Halting and reversing diabetic retinopathy plays an important role in vision preservation in our patients with diabetes. Part 1 of this series focused on systemic disease control, laser photocoagulation, and surgical and pharmacologic vitreolysis in the treatment of DR. Part 2 of this series will look at the evidence presented over the last decade, showing the markedly positive effects of intravitreal anti-VEGF and steroids on DR progression.
As mentioned in part 1 of this three-part series, various methods to assess DR progression and treatment response have been utilized in major clinical trials. A number of the methods utilized in several key anti-VEGF and steroid treatment trials are summarized in the Table.
It is worth noting that some measures focus on the structural assessment of progression, including the DR severity score (DRSS), while others consider the severity of DR (nonproliferative DR [NPDR] vs proliferative DR [PDR]), and still others assess indirect measures that may be surrogates for DR progression, including changes in best-corrected visual acuity and structural changes, as assessed by optical coherence tomography.
Framing the results of these studies in light of the metrics presented can help clinicians to interpret the value of DR progression as a treatment outcome. Determining the clinical value of changes in DRSS will be the focus of part 3 of this series.
The introduction of intravitreal anti-VEGF therapy has been perhaps the single greatest therapeutic advancement in medical retina in the last 50 years. Several multicenter, randomized, controlled trials have conclusively demonstrated the superiority of anti-VEGF injections for diabetic macular edema, compared to sham, laser, and intravitreal triamcinolone acetonide injections.
RIDE and RISE were pivotal studies investigating the role of ranibizumab (Lucentis, Genentech, South San Francisco, CA) for DME.1 A secondary analysis of these studies was DR progression utilizing the DRSS. Ip and colleagues 9 reported that a ≥3-step DR improvement in patients with NPDR or PDR was achieved at 36 months in 15.0% and 13.2% of patients receiving 0.3 mg or 0.5 mg of ranibizumab monthly, respectively. In contrast, only 3.3% of patients in the sham/0.5-mg ranibizumab crossover group achieved the same degree of DR improvement.
The cumulative probability of DR progression to PDR by month 36 was 39.1% of eyes in the sham/crossover group vs 18.3% and 17.1% of eyes treated with 0.3 mg or 0.5 mg of ranibizumab monthly, respectively. After switching to monthly ranibizumab, the patients in the sham group had an attenuated rate of PDR development more comparable to the arms receiving intensive anti-VEGF.
To further explore the possibility of an extended treatment benefit following initial intensive anti-VEGF therapy, the open-label extension of RIDE and RISE enrolled 500 patients who had previously completed the 36-month randomized core studies. For these patients, retreatment with 0.5 mg of ranibizumab was offered PRN, based on pre-defined criteria.
|TRIAL||OUTCOME MEASURES (PARTIAL LIST)|
|RIDE and RISE1||BCVA improvement of ≥15 ETDRS letters||Anatomic improvement (OCT, clinical findings)||DR progression assessed via the early treatment diabetic retinopathy study (ETDRS) DRSS||Occurrence of a new PDR event2|
|DRCR.net protocoI3||BCVA improvement of ≥10 ETDRS letters||Central retinal thickness (OCT)||DR progression (7-field color stereoscopic images obtained at baseline and 12 months)||Development of PDR, ≥2 step ETDRS DR score worsening, needing PRP, development of vitreous hemorrhage, and requiring surgery for PDR4|
|VISTA and VIVID5||Mean change in BCVA, including proportion of eyes gaining ≥15 ETDRS letters||Proportion of eyes with a ≥2 step improvement in the DRSS|
|DRCR.net Protocol B6||Visual acuity assessed via ETDRS letters||Central retinal thickness (OCT)|
|MEAD7||Percentage of patients achieving ≥15 ETDRS letters||Central retinal thickness (OCT)|
|FAME8||Percentage of patients achieving ≥15 ETDRS letters||Central retinal thickness (OCT)||≥2 step DRSS improvement|
At month 48, 11.2% and 7.6% of patients in the 0.3-mg and 0.5-mg ranibizumab groups, respectively, achieved ≥3-step DRSS improvement vs only 4.8% in the sham group with ranibizumab crossover. A ≥2-step DRSS worsening occurred in approximately 2.5% of patients in the ranibizumab groups vs 11.3% in the sham/crossover group.
Patients originally randomized to ranibizumab had a lower risk of developing a new PDR event compared with patients originally randomized to sham, and these results persisted through month 54.9 These data suggested that early, frequent anti-VEGF was essential to halting, and in many cases reversing, DR progression.
Protocol I from the DRCR.net was a prospective, randomized trial comparing sham plus focal laser (S+FL), triamcinolone plus prompt focal laser (T+pFL), and anti-VEGF (ranibizumab) with either prompt (R+pFL) or deferred focal laser (R+dFL) for patients with center-involved DME.3
Patients in the injection arms of the trial received monthly injections through week 12 and then were assigned to receive additional injections, based on strictly defined criteria. To assess DR progression, the researchers had the cohort separated into patients with and without PDR at the time of randomization.4
For patients without PDR, at 36 months, 7%, 18%, 23%, and 37% of patients had worsening in the R+dFL, R+pFL, S+FL, and T+pFL groups, respectively. For patients with PDR at randomization, 18%, 21%, 40%, and 12% had worsening in the R+dFL, R+pFL, S+FL, and T+pFL groups, respectively.
Eyes assigned to R+dFL, R+pFL, or T+pFL had decreased rates of vitreous hemorrhage and were less likely to require panretinal photocoagulation, compared to patients in the S+FL group. These data again showed the protective effect of ranibizumab against DR progression.
More recently, the DRCR.net group released data comparing ranibizumab to PRP for high-risk PDR.10 With two years of follow-up, they found ranibizumab to be noninferior to PRP for the management of PDR in terms of VA change.
Eyes with inactive or regressed neovascularization at two years were not significantly different between the groups, providing additional evidence that ranibizumab halts DR progression in many patients with PDR at baseline.
Data presented at the 2016 Retina Society meeting showed that eyes with PDR at randomization that were treated with intravitreal ranibizumab had a lower rate of PDR progression, compared to eyes treated with PRP.11 These results persisted through two years of follow-up.
The VISTA and VIVID studies compared aflibercept (Eylea, Regeneron, Tarrytown, NY) to macular laser for DME.5 These studies definitively showed the superiority of aflibercept in terms of VA gains and ≥2-step improvement in DRSS score.
Patients receiving intravitreal aflibercept either monthly or every two months after five monthly loading doses were approximately three times more likely to achieve a ≥2-step improvement in DRSS score, compared to patients receiving laser photocoagulation. Patients were not subdivided into those with NPDR vs those with PDR, and no data were reported regarding rates of progression to PDR between the two groups.
Baseline DRSS score was the only factor significantly associated with ≥2-step improvement in DRSS score.12 Aflibercept is FDA approved as a treatment for patients with DR and DME, but it is not approved for use to stop DR progression.
The BOLT study investigated bevacizumab (Avastin, Genentech, South San Francisco, CA) vs laser therapy for DME and found that eyes treated with bevacizumab had a statistically significant improvement in BCVA.13
ETDRS retinopathy levels were also reported, and the bevacizumab arm demonstrated a trend toward a reduction in DR severity, although statistical significance was not attained, perhaps because only 80 patients were included in the analysis (42 receiving bevacizumab and 38 receiving focal laser).
Recent studies comparing all three anti-VEGF agents currently used in the United States have shown that they all have efficacy in the treatment of DR, and these results have been confirmed with two-year follow-up data.14 More data are needed to fully ascertain the effect of bevacizumab on DR progression.
Several large, randomized, multicenter clinical trials have definitively shown the protective effect of early anti-VEGF for stopping and, in some cases reversing, DR progression. The reason for DR reversal with anti-VEGF is not fully known, although it has been postulated that capillary nonperfusion is a primary contributor to DR progression in patients with more advanced DR at baseline.9 In patients with DME, there is a time-dependent increase in retinal nonperfusion (RNP), and anti-VEGF therapy blocks the feedback loop responsible for this phenomenon.
In RIDE and RISE, secondary analysis of fluorescein angiograms was performed by masked graders, using a modified ETDRS FA grading protocol. Once patients previously in the sham treatment group were treated with ranibizumab, RNP growth halted and was reversed in many cases.15 This finding suggests that blocking the downstream effects of VEGF is key to halting and reversing DR progression.
Recent OCT angiography data have suggested that patients with deep capillary plexus damage are more likely to respond poorly to anti-VEGF treatment, and this imaging modality could play a role in helping to predict treatment response.16
LOCAL CORTICOSTEROID THERAPY
Steroid therapy exerts a treatment effect in DR through the inhibition of leukostasis, enhancement of the barrier function of vascular endothelial-cell tight junctions, and mitigation of inflammatory factors including VEGF.7 The place of steroids in DR treatment regimens has been confirmed in several large, multicenter trials, and ongoing research is focusing on continued optimization of appropriate patient selection.
DRCRnet Protocol B compared intravitreal triamcinolone acetonide injections to macular laser for the treatment of DME. The primary outcome measurements were changes in VA and central retinal thickness, and triamcinolone was not found to be superior to macular laser.
Side effects in the triamcinolone groups were more common than those in the laser treatment group. However, additional analysis of the data obtained in this study focused on DR progression, and high-dose intravitreal triamcinolone (0.4 mg) was found to result in a statistically significant reduction in DR progression, compared to laser alone. This result persisted through three years of follow-up.
Due to the side effects experienced by patients receiving intravitreal triamcinolone, the authors cautioned that a reduction in DR progression alone should not be used to change treatment protocols. DRCRnet Protocol I showed that triamcinolone was effective in reducing DR progression, particularly in patients with pre-existing PDR.
Subgroup analysis of eyes that were pseudophakic showed better VA gains, as would be expected given the elimination of cataracts as a potential side effect. The difference in efficacy of triamcinolone between Protocols B and I might be due to patients in Protocol I receiving prompt focal laser following intravitreal triamcinolone.4
The pivotal MEAD study investigated a dexamethasone implant (Ozurdex, Allergan, Irvine, CA) compared to sham in the treatment of DME.7 The group treated with the implant had a statistically significant improvement in the percentage of patients achieving ≥15-ETDRS letters of improvement at study completion.
Compared with sham-treated patients, patients receiving the dexamethasone implant (either dose) had an approximately 12-month delay in two-step DR progression (36 months vs 24 months).17 The 10th percentile of the time to two-step DR improvement occurred at 13 months in the low-dose group vs 24 months for the patients receiving sham or the high-dose implant. Cataract formation and intraocular pressure elevation were the two most common side effects.
Fluocinolone Acetonide Implant
The fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences, Alpharetta, GA) is an injectable, nonerodible, corticosteroid implant that has been shown to provide treatment benefit for at least three years. This implant represents one of the newest additions to the DR treatment armamentarium and holds promise for patients with treatment-resistant DME.
The FAME study group8 investigated a low- (0.2 µg/day) and high-dose (0.5 µg/day) fluocinolone implant in patients with persistent DME despite at least one macular laser treatment. A ≥2-step improvement in DRSS occurred in 13.7% of the patients receiving the low-dose implant, compared to only 8.9% in the sham group.
The side effects of the fluocinolone implant included cataract formation and elevated IOP requiring tube shunt surgery in just under 5% of patients receiving the low-dose implant vs 8% in the high-dose group. This finding highlights the importance of careful selection criteria for this implant, and recent work has focused on providing patient selection guidelines based on the FAME trial data.18
SUMMARY AND FUTURE DIRECTIONS
In summary, the single most important factor for slowing DR progression remains aggressive blood glucose control, with a target A1C of less than 7%. Continuing to educate our patients on the importance of blood glucose, blood pressure, and lipid control remains paramount, even in the age of anti-VEGF therapy.
However, the importance of the early identification and treatment of DME with anti-VEGF agents should not be understated. The data strongly support early, aggressive treatment, with a corresponding stabilization, and in many cases reversal, of retinopathy progression. After this initial intensive treatment period, the data suggest that de-escalation of anti-VEGF therapy is possible without compromising initial VA gains.
The pathophysiology underlying the ocular response to anti-VEGF is only partially understood, and data utilizing new imaging techniques, including OCT angiography and ultrawidefield FA, may provide additional answers to help guide treatment.
Steroid therapy may play a role as a second-line therapy in patients with anti-VEGF resistant DME. Sustained-release steroid formations hold promise, particularly for pseudophakic patients who have passed a steroid IOP challenge. Additional research is needed to help identify ideal treatment regimens for patients earlier in their disease courses. RP
- Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801.
- Boyer DS, Nguyen QD, Brown DM, et al. Outcomes with as-needed ranibizumab after initial monthly therapy: Long-term outcomes of the phase III RIDE and RISE Trials. Ophthalmology. 2015;122:2504-2413.
- Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-1077.
- Bressler SB, Qin H, Melia M, et al. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013;131:1033-1040.
- Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122(10):2044-2052.
- Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1449.
- Boyer DS, Yoon YH, Belfort R Jr, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121:1904-1914.
- Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119:2125-2132.
- Ip MS, Domalpally A, Sun JK, et al. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122:367-374.
- Writing Committee for the Diabetic Retinopathy Clinical Research Network; Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314:2137-2146.
- Bressler SB. Panretinal photocoagulation versus intravitreous ranibizumab for proliferative diabetic retinopathy (PDR): worsening of PDR. Paper presented at: Annual meeting of the Retina Society; San Diego, CA; September 16, 2016.
- Singh R. Association between baseline characteristics and changes in diabetic retinopathy severity scale (DRSS) score: analyses from the VISTA and VIVID studies. Paper presented at: Annual meeting of the Retina Society; San Diego, CA; September 15, 2016.
- Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010;117:1078-1086.
- Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123:1351-1359.
- Campochiaro PA, Wykoff CC, Shapiro H, et al. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014;121:1783-1789.
- Lee J, Moon BG, Cho AR, et al. Optical coherence tomography angiography of DME and its association with anti-VEGF treatment response. Ophthalmology. 2016;123:2368-2375.
- Danis RP, Sadda S, Li XY, et al. Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials. Br J Ophthalmol. 2016;100:796-801.
- Parrish RK 2nd, Campochiaro PA, Pearson PA, et al. Characterization of intraocular pressure increases and management strategies following treatment with fluocinolone acetonide intravitreal implants in the FAME trials. Ophthalmic Surg Lasers Imaging Retina. 2016;47:426-435.