A recurring e-newsletter to help increase awareness and support patient education around retinal disease. This edition features tips to help encourage patient ownership of their condition, as well as new developments in treatment options for diabetic eye disease.

While pharmacotherapy is increasingly playing a role in the treatment of diabetic retinopathy (DR), there is inherent wisdom to the adage that prevention is the best medicine. In the case of diabetic eye disease, empowering patients to take ownership of their condition is particularly crucial for avoiding the development of ocular sequelae or slowing or stopping progression.

Make a Plan with the Patient

Educating patients about modifiable risk factors may help the newly diagnosed patient avoid retinopathy, slow progression in those with DR, and preserve existing visual function in individuals with more severe DR.

  • 1. BE PROACTIVE ABOUT THE A1C.
  • Hemoglobin A1c (A1c) is the standard test to measure blood sugar in patients with diabetes. Elevated A1c levels are strongly correlated with development of retinopathy.
  • Encourage patients to control A1c to significantly reduce the rate of progression of microvascular complications.1,2
  • Ask patients to know their A1c level at every visit. Patients should aim to keep their A1c level below 7.0%, which is considered diagnostic for diabetes.
  • 2. ENCOURAGE A HEALTHY LIFESTYLE.
  • Educate patients on ways to manage modifiable risk factors. While genetics play a role in the development of type 2 diabetes, large-scale population studies suggest that excess weight, lack of exercise, a less-than-healthy diet, smoking, and alcohol use might be the most important determinants in the development of diabetes and subsequent complications.3,4 Encourage patients to take ownership of their lifestyle.
  • 3. MANAGE HYPERTENSIONS AND HYPERLIPIDEMIA.
  • Encourage patients to manage high blood pressure and high blood lipid levels, which are both known to contribute to the development and progression of retinopathy. These levels may be modified through diet changes or with medical therapy.

New Data for Treating DR with Anti-VEGF versus Laser

Patients with mild to moderate nonproliferative DR (NPDR) can typically be followed yearly with a dilated fundus examination. Individuals with severe NPDR and those with proliferative DR (PDR) require much closer monitoring until the disease is under control. Historically, conversion to PDR was considered a trigger to start therapy, with panretinal photocoagulation (PRP) being the primary approach.5,6

The treatment paradigm may be changing, however. New data suggests that intravitreal anti-VEGF injections:

  • (1) have a benefit for visual acuity outcomes
  • (2) and may yield regression of DR (whereas PRP halts progression).

Compare Outcomes

WHEN TREATED WITH ANTI-VEGF

Widefield (Optos Inc., Scotland) color photos of a patient with moderate NPDR OU at baseline (A) and following 2 years of monthly treatment with ranibizumab (B).

WHEN TREATED WITH LASER

Photo of a patient treated with PRP and macular laser OU for PDR and macular edema who also developed progressive enlargement of laser-induced atrophy over time, known as “atrophic creep.”

WHEN TREATED WITH LASER FOLLOWED BY ANTI-VEGF

Widefield (Optos Inc., Scotland) color photos of a patient with PDR and inferior vitreous hemorrhage OS. The patient was treated with PRP at that time (A, B). Seven months later, she developed a mild recurrent vitreous hemorrhage (C) and was treated with an anti-VEGF injection. She has been stable with no further treatment in the OS since that time (D, 17 months following last treatment).

Study the Data

  • The phase III RISE/RIDE study, which established the safety and efficacy of ranibizumab (Lucentis, Genentech) for diabetic macular edema (DME), also showed that anti-VEGF therapy yielded improvement in DR severity score (DRSS): 37.2% and 13.2% of patients in the 0.3 mg ranibizumab treatment groups experienced 2-step and 3-step improvements, respectively.7
  • A subgroup analysis of RISE/RIDE that focused on individuals with DRSS scores between 47 and 53 (ie, eyes at high risk for progression to PDR), found that ranibizumab yielded stabilization or improvement in severity in 75% of these patients.8
  • In the DRCR.net Protocol S study,9 0.5 mg ranibizumab was shown to be noninferior to PRP for visual acuity outcomes in patients with PDR: those in the ranibizumab group experienced +2.8 mean visual acuity letter improvement versus +0.2 in the PRP group (difference, +2.2; 95%CI, −0.5 to +5.0; P < .001 for noninferiority) at 2 years.
  • The visual acuity outcomes based on the area under the curve, reduction in DME, rate of vitrectomy, and improvement in central subfield thickness all favored the ranibizumab group in the DRCR.net Protocol S study.9 Because patients in the laser group could receive ranibizumab for any DME, the visual acuity outcomes and/or anatomic outcomes may have been affected.
  • In a phase 2b study, aflibercept (Eylea, Regeneron) was shown to be noninferior and superior to PRP for treatment of PDR, with patients gaining 3.9 more letters of BCVA at 52 weeks compared with PRP in an intention-to-treat population and +4.0 letters in a per-protocol population.10
  • Results from the Phase 3 PANORAMA trial evaluating aflibercept for moderately severe to severe NPDR were recently announced.11 According to the company sponsoring the trial, 58% of patients in the anti-VEGF group experienced a 2-step or greater improvement from baseline in DRSS at 24 weeks compared to 6% in the sham group.

Tailor Treatment to The Patient

It is imperative to encourage patients to become involved in their own care in the hopes to prevent or slow progression of diabetic eye disease.

  • Encourage patients to modify their behavior around high-risk factors, such as diet and exercise.
  • Give patients the tools to know and understand their A1c levels and take ownership of their health.

Clinicians should also be aware of shifting paradigms in treatment of diabetic eye disease while still tailoring treatment.

  • Individualize treatment choices. Based on Protocol S outcomes,9 the FDA approved an amended label for ranibizumab for treatment of “all forms of DR.” However, we do not have the data to determine when to intervene, how frequently to treat, at what interval, and when/if to taper anti-VEGF therapy.
  • Educate patients that intervening earlier with anti-VEGF therapy might avoid the need for laser or surgery while yielding regression in their DR. It may be possible to follow individuals with mild PDR and moderate NPDR off therapy.
  • Patients with severe NPDR may experience a benefit after intravitreal anti-VEGF injections.
  • Decide whether patients at other stages of DR need to ultimately be treated after proper education has been provided.

Use of anti-VEGF therapy requires a compliant patient, but there may be a hidden benefit in the need for close monitoring of patients undergoing medical treatment of their DR. Each visit is an opportunity for education, both about the nature of the treatment they are undergoing, as well as lifestyle choices and how patients can have an impact on their own health by controlling modifiable risk factors. By encouraging patients to take ownership of their disease, you may be able to avoid the development of diabetic eye disease or slow or stop disease progression.


1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
2. UK Prospective Diabetes Study (UKPDS) 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;352:837-853.
3. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345:790-797.
4. van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med. 2002;136:201-209.
5. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology. 1991;98:766-785.
6. Diabetic Retinopathy Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS report number 8. Ophthalmology. 1981;88:583–600.
7. 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.
8. Wykoff C. Ranibizumab induces regression of diabetic retinopathy (DR), prevents retinal nonperfusion in patients at high risk of conversion to proliferative DR. Presented at: ASRS; Aug. 9-14, 2016; San Francisco.
9. 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.
10. Sivaprasad S, Prevost AT, Vasconcelos JC, et al; CLARITY Study Group. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet. 2017;389(10085):2193-2203.
11. Eylea (aflibercept) injection demonstrates positive topline results in phase 3 non-proliferative diabetic retinopathy trial [news release]. PR Newsire. March 19, 2018. https://www.prnewswire.com/news-releases/eylea-aflibercept-injection-demonstrates-positive-topline-results-in-phase-3-non-proliferative-diabetic-retinopathy-trial-300615723.html. Accessed April 30, 2018.

Goal: to help increase awareness and support patient education around retinal disease. This edition features insights on how to translate diabetic retinopathy clinical trial data to real-world settings.

For the patient sitting in your exam chair, it is critical to be able to extrapolate clinical trial data that established the role of intravitreous anti-VEGF injections in the treatment of diabetic retinopathy (DR) to everyday clinical practice. Using the available evidence for anti-VEGF therapy for treatment of the various manifestations of DR does not inform us exactly how to treat every patient but helps guide therapy for the greatest patient benefit. Who to treat, how to treat, whether to treat, and how long to treat is considered on a case-by-case basis.

Although we have accumulated knowledge over the past decade regarding the treatment of diabetic macular edema (DME), there are still unanswered questions in the current, nascent era of the medical management of DR without DME.

Who to Treat

Results in clinical practice will likely differ from those in controlled clinical trials by virtue of refined patient selection. In our experience, certain characteristics might inform a decision to offer anti-VEGF injections in addition to or instead of laser treatment for DR:

  1. DME and proliferative DR (PDR) patients who are symptomatic, and are therefore motivated to initiate what may be a long-term treatment plan
  2. Patients with a history of prior treatment for significant disease, such as previous macular or panretinal laser or surgery
  3. Patients who are assessed to be compliant
  4. Progressive eye disease (ie, vitreous hemorrhage) or new/advancing PDR; even asymptomatic active high-risk PDR is an indication of severe diabetic disease worthy of treatment
  5. Uncontrolled hemoglobin A1C levels or advanced systemic disease

How to Treat

The available data for intravitreal anti-VEGF injections demonstrate superiority to macular laser in DME and noninferior visual acuity versus panretinal laser in PDR.1-4 However, the remarkable potential to yield clinically significant DR regression or stop progression with intravitreal anti-VEGF therapy as opposed to laser, in both non-proliferative and proliferative disease, dramatically changes how we approach the individual cases we see in clinical practice (Figure 1).

  • Mild nonproliferative DR (NPDR) with no DME can likely be followed off therapy.
  • Treatment of moderate to severe NPDR is discretionary but could “turn back the clock” on DR severity;2 as a result, other factors may become important when considering treatment, such as presence of DME and the prognosis for the fellow eye.

Figure 1. A case of 56-year-old Asian woman complaining of floaters OD is presented. Past medical history included type 2 diabetes mellitus, hypertension, and kidney disease; ocular history included a diagnosis of DR and cataracts. Visual acuity was 20/25 OU, and IOP measured 14 (OD) and 16 (OS). There was no DME on OCT, but baseline angiography (A–Left) indicated active high-risk proliferative disease. Following four injections of 0.3 mg ranibizumab between November 2017 and May 2018, regression of DR was evident on follow-up angiography (B–Right).

While the clock analogy for understanding DR regression is certainly appropriate, another way to conceptualize disease regression is in terms of applying brakes to a moving train. Ocular manifestations of diabetic eye disease are often a consequence of long-standing or uncontrolled systemic disease—and so applying the brakes requires steady pressure over time.

  • Pump the Brakes: The loading phase (typically three to six anti-VEGF injections at a 4- to 6-week interval) is often employed for starting to gain control of DR, establishing a biologic effect, and to set expectations for follow-up.
  • Slow the Disease: The interval for retreatment is often extended after the loading phase through the first year of therapy—like slowing a moving train, continued therapy applied at the right time ultimately yields regression or stops progression.

Whether to Treat

The relative newness of using anti-VEGF therapy for DR presents a need to examine the nuances of treatment on a case-by-case basis. However, these decisions may be guided by existing clinical data.

  • Anti-VEGF treatment is often initiated due to a particular presenting feature (ie, progression of retinal microaneurysms or hemorrhages over time, leakage, neovascularization, or vitreous hemorrhage); corresponding reductions or improvements will be useful as individualized treatment endpoints—especially crucial for patients with asymptomatic NPDR.
  • The role of imaging for determining retreatment is evolving and is useful for determining treatment options; endpoints used in clinical trials, such as calculating DR severity score, may be impractical for routine clinical use. However, color fundus photographs and wide-field angiography have high clinical utility.
  • Patients with PDR demonstrate an exquisitely high response rate to anti-VEGF therapy;5 following from this, it is our impression that patients with DME often require more frequent treatment and a more gradual extension after the loading phase than those being treated for PDR.
  • Some patients with DME may respond to anti-VEGF therapy as late as 9 months after the initiation of treatment;1 as there is an incomplete understanding of how to determine non- or suboptimal response to therapy, it is reasonable to continue regular treatment for several months or 1 year in select cases before declaring a patient a “non-responder.”

How Long to Treat

We enter unchartered territory in considering how long to treat. Every specialist will have their criteria for clinical endpoints warranting an extension or cessation of ongoing treatment. We offer some guidelines below:

  • PDR: can be treated until regression or stabilization of neovascularization elsewhere (NVE) or neovascularization of the disc (NVD) on exam or multimodal imaging
  • DME: can be treated regularly until either or both OCT and/or visual acuity measurements improve or stabilize
  • Severe NPDR: can be treated until severity characteristics regress or stabilize
  • Mild to moderate NPDR: this is a more difficult category, as is the decision to initiate treatment in this group of patients. As we gain more experience with anti-VEGF therapy in this category, this will inform our treatment paradigms.

The potential to yield regression of disease with anti-VEGF injections is a powerful message that may help gain adherence with follow-up protocols. As the role of medical management of DR continues to grow, understanding the art of how to work with patients and tailor therapy will help bridge the divide between clinical trial data and real-world experience.


1. 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.
2. Wykoff C. Ranibizumab induces regression of diabetic retinopathy (DR), prevents retinal nonperfusion in patients at high risk of conversion to proliferative DR. Presented at: ASRS; Aug. 9-14, 2016; San Francisco, CA.
3. Sivaprasad S, Prevost AT, Vasconcelos JC, et al; CLARITY Study Group. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomized, controlled, phase 2b, non-inferiority trial. Lancet. 2017;389(10085):2193-2203.
4. Eylea (aflibercept) injection demonstrates positive topline results in phase 3 non-proliferative diabetic retinopathy trial [news release]. PR Newsire. March 19, 2018. https://www.prnewswire.com/news-releases/eylea-aflibercept-injection-demonstrates-positive-topline-results-in-phase-3-non-proliferative-diabetic-retinopathy-trial-300615723.html. Accessed April 30, 2018.
5. 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.

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About Retina Today

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.