Intravitreal Anti-VEGF Injection Treatment Algorithms for DME

Benefits and limitations of common approaches to managing patients with diabetic macular edema.

By Christopher M. Aderman, MD, and Sunir J. Garg, MD

Diabetic macular edema (DME) affects an estimated 746,000 Americans.1 Although available treatments can preserve and improve vision for the vast majority of patients, these treatments can be associated with substantial costs and visit burdens; therefore, determining the optimal treatment regimen is critical. Focal laser and intravitreal steroids remain important in the treatment of patients with DME,2-4 but most patients today receive intravitreal anti-VEGF therapy. In this article we discuss the pluses and minuses of common anti-VEGF injection treatment algorithms for patients with DME.


• For eyes with center-involving DME, monthly treatment leads to rapid visual acuity improvement that is maintained for at least 3 years.

• Although PRN treatment leads to gains in visual acuity and a substantial reduction in the number of injections and visits over time, patients still need frequent monitoring.

• Monthly, PRN, and treat-and-extend injection protocols can each achieve significant visual acuity improvement. A treat-and-extend regimen can provide visual acuity benefits similar to those of monthly and PRN regimens with fewer visits and injections.


The phase 3 RISE and RIDE clinical trials5 and the phase 3 VIVID and VISTA trials6 established the superiority of anti-VEGF drugs over focal laser for the treatment of eyes with DME. These pivotal clinical trials were designed to establish treatment superiority over focal laser and were modeled after earlier studies in which intravitreal injections of an anti-VEGF agent were administered monthly for treatment of exudative age-related macular degeneration (AMD).


There are several advantages to treating eyes with center-involving DME with monthly intravitreal injections regardless of the presence or absence of edema. Visual acuity and anatomic data suggest that this fixed treatment regimen leads to rapid visual acuity improvement and that the gain is maintained for at least 3 years. For some patients, visual acuity continues to improve for up to 1 year before stabilizing. The other main benefit of monthly treatment is regression of diabetic retinopathy (DR). With monthly treatment, 35.9% to 47.0% of patients experienced regression of 2 or more steps in DR severity score, and 13.2% to 15.0% had regression of 3 or more steps in retinopathy severity.7-10


Drawbacks to monthly treatment include the financial cost to patients and insurers and substantial investment of time. Patients must dedicate several hours each month to traveling to the office, and family members often share this burden, further increasing indirect costs. In addition, the repeated injections carry a low but real risk of endophthalmitis and other complications related to the injection itself.


In contrast to fixed monthly injections, as-needed (PRN) treatment protocol injections are administered based on the presence of DME. The decision to inject is at the discretion of the physician, who may take into account such factors as changes in visual acuity or persistent or worsening center-involving DME on clinical examination or optical coherence tomography (OCT) imaging.

The Diabetic Retinopathy Clinical Research Network ( Protocol I study11 provides the best data we have on a PRN treatment protocol for patients with DME. In the algorithm used in that study, patients randomly assigned to ranibizumab (Lucentis, Genentech) treatment received monthly injections for 6 months and then continued to receive monthly injections until their visual acuity reached 20/20, until OCT central subfield thickness was less than 250 µm, or until there was a less than 10% change in OCT thickness or less than 5 letter change in visual acuity since the last treatment. Treatment could then be restarted at a subsequent visit if visual acuity dropped by 10 or more letters from baseline, if OCT central subfield thickness was greater than 250 µm, or if DME was judged to be the cause of visual acuity loss.

During year 1 in Protocol I, patients had an average of 13 visits and received injections of ranibizumab either with prompt laser or with deferred laser. During year 2, patients had an average of eight or 10 visits and received two or three injections of ranibizumab with prompt or deferred laser, respectively. The burden of visits and injections further decreased in year 3, with a mean of seven or eight visits and one or two injections in the prompt and deferred laser groups, respectively. This benefit was maintained to year 5, when four or five clinic visits were needed with a median of zero injections while visual acuity gains were maintained in each group.12

The Good and the Bad

An advantage of this approach is that eyes have robust visual acuity gains, followed by stability, with a substantial reduction in the number of injections and visits over time. However, patients still need frequent follow-up, particularly early after initiation of treatment to determine whether treatment is required, so issues with visit burden still exist.

Figure 1. The number of retina specialists using a treat-andextend protocol has been steadily increasing over the past few years.13 Most respondents to the 2016 ASRS Practices and Trends survey would use a treat-and-extend protocol if they themselves had AMD. Graph used with permission of American Society of Retina Specialists.


Based on responses to the 2016 American Society of Retina Specialists (ASRS) Preferences and Trends survey, the number of retina specialists using a treat-and-extend protocol has been increasing over the past 7 years, and most retina specialists would treat their own exudative AMD with a treat-and-extend protocol (Figure 1).13 This strategy has also been used in treatment of patients with retinal vein occlusions14 and patients with DME.15-17 The goal of this treatment regimen is to find the longest amount of time between visits (and therefore the fewest visits and number of injections) at which visual acuity is maintained along with continued resolution or stability of edema.

A treat-and-extend regimen incorporates elements of both monthly and PRN treatment regimens. As with a monthly regimen, the physician administers intravitreal injections at each clinic visit, but, instead of a fixed 4-week follow-up interval, the length of the interval varies based on disease activity. On presentation, eyes are often treated monthly until macular edema resolves or until there is no further improvement in macular edema or visual acuity. As soon as the eye is deemed to have no edema, stable visual acuity, or stable macular thickness on OCT over several visits, a baseline has been established. The treatment interval is then extended by 1 to 2 weeks at a time, as long as vision and macular edema remain stable. If macular edema recurs or the visual acuity decreases, the interval is shortened by 1 to 2 weeks until the eyes return to their baseline (Figure 2).

Figure 2. A 47-year-old patient presented with center-involving DME and visual acuity of 20/50 (top). The patient responded well to initial injections at 4-week intervals with stabilization after four visits, so the visit interval was increased from every 4 weeks to every 6 weeks. When the interval was extended to 8 weeks, the edema returned. The interval was reduced to 6 weeks, and the edema again decreased (bottom).


A treat-and-extend regimen has several potential advantages. Unlike with a PRN schedule, the clinician does not have to wait until macular edema is worse before treating the patient. Chronic macular edema can lead to irreversible vision loss, so preventing recurrence of edema can potentially preserve visual acuity in the long term, although studies are needed to confirm this.

A treat-and-extend regimen can also reduce the number of office visits without sacrificing visual acuity. One retrospective case series compared a visual acuity–guided PRN (VAPRN) protocol with an OCT-guided treat-and-extend (OCTAE) regimen in patients with DME treated with ranibizumab.15 At 1-year follow-up, there was no significant difference in visual acuity (+8.3 letters vs. +9.3 letters) in the VAPRN and OCTAE groups, respectively, although the VAPRN group required fewer injections (5.9 vs. 8.9) than the OCTAE group (P < .001). It is not clear whether these visual acuity and OCT outcomes would be maintained over time.

In another retrospective series, the mean number of injections using a treat-and-extend regimen was 8.8 over a 2-year follow-up period with a mean injection interval of 11 weeks.16 Best corrected visual acuity (BCVA) improved from 0.37 logMAR at baseline to 0.19 logMAR at 2 years, an improvement of 0.18 logMAR (equivalent to +9 ETDRS letters), and 37.5% of participants gained more than 2 lines.

A multicenter randomized study recently compared ranibizumab for the treatment of patients with DME administered in one of three regimens: monthly, or on a treat-and-extend basis either with or without macular laser administered at month 1 and again every 3 months based on microaneurysm leakage on fluorescein angiography.17 At 1 year, mean BCVA was not statistically significantly different among the three cohorts (+8.6 letters for monthly treatment, +9.6 letters for treat-and-extend without laser, and +9.5 letters for treat-and-extend with laser; P = .8). Although there was no difference in BCVA among the groups, the number of injections required to achieve these visual acuity gains was significantly lower in both treat-and-extend groups compared with the monthly group (10.7 injections for treat-and-extend without laser, 10.1 injections for treat-and-extend with laser, and 13.1 injections for the monthly group; P = < .001).


All three intravitreal anti-VEGF injection treatment protocols discussed above can achieve significant visual acuity improvement over the short term; however a treat-and-extend regimen can provide visual acuity benefits similar to those of the other two regimens but with fewer visits and injections. This individualized treatment schedule allows efficient dosing of anti-VEGF therapy, minimizing the amount of time edema is present while requiring the fewest possible injections and patient visits. However, long-term data and the effect of a treat-and-extend regimen on DR severity are not well established.

1. Varma R, Bressler NM, Doan QV, et al. Prevalence of and risk factors for diabetic macular edema in the United States. JAMA Ophthalmol. 2014;132(11):1334-1340.

2. [no authors listed]. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103(12):1796-1806.

3. Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006;113(9):1533-1538.

4. Gillies MC, Simpson JM, Gaston C, et al. Five-year results of a randomized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmology. 2009;116(11):2182-2187.

5. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.

6. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.

7. Gross JG, Glassman AR, Jampol LM, et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314(20):2137-2146.

8. Ip MS, Domalpally A, Hopkins JJ, et al. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012;130(9):1145-1152.

9. Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122(2):367-374.

10. Ip MS, Zhang J, Ehrlich JS. The clinical importance of changes in diabetic retinopathy severity score. Ophthalmology. 2017;124(5):596-603.

11. 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(6):1064-1077.

12. Bressler SB, Glassman AR, Almukhtar T, et al; Diabetic Retinopathy Clinical Research Network. Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. Am J Ophthalmol. 2016;164:57-68.

13. Stone TW, ed. ASRS 2016 Preferences and Trends Membership Survey: Chicago, IL. American Society of Retina Specialists; 2016.

14. Rush RB, Simunovic MP, Aragon AV 2nd, Ysasaga JE. Treat-and-extend intravitreal bevacizumab for branch retinal vein occlusion. Ophthalmic Surg Lasers Imaging Retina. 2014;45(3):212-216.

15. Ebneter A, Waldmeier D, Zysset-Burri DC, Wolf S, Zinkernagel MS. Comparison of two individualized treatment regimens with ranibizumab for diabetic macular edema. GraefesArch Clin Exper Ophthalmol. 2017;255(3):549-555.

16. Sugimoto M, Ichio A, Nunome T, Kondo M. Two year result of intravitreal bevacizumab for diabetic macular edema using treat and extend protocol. Medicine (Baltimore). 2017;96(16):e6406.

17. Payne JF, Wykoff CC, Clark WL, Bruce BB, Boyer DS, Brown DM; TREX-DME Study Group. Randomized trial of treat and extend ranibizumab with and without navigated laser for diabetic macular edema: TREX-DME 1 Year Outcomes. Ophthalmology. 2017;124(1):74-81.11

Christopher M. Aderman, MD
• second-year retina fellow at Wills Eye Hospital in Philadelphia, Pa.
• financial interest: none acknowledged

Sunir J. Garg, MD
• professor of ophthalmology, the retina service of Thomas Jefferson University; co-director, Retina Research, Mid Atlantic Retina, the retina service of Wills Eye Hospital, both in Philadelphia, Pa.
• financial interest: none acknowledged


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Retina Today is a publication that delivers the latest research and clinical developments from areas such as medical retina, retinal surgery, vitreous, diabetes, retinal imaging, posterior segment oncology and ocular trauma. Each issue provides insight from well-respected specialists on cutting-edge therapies and surgical techniques that are currently in use and on the horizon.