Retina · Clinical Trials
Landmark Clinical Trials in Diabetic Retinopathy and Diabetic Macular Oedema
A trial-to-practice review of the evidence that established systemic control, anti-VEGF therapy, deferred macular laser, observation in good-vision DME and modern treatment strategies for proliferative diabetic retinopathy.
- DCCT & UKPDS
- RISE & RIDE
- VIVID & VISTA
- PHOTON
- DRCR Protocols
Companion note:
Focus on the question each trial asked, its principal result and how
that result should influence clinical decision-making.
Watch the Lecture
Watch the lecture first, or use this companion note to revise the clinical question, principal result and present-day implication of each landmark trial.
Insight Ophthalmology companion lecture on systemic-control trials, anti-VEGF studies and selected DRCR Retina Network protocols.
How to Read a Clinical Trial
Trial names are easier to remember when each study is reduced to the clinical decision it was designed to answer.
Clinical question
Study population
Treatment comparison
Principal result
Practice change
Revision principle:
Do not memorise a trial only by its drug or acronym. Link it to the
clinical question it answered and the decision it changed.
Systemic Control Changes Retinal Outcomes
Before studying eye injections and laser treatment, remember that controlling diabetes and blood pressure can reduce the development and progression of diabetic retinopathy.
DCCT
Type 1 diabetes- Full name: Diabetes Control and Complications Trial.
- It compared intensive glucose control with conventional glucose control.
- Intensive treatment reduced the development and progression of diabetic retinopathy by approximately 34%–76%, depending on the patient group and outcome studied. [1]
- Main lesson: Good glycaemic control should begin early in type 1 diabetes.
UKPDS
Type 2 diabetesThe United Kingdom Prospective Diabetes Study produced several reports. Two are especially important for diabetic retinopathy.
UKPDS 33 — Glucose control
- It compared intensive with conventional glucose control.
- Intensive glucose control reduced microvascular complications by approximately 25%. [2]
- Fewer patients required retinal photocoagulation.
- Main lesson: Better glucose control reduces diabetic microvascular disease.
UKPDS 38 — Blood-pressure control
- It studied patients with type 2 diabetes and hypertension.
- Tighter blood-pressure control reduced microvascular endpoints by approximately 37%. [3]
- It also reduced retinopathy progression and visual-acuity deterioration.
- Main lesson: Blood-pressure control is an essential part of protecting vision in type 2 diabetes.
Clinical Pearl:
Systemic control reduces long-term retinal risk, but it does not replace
injections or laser once vision-threatening diabetic eye disease has
developed.
Ranibizumab Trials in DME
These trials answered two simple questions: whether a higher dose of ranibizumab was better, and whether ranibizumab improved vision compared with sham treatment.
READ-3
Dose-comparison trial- Clinical question: Does a higher dose of ranibizumab produce better results in centre-involved diabetic macular oedema?
- Comparison: Ranibizumab 0.5 mg versus ranibizumab 2 mg.
- At six months, the higher 2 mg dose did not provide an important additional visual or anatomical benefit.
- At 24 months, both groups improved, but the 0.5 mg group had a greater mean visual gain in this study. [4]
Main lesson:
Increasing the ranibizumab dose to 2 mg did not provide additional
benefit over 0.5 mg.
RISE and RIDE
Ranibizumab versus sham- These were two parallel phase 3 trials in eyes with vision-impairing DME.
- Patients received monthly ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injections.
- The main endpoint was the proportion of eyes gaining at least 15 ETDRS letters at 24 months.
- Approximately 33.6%–45.7% of ranibizumab-treated eyes gained at least 15 letters.
- Only approximately 12.3%–18.1% of sham-treated eyes achieved the same gain. [5]
- Ranibizumab also improved retinal thickness and reduced the need for macular laser.
- The benefits were largely maintained through 36 months. [6]
Main lesson:
Ranibizumab produced substantially better visual and anatomical
outcomes than sham treatment in vision-impairing DME.
Aflibercept Trials in DME
These trials answered two related questions: whether aflibercept was better than macular laser, and whether its visual benefit could be maintained over several years.
DA VINCI
Phase 2 trial- Clinical question: Does aflibercept provide better visual outcomes than modified ETDRS macular laser in centre-involved DME?
-
Treatment groups:
- Aflibercept 0.5 mg every 4 weeks
- Aflibercept 2 mg every 4 weeks
- Aflibercept 2 mg every 8 weeks after 3 initial monthly doses
- Aflibercept 2 mg as needed after 3 initial monthly doses
- Modified ETDRS macular laser
- At 24 weeks, mean visual gain with the aflibercept regimens was approximately +8.5 to +11.4 letters.
- The laser group gained approximately +2.5 letters.
- The visual and anatomical benefits of aflibercept were maintained through one year. [7]
Main lesson:
All four aflibercept regimens produced better visual and anatomical
outcomes than macular laser. The trial was not designed to establish
one aflibercept regimen as definitively superior to the others.
VIVID and VISTA
Phase 3 trials- These were two large phase 3 trials comparing aflibercept with macular laser.
-
Treatment groups:
- Aflibercept 2 mg every 4 weeks
- Aflibercept 2 mg every 8 weeks after 5 initial monthly doses
- Macular laser
- At 148 weeks, both aflibercept groups maintained mean visual gains of approximately 10–12 letters.
- The laser groups gained only approximately 1–2 letters.
- The every-four-week and every-eight-week aflibercept regimens had broadly similar visual efficacy. [8]
Main lesson:
Aflibercept provided durable visual benefit over three years. The
2 mg every 8 weeks regimen after five monthly loading doses
achieved broadly similar efficacy to dosing every four weeks.
PHOTON: Extending Aflibercept Treatment Intervals
The PHOTON trial asked whether aflibercept 8 mg could maintain vision with longer intervals between injections.
PHOTON
Aflibercept 8 mg in DME- Population: Eyes with diabetic macular oedema requiring anti-VEGF treatment.
-
Treatment groups:
- Aflibercept 2 mg every 8 weeks after 5 initial monthly doses
- Aflibercept 8 mg every 12 weeks after 3 initial monthly doses
- Aflibercept 8 mg every 16 weeks after 3 initial monthly doses
- Treatment intervals in the 8 mg groups could be shortened if prespecified visual or anatomical disease-activity criteria were met.
- At 48 weeks, aflibercept 8 mg given at intended 12- or 16-week intervals produced visual outcomes that were non-inferior to aflibercept 2 mg every 8 weeks. [9]
- At 96 weeks, visual outcomes remained comparable, with fewer injections in the aflibercept 8 mg groups. [10]
- Many patients maintained extended treatment intervals, but not every eye could remain at the longest interval.
Main lesson:
Aflibercept 8 mg can reduce treatment frequency in many eyes while
maintaining visual outcomes comparable to aflibercept 2 mg every
eight weeks.
Protocol T: Which Anti-VEGF Agent?
Protocol T asked whether aflibercept, bevacizumab or ranibizumab produced better visual outcomes in centre-involved DME.
DRCR Retina Network Protocol T
Comparative-effectiveness trial- Population: Eyes with centre-involved diabetic macular oedema and reduced visual acuity.
- Treatments compared: Aflibercept 2 mg, bevacizumab 1.25 mg and ranibizumab 0.3 mg.
- The results depended mainly on the patient’s visual acuity before treatment.
| Baseline vision | Main finding | Clinical meaning |
|---|---|---|
| 20/32–20/40 | Mean visual outcomes were similar with aflibercept, bevacizumab and ranibizumab. | When initial visual loss was mild, no drug had a major average visual advantage. |
| 20/50 or worse at 1 year | Aflibercept produced greater mean visual gain than both bevacizumab and ranibizumab. | Aflibercept had the clearest early advantage when starting vision was poorer. |
| 20/50 or worse at 2 years | Aflibercept remained better than bevacizumab, but was no longer significantly better than ranibizumab. | The difference between aflibercept and ranibizumab became smaller with longer follow-up. |
- In eyes starting with vision of 20/50 or worse, the mean two-year visual gains were approximately:
- Aflibercept: +18.1 letters
- Bevacizumab: +13.3 letters
- Ranibizumab: +16.1 letters [12]
Main lesson:
The preferred initial anti-VEGF agent cannot be decided from the trial
name alone. The result must be interpreted according to
baseline visual acuity.
Protocol I: Should Macular Laser Be Added?
Protocol I asked whether focal or grid laser should be given immediately when ranibizumab treatment is started for vision-impairing DME.
DRCR Protocol I
Ranibizumab with prompt versus deferred laser- Population: Eyes with centre-involved DME and reduced visual acuity.
-
Original treatment groups:
- Sham injection with prompt focal/grid laser
- Ranibizumab with prompt focal/grid laser
- Ranibizumab with laser deferred for at least 24 weeks
- Intravitreal triamcinolone with prompt focal/grid laser
- The most important long-term comparison was between ranibizumab with prompt laser and ranibizumab with deferred laser.
Prompt laser
Focal or grid laser was performed when ranibizumab treatment began.
Deferred laser
Laser was withheld for at least 24 weeks and was considered later
only if persistent oedema remained despite ranibizumab treatment.
Five-year result
Starting laser immediately did not produce better long-term visual
outcomes than deferring laser.
Laser avoided
In the deferred group, 56% of eyes did not require laser
during five years of follow-up.
[13]
Main lesson:
When ranibizumab is started for vision-impairing centre-involved DME,
macular laser does not need to be given routinely at the first visit.
It can be deferred and considered later if oedema persists.
Protocol S: Anti-VEGF or PRP for PDR?
Protocol S asked whether ranibizumab could provide visual outcomes comparable to panretinal photocoagulation in proliferative diabetic retinopathy.
DRCR Protocol S
Ranibizumab versus panretinal photocoagulation- Population: Eyes with proliferative diabetic retinopathy.
- Treatments compared: Intravitreal ranibizumab versus panretinal photocoagulation.
- At five years, mean visual acuity was approximately 20/25 in both groups. [14]
| Feature | Anti-VEGF treatment | Panretinal photocoagulation |
|---|---|---|
| Advantages |
|
|
| Disadvantages |
|
|
Swipe horizontally to view the complete comparison.
Treatment burden over five years
- The ranibizumab group received a mean of approximately 19.2 injections over five years for protocol-directed PDR treatment, with treatment for DME also permitted.
- The PRP group received a mean of approximately 5.4 ranibizumab injections, principally for coexisting or incident DME. [14]
Why follow-up reliability matters
- Anti-VEGF treatment controls neovascular activity only while treatment and monitoring are maintained.
- Eyes treated only with anti-VEGF have shown worse anatomical and visual outcomes when subsequently lost to follow-up than eyes previously treated with PRP. [15]
- PRP is therefore particularly valuable when repeated visits or injections may not be maintained reliably.
Main lesson:
Ranibizumab and PRP can both provide good long-term visual outcomes in
PDR. The safer choice depends on coexisting DME, treatment burden, cost
and the patient’s ability to return reliably for follow-up.
Protocol U: Adding Steroid in Persistent DME
Protocol U asked whether adding a dexamethasone implant to continued ranibizumab could improve outcomes in eyes with persistent DME.
DRCR Protocol U
Persistent DME despite anti-VEGF treatment- Population: Eyes with persistent diabetic macular oedema and visual impairment despite several previous anti-VEGF injections.
- All eyes first received additional ranibizumab during a run-in phase.
- Eyes with persistent oedema were then assigned to:
- Continued ranibizumab alone, or
- Ranibizumab plus a dexamethasone intravitreal implant.
| Outcome at 24 weeks | Ranibizumab alone | Ranibizumab + dexamethasone |
|---|---|---|
| Central subfield thickness | Mean reduction of approximately 62 µm | Greater mean reduction of approximately 110 µm |
| Visual-acuity gain | Approximately +3.0 letters | Approximately +2.7 letters |
| IOP-related adverse effects | No eyes developed the study’s pressure-related outcome | Approximately 29% developed increased IOP or required pressure-lowering medication [17] |
Swipe horizontally to view the complete comparison.
Main lesson:
Adding dexamethasone produced greater OCT thinning, but it did
not improve mean visual acuity compared with continued
ranibizumab alone.
Protocol V: CI-DME With Good Vision
Protocol V asked whether eyes with centre-involved DME but visual acuity of 20/25 or better need immediate treatment.
DRCR Protocol V
Good-vision centre-involved DME- Population: Eyes with centre-involved diabetic macular oedema and visual acuity of 20/25 or better.
-
Initial treatment groups:
- Immediate aflibercept
- Focal or grid laser
- Observation
- Eyes in the laser and observation groups could receive aflibercept if prespecified visual-acuity deterioration developed.
- At two years, there was no significant difference among the three groups in the proportion of eyes losing at least five letters. [18]
- Approximately 34% of initially observed eyes eventually required aflibercept during follow-up.
Main lesson:
Immediate injection is not necessary in every eye with centre-involved
DME. When visual acuity is 20/25 or better, structured
observation is a reasonable initial strategy.
Preventive Anti-VEGF in NPDR
PANORAMA and Protocol W asked whether anti-VEGF treatment should be started before proliferative diabetic retinopathy or vision-reducing DME develops.
PANORAMA
Aflibercept in severe NPDR without DME- Population: Eyes with moderately severe to severe nonproliferative diabetic retinopathy, without diabetic macular oedema.
- Clinical question: Can aflibercept improve retinopathy severity and prevent vision-threatening complications?
- Aflibercept-treated eyes were more likely to achieve a two-step or greater improvement in the Diabetic Retinopathy Severity Scale.
- By week 100, vision-threatening complications or centre-involved DME developed in approximately 16%–19% of aflibercept-treated eyes.
- The same outcome developed in approximately 50% of control eyes. [19]
Main lesson:
Preventive aflibercept improved retinopathy severity and reduced the
development of PDR and centre-involved DME.
DRCR Protocol W
Does prevention improve final vision?- Population: Eyes with moderate to severe NPDR without centre-involved DME.
- Comparison: Preventive aflibercept versus sham treatment, with treatment started in the sham group if vision-threatening complications developed.
- At four years, PDR or vision-reducing centre-involved DME developed in 33.9% of aflibercept-treated eyes.
- The same outcome developed in 56.9% of sham-treated eyes.
- Despite reducing disease progression, mean visual-acuity change was similar: −2.7 letters with aflibercept and −2.4 letters with sham treatment. [20]
| Question | PANORAMA | Protocol W |
|---|---|---|
| What improved? | Retinopathy severity and risk of vision-threatening complications. | Risk of progression to PDR or vision-reducing centre-involved DME. |
| Did final vision improve? | The main evidence was anatomical and disease-progression benefit. | No significant mean visual-acuity advantage at four years. |
| Clinical meaning | Anti-VEGF can modify the course of severe NPDR. | Treating complications when they develop can achieve similar long-term visual outcomes. |
Swipe horizontally to view the complete comparison.
From Trial to Clinical Decision
Each landmark trial should be linked to the practical question it answered.
| Clinical question | Key trial | Practical answer |
|---|---|---|
| Does systemic control affect diabetic retinopathy? | DCCT and UKPDS | Yes. Glycaemic and blood-pressure control reduce long-term retinal risk. |
| Does ranibizumab improve vision in DME? | RISE and RIDE | Yes. Ranibizumab produced substantially better visual outcomes than sham treatment. |
| Is a higher ranibizumab dose better? | READ-3 | No clear additional benefit was obtained with the 2 mg dose. |
| Is aflibercept better than macular laser? | DA VINCI, VIVID and VISTA | Yes, for vision-impairing centre-involved DME. |
| Can aflibercept treatment intervals be extended? | PHOTON | Aflibercept 8 mg allowed longer intervals in many eyes while maintaining comparable visual outcomes. |
| Which anti-VEGF agent should be selected? | Protocol T | The result depends mainly on baseline visual acuity, as well as cost, access and previous response. |
| Should macular laser be added immediately? | Protocol I | Usually not. Laser can be deferred when ranibizumab treatment is started. |
| Can anti-VEGF treatment be used instead of PRP? | Protocol S | Yes, in selected patients who can maintain reliable long-term treatment and follow-up. |
| Does adding dexamethasone improve persistent DME? | Protocol U | It improves OCT anatomy, but not mean visual acuity. |
| Must good-vision CI-DME be injected immediately? | Protocol V | No. Structured observation is reasonable when vision is 20/25 or better. |
| Should every eye with severe NPDR receive preventive injections? | PANORAMA and Protocol W | No. Preventive treatment reduces progression but does not improve mean long-term visual acuity. |
Swipe horizontally to view the complete table.
References
- Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology. 1995;102(4):647–661. doi:10.1016/S0161-6420(95)30973-6
- UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes: UKPDS 33. Lancet. 1998;352(9131):837–853. doi:10.1016/S0140-6736(98)07019-6
- UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317(7160):703–713. doi:10.1136/bmj.317.7160.703
- Sepah YJ, Sadiq MA, Boyer D, et al.; READ-3 Study Group. Twenty-four-month outcomes of the Ranibizumab for Edema of the Macula in Diabetes—Protocol 3 with High Dose study. Ophthalmology. 2016;123(12):2581–2587. doi:10.1016/j.ophtha.2016.08.040
- Nguyen QD, Brown DM, Marcus DM, et al.; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from two phase III randomized trials—RISE and RIDE. Ophthalmology. 2012;119(4):789–801. doi:10.1016/j.ophtha.2011.12.039
- 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(10):2013–2022. doi:10.1016/j.ophtha.2013.02.034
- Do DV, Nguyen QD, Boyer D, et al.; da Vinci Study Group. One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119(8):1658–1665. doi:10.1016/j.ophtha.2012.02.010
- Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology. 2016;123(11):2376–2385. doi:10.1016/j.ophtha.2016.07.032
- Brown DM, Boyer DS, Do DV, et al.; PHOTON Investigators. Intravitreal aflibercept 8 mg in diabetic macular oedema: 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial. Lancet. 2024;403(10432):1153–1163. doi:10.1016/S0140-6736(23)02577-1
- Do DV, Wykoff CC, Sivaprasad S, et al.; PHOTON Investigators. Intravitreal aflibercept 8 mg for diabetic macular edema: ninety-six-week results from the randomized phase 2/3 PHOTON trial. Ophthalmology. 2026;133(5):577–588. doi:10.1016/j.ophtha.2025.10.028
- Regeneron Pharmaceuticals, Inc. EYLEA HD® (aflibercept) injection, for intravitreal use: US prescribing information. Revised April 2026. Official prescribing information
- Wells JA, Glassman AR, Ayala AR, et al.; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative-effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351–1359. doi:10.1016/j.ophtha.2016.02.022
- Elman MJ, Ayala A, Bressler NM, et al.; Diabetic Retinopathy Clinical Research Network. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: five-year randomized trial results. Ophthalmology. 2015;122(2):375–381. doi:10.1016/j.ophtha.2014.08.047
- Gross JG, Glassman AR, Liu D, et al.; Diabetic Retinopathy Clinical Research Network. Five-year outcomes of panretinal photocoagulation versus intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA Ophthalmology. 2018;136(10):1138–1148. doi:10.1001/jamaophthalmol.2018.3255
- Obeid A, Su D, Patel SN, et al. Outcomes of eyes lost to follow-up with proliferative diabetic retinopathy that received panretinal photocoagulation versus intravitreal anti-vascular endothelial growth factor. Ophthalmology. 2019;126(3):407–413. doi:10.1016/j.ophtha.2018.07.027
- Bressler NM, Beaulieu WT, Bressler SB, et al.; DRCR Retina Network. Anti-vascular endothelial growth factor therapy and risk of traction retinal detachment in eyes with proliferative diabetic retinopathy: pooled analysis of five DRCR Retina Network randomized clinical trials. Retina. 2020;40(6):1021–1028. doi:10.1097/IAE.0000000000002633
- Maturi RK, Glassman AR, Liu D, et al.; Diabetic Retinopathy Clinical Research Network. Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a DRCR Network phase 2 randomized clinical trial. JAMA Ophthalmology. 2018;136(1):29–38. doi:10.1001/jamaophthalmol.2017.4914
- Baker CW, Glassman AR, Beaulieu WT, et al.; DRCR Retina Network. Effect of initial management with aflibercept versus laser photocoagulation versus observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA. 2019;321(19):1880–1894. doi:10.1001/jama.2019.5790
- Brown DM, Wykoff CC, Boyer D, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: results from the PANORAMA randomized clinical trial. JAMA Ophthalmology. 2021;139(9):946–955. doi:10.1001/jamaophthalmol.2021.2809
- Maturi RK, Glassman AR, Josic K, et al.; DRCR Retina Network. Four-year visual outcomes in the Protocol W randomized trial of intravitreous aflibercept for prevention of vision-threatening complications of diabetic retinopathy. JAMA. 2023;329(5):376–385. doi:10.1001/jama.2022.25029
