diabetic macular edema (DME) is complex. Numerous factors associated with sustained hyperglycemia are responsible for disruption of the blood-retinal barrier and the resulting macular edema, including inflammation, elevated VEGF levels, and mechanical components, such as vitreomacular traction or pre-retinal membranes (Figure 1).

FIGURE 1. Sustained hyperglycemia from diabetes causes a complex cascade of responses leading to a wide range of complications, including diabetic macular edema.
FIGURE 1. Sustained hyperglycemia from diabetes causes a complex cascade of responses leading to a wide range of complications, including diabetic macular edema.

As retina specialists, we need to assess the treatments available to us in terms of efficacy, duration of action, safety, and cost to enable us to customize therapy, not only to the patient but also to each eye of each patient.

Efficacy

Once the gold standard for treating DME, focal laser photocoagulation generally only decreases the rate of vision loss. Although it still has a role for treating specific presentations of DME, it has been supplanted as first-line therapy by the anti-VEGF and sustained delivery corticosteroid agents, which improve visual acuity without destroying retinal tissue.

Some distinct differences exist between the anti-VEGF agents. For example, ranibizumab (Lucentis, Genentech) has a strong history of efficacy, but as shown in the Diabetic Retinopathy Clinical Research (DRCR) Network’s Protocol T study, aflibercept (Eylea, Regeneron) requires one less injection and has an efficacy advantage when presenting visual acuity is worse than 20/40.1

Corticosteroids can have similar efficacy to anti-VEGF agents in pseudophakic eyes.2 In previously vitrectomized eyes, the dexamethasone 0.7 mg intravitreal implant (Ozurdex, Allergan) is the treatment of choice, because its half-life does not change as opposed to the anti-VEGF agents whose half-life decreases markedly in vitrectomized eyes.3

Vitrectomy continues to have a role in managing DME, particularly in patients with distinct mechanical traction or those who are not responding to other therapies.4

Duration of Action

In terms of duration of action, our therapies for DME are quite different from one another. Ranibizumab has a recommended injection frequency of once a month, while the recommended injection frequency for aflibercept is once every 8 weeks, after the initial loading dose of 5 monthly injections.5,6 In addition, DRCR Protocol T found that at 1 year, 1 less injection of aflibercept was required compared with ranibizumab and bevacizumab.1 The 2-year DRCR Protocol T data should be available by this spring, and that will be enlightening in terms of whether these differences magnify or become less prominent.

In terms of durability, nothing beats the implantable corticosteroids. Eyes treated with the dexamethasone implant in the MEAD study needed only four or five injections in 36 months, which is a vast improvement over the 36 injections that were investigated in the RISE and RIDE trials during the same time period.7,8 What’s more, 75% of subjects who received the fluocinolone acetonide 0.19 mg implant (Iluvien, Alimera Sciences) needed only 1 treatment in 3 years.9 The durability of any treatment for DME is important, because compliance may become poor as the number of required visits increases.

Safety

Anti-VEGF agents demonstrate excellent local safety results.4,10 Corticosteroids can cause cataract and increased IOP; however, studies have shown that vision improves in steroid-treated eyes after cataract extraction, and IOP elevation usually can be managed with topical treatment.6,8

We are not aware of any systemic issues with the corticosteroids. However, some clinical trial data suggest a higher percentage of stroke and death may occur with ranibizumab compared with aflibercept and bevacizumab.11

Safety signals were observed in the RISE and RIDE trial in which there was a dose response in terms of the rate of death.8 In DRCR Protocol T, aflibercept and bevacizumab were safer from a cardiovascular and stroke standpoint compared with ranibizumab as discovered in a post-hoc analysis.1 DRCR Protocol T 2-year data should provide clarity regarding these signals seen in the year 1 data.

Cost of Treatment

Cost of treatment is a complicated calculation. Based solely on the recommended dosing schedules, ranibizumab is the most expensive pharmacotherapy, followed by aflibercept, fluocinolone, and dexamethasone. However, other variables also affect cost, such as the dosing regimen for a specific patient, the number of office visits, and the need for retinal imaging. Adding to the cost is the patient’s and/or caregiver’s time and expense to attend each visit. In addition, we need to factor in the cost of managing ocular and systemic adverse events, which can significantly add to the cost.

Another consideration is whether a patient has unilateral or bilateral disease. One advantage of more durable treatments is that patients with bilateral disease may be able to decrease the number of visits if their retina specialists do not perform same-day injections.

Summary

Diabetic macular edema clearly has a multifactorial etiology, and given the availability of different drug classes, we can now intervene at different points in the DME pathogenesis pathway with combined or sequential therapies. Our challenge is to determine in what combination and what frequency to use the tools we have available to us. We also need to consider switching therapies if a patient is not responding to the current dosing regimen, and we need to be flexible and customize treatment, taking into consideration efficacy, duration of effect, safety, and cost.

The following case represents some of the typical challenges we face when treating DME. ?

References

  1. Wells JA, Glassman AR, Ayala AR, et al.; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-1203.
  2. Elman MJ, Aiello LP, Beck RW, et al.; Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-1077.
  3. Boyer DS, Faber D, Gupta S, et al.; Ozurdex CHAMPLAIN Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011;31:915-923.
  4. Lim LT, Chia SN, Ah-Kee EY, Chew N, Gupta M. Advances in the management of diabetic macular oedema based on evidence from the Diabetic Retinopathy Clinical Research Network. Singapore Med J. 2015;56:237-247.
  5. Lucentis (ranibizumab) [package insert]. South San Francisco, CA; Genentech; revised February 2015.
  6. Eylea (aflibercept) [package insert]. Tarrytown, NY; Regeneron; revised July 2015.
  7. Boyer DS, Yoon YH, Belfort R Jr, et al.; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121:1904-1914.
  8. Brown DM, Nguyen QD, Marcus DM, et al.; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120:2013-2022.
  9. Campochiaro PA, Brown DM, Pearson A, et al.; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119:2125-2132.
  10. Korobelnik JF, Kleijnen J, Lang SH, et al. Systematic review and mixed treatment comparison of intravitreal aflibercept with other therapies for diabetic macular edema (DME). BMC Ophthalmol. 2015;15:52.
  11. Avery RL, Gordon GM. Systemic safety of prolonged monthly anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis. JAMA Ophthalmol. 2016;134:21-29.

CASE STUDY: Suboptimal Response

This 55-year-old African-American man has diabetes, hypertension, and hyperlipidemia, requiring several medications and visits with various medical specialists. He had undergone vitrectomy in both eyes for traction retinal detachment, and had been treated with bevacizumab, ranibizumab, and focal laser. He had suboptimal responses to all of these treatments, and has difficulty complying with required visits because of his bilateral disease and his work schedule.

In March 2014, the patient’s visual acuity was 20/70 OD and 20/100 OS, and he had profound macular edema in both eyes (Figure 1). We treated him with ranibizumab monotherapy in each eye.

FIGURE 1. The patient received ranibizumab in each eye at this visit.
FIGURE 1. The patient received ranibizumab in each eye at this visit.

At the patient’s next visit, his visual acuity had improved to 20/50 OD and 20/80 OS, but his macular edema persisted. We treated him again with ranibizumab in each eye. At the next visit, OCT showed some improvement, the right eye more than the left, and visual acuity was stable (Figure 2). We treated him again with ranibizumab.

FIGURE 2. At this visit, visual acuity was stable and some improvement was shown on OCT. Ranibizumab was administered in both eyes.
FIGURE 2. At this visit, visual acuity was stable and some improvement was shown on OCT. Ranibizumab was administered in both eyes.

At the next visit, visual acuity was stable. Macular edema remained stable in the left eye remained stable, but had increased in the right eye. At this point, the dexamethasone 0.7 mg intravitreal implant had just been cleared by FDA to treat DME, so we decided to use it to treat each eye. At the patient’s next visit (Figure 3), his visual acuity had improved to 20/40 OD, 20/70 OS, and the macular edema in both eyes had decreased significantly. We decided to withhold treatment at this visit.

FIGURE 3. After suboptimal response to anti-VEGF therapy, the patient received the dexamethasone 0.7 mg intravitreal implant, which produced improvements in both macular edema and visual acuity.
FIGURE 3. After suboptimal response to anti-VEGF therapy, the patient received the dexamethasone 0.7 mg intravitreal implant, which produced improvements in both macular edema and visual acuity.

This case illustrates the benefit of switching therapy to a completely different class in a patient with a suboptimal response.

Evidence-based Management of Diabetic Eye Diseases

CME POST-TEST QUESTIONS

  1. According to the International Diabetes Federation, approximately what percentage of people worldwide who are living with diabetes are undiagnosed?
    1. <20%
    2. <30%
    3. <40%
    4. >40%
  2. By what percentage did the number of diabetic retinopathy cases increase from 2000 to 2010, according to the National Eye Institute?
    1. ~10%
    2. <20%
    3. 50%
    4. 90%
  3. Based on results from the Diabetic Retinopathy Clinical Research Network’s Protocol T study, which of the following agents is most effective in eyes with visual acuities of 20/50 or worse?
    1. aflibercept
    2. bevacizumab
    3. dexamethasone
    4. ranibizumab
  4. In a post-hoc analysis of the DRCR Protocol T study, which of the following agents had the highest incidence of any cardiovascular event, excluding hypertension?
    1. aflibercept
    2. bevacizumab
    3. dexamethasone
    4. ranibizumab
  5. What was the difference in visual acuity gains in eyes that were pseudophakic at baseline and treated with triamcinolone and prompt laser versus eyes treated with ranibizumab and prompt or deferred laser in Protocol I?
    1. Both groups had similar visual acuity gains.
    2. Triamcinolone/laser eyes had significantly greater gains than ranibizumab/laser eyes.
    3. Ranibizumab/laser eyes had significantly greater gains than triamcinolone/laser eyes.
    4. This comparison was outside the scope of the study.
  6. Which of the following agents is FDA-approved for the treatment of DME in patients who have been previously treated with a steroid and did not have a clinically significant rise in IOP?
    1. aflibercept
    2. dexamethasone
    3. fluocinolone
    4. triamcinolone
  7. Which of the following agents may be preferred for treating DME in vitrectomized eyes because its half-life does not change?
    1. aflibercept
    2. dexamethasone
    3. ranibizumab
    4. triamcinolone
  8. Which therapy continues to have a role in managing DME in eyes with vitreomacular traction?
    1. anti-VEGF agents
    2. corticosteroids
    3. laser photocoagulation
    4. vitrectomy
  9. Which of the following agents maintains its potency for the longest period?
    1. aflibercept
    2. dexamethasone
    3. fluocinolone
    4. ranibizumab
  10. Based solely on the recommended dosing schedule, which of the following agents is least expensive?
    1. aflibercept
    2. dexamethasone
    3. fluocinolone
    4. ranibizumab

Please visit dannemiller.com/test/1034 to view this activity online, complete the post-test and evaluation.

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