Retina - Diabetic Retinopathy

---

When to laser, when to watch: a difficult, but fateful question?  Diabetic retinopathy (DR) is a leading cause of blindness and visual disability worldwide. If left untreated, chronic retinal ischemia can lead to increased capillary permeability, microvascular occlusions, and neovascularization – increasing risk for eventual retinal detachments. The diabetic retinopathy study (DRS) was a multi-center, randomized control trial designed to determine whether intervention with panretinal photocoagulation (PRP) could help prevent severe vision loss (VA <5/200) in patients with advanced DR.

Key Points:  

• PRP reduced incidence of SVL by greater than 50% in eyes with proliferative diabetic retinopathy (PDR) compared to no treatment through 5 year follow up
• Risk of developing SVL varied depending on severity of DR and should be considered when deciding whether PRP is required
• It identified three criteria for PDR as high-risk characteristics (HRCs) for which PRP is indicated
• Eyes treated with xenon arc were more likely to develop visual field defects (50%) and decreased BVCA (19%) compared to argon-treated eyes (5% and 11% respectively)

The DRS was one of the early landmark studies in ophthalmology that is still quite relevant today. The DRS established firm evidence for the benefits of PRP and identified important prognostic indicators of severe vision loss in DR.

To develop or not to develop… a study on diabetic retinopathy. Diabetic retinopathy is the second leading cause of blindness in the United States. This population-based epidemiological study over 25 years aimed to determine the incidence, prevalence, and severity of diabetic retinopathy and visual impairment and associated risk factors in diabetic patients. The original study was 1980-1982 and there have been six patient follow-ups 1984-86, 1990-92, 1995-96, 2000-01, 2006-07, and 2012-14. There were 996 type 1 diabetic patients and 1370 type 2 diabetic patients who were analyzed for the incidence rate and severity of diabetic retinopathy using stereoscopic color fundus photographs. 

Key Points:  

• Diabetic retinopathy was found to be related to longer duration with the disease, high levels of glycosylated hemoglobin, proteinuria, increased diastolic BP, and male sex.
• Incidence and progression of diabetic retinopathy was greatest in those who were younger at the time of diagnosis
• After 20 years of diabetes mellitus, nearly 99% of patients with type 1 and 60% with type 2 disease demonstrated some degree of diabetic retinopathy. 

Overall, after 25 years there have been over 230 reports from the WESDR study to show glycemic control is associated with a decreased risk of diabetic retinopathy and other diabetic complications. It furthermore identified additional risk factors for diabetic retinopathy in those with diabetes. 

Victory for the vitrectomy! In this 1990 trial, three distinct sub-investigations sought to:

1. Understand the natural history of proliferative diabetic retinopathy (PDR) 
2. Compare early vitrectomy (1-6 months) and traditional management (late vitrectomy, ≥12 months, or immediate vitrectomy if a retinal detachment occurred involving the macula) in PDR without significant vision loss (VA > 20/400)
3. Compare early vitrectomy and traditional management in PDR with significant vision loss (VA < 20/800, but not no light perception (NLP)) due to severe vitreous hemorrhage (VH)

Key Points:

• Overall, patients in the early vitrectomy cohort had better visual outcomes than those in the delayed vitrectomy cohort
• Patients with Type 1 Diabetes and severe vision loss from VH, monocular patients (regardless of diabetes type), and patients with advanced PDR had better visual outcomes when vitrectomy was performed early
• No significant difference in visual outcomes was identified when comparing early versus late vitrectomy for Type 2 Diabetics
• Patients who received panretinal photocoagulation (PRP) had better visual outcome
• Regardless of intervention, NLP vision developed in 20% of eyes after vitreous hemorrhage 

Overall, the DRVS is a landmark study because it highlighted how early vitrectomy can result in significantly better visual outcomes both immediately and long term for patients with Type 1 Diabetes, monocular patients, and those with advanced diabetic eye disease. Beyond removing hemorrhaged blood, vitrectomies relieve traction on the retina and eliminate the scaffolding that promotes new vessel proliferation. 

Ever wonder where those famous “EDTRS letters” come from?The Early Treatment Diabetic Retinopathy Study (ETDRS) explored the role of focal laser coagulation, panretinal photocoagulation (PRP), and aspirin use for the treatment of non-proliferative diabetic retinopathy (NPDR) and early proliferative diabetic retinopathy (PDR). A total of 3,711 patients were included in ETDRS and randomized into two cohorts according to aspirin use (aspirin, 650 mg/day, n = 1,856; placebo, n = 1855). For each patient, each eye was assigned to early or deferred photocoagulation. The cohort of early photocoagulation eyes was further subdivided according to timing of focal and panretinal/scatter photocoagulation. Photocoagulation in deferred eyes was initiated upon detection of high-risk PDR. 

Key Points:  

• Defined grading criteria for NPDR (see linked study with images)
• Early focal photocoagulation reduced the risk of vision loss from diabetic macular edema (ETDRS Report Number 1, 9)
• PRP decreased the risk of severe vision loss in patients with proliferative or severe non-proliferative diabetic retinopathy, but should be withheld in those with moderate or mild non-proliferative diabetic retinopathy due to adverse effects on visual field and acuity (ETDRS Report Number 9)
• Aspirin did not alter the disease course of diabetic retinopathy. Furthermore, aspirin use was not associated with adverse ocular events, including vitreous or preretinal hemorrhage. (ETDRS Report Number 8, 19, 20)

Overall, the ETDRS demonstrated that early focal photocoagulation can avert vision loss related to diabetic macular edema. PRP is beneficial for patients with PDR or severe NPDR, but the risks outweigh the benefits for patients with mild or moderate NPDR. This study further laid the groundwork for many future Diabetic Retinopathy and other retina studies.

Is putting off the sweets worth the reward? The DCCT sought to understand whether tighter glycemic control would lead to better outcomes in diabetic retinopathy (DR). Prior to this study, there were limited cutoffs and guidance as to what Hemoglobin A1c levels and what type of insulin regimens were best for managing patients with Type 1 Diabetes. The DCCT randomized 1441 patients with Type 1 Diabetes to “intensive” versus “conventional” glucose control, and measured both the rate of retinopathy development (cohort 1) and retinopathy progression (cohort 2).

Key Points:

• “Intensive” glycemic control led to a 78.5% risk reduction in the development of DR and a 64.5% risk reduction in the progression of DR in those who had mild-moderate NPDR
• Across both treatment groups and both cohorts, lowering A1c led to significant reductions in the likelihood of DR development (10% A1c reduction led to 45% relative risk reduction) and DR progression (10% A1c reduction led to 43% relative risk reduction)

The DCCT (and the similar themed UKPDS for Type 2 Diabetes) illustrated across large sample sizes and randomized controlled trials the importance of tight glycemic control. Together, these two studies created a target goal for Hgb A1c < 7.0% for patients to avoid long-term ophthalmic complications from diabetes.

This UKPDS sought to answer a variety of questions related to the natural history and impact of hyperglycemia control for patients with Type II Diabetes. Such questions included what risk factors dictate the incidence and progression of diabetic retinopathy, in addition to what impact intensive glycemic control would yield on incidence and progression.

Key Points:  

• Risk factors for development and progression of diabetic retinopathy were noted to be higher blood glucose levels, high blood pressure, and interestingly, not smoking
• The intensive glycemic control group had a lower A1c at study endpoints than the conventional diet-control group (7.0% versus 7.9%)
• The intensive glycemic control group had lower likelihood of development of microvascular complications (need for PRP), but did have elevated risk of hypoglycemia

Overall, the UKPDS is a landmark study because it highlighted the important risk factors of high blood pressure and hyperglycemia in promoting the onset or progression of retinopathy in patients with Type II (non-insulin-dependent) diabetes mellitus. Furthermore, along with the DCCT (which studied Type I Diabetics), these studies helped to identify a new target for blood glucose control in Diabetic patients.

Trick or treat? While eyeball injections and lasers give off haunted house vibes, patients may be in for a treat! The DRCR I evaluated the safety and efficacy of intravitreal ranibizumab with prompt or deferred laser and intravitreal triamcinolone with laser as compared to laser alone for the treatment of diabetic macular edema over 1 year.

Key Points:

• Regardless of laser timeline, ranibizumab treatment led to significantly improved visual acuity
• Treatment with either ranibizumab or triamcinolone in addition to laser led to a decrease in mean central subfield thickness on OCT compared to laser alone
• While ranibizumab may uncommonly lead to retinal detachments or endophthalmitis secondary to injection, it is an overall safe treatment option  

DRCR I demonstrated that treating patients with intravitreal ranibizumab + prompt or deferred laser is a safe and efficacious option to improve visual acuity and decrease central subfield thickness in patients with diabetic macular edema. This study introduced anti-VEGF agents as a leading option for the treatment of diabetic macular edema.

Same, same...but different? Of the three commonly used VEGF-inhibitors for treatment of diabetic macular edema, only bevacizumab is not approved by the FDA for ocular use, and is given as an off-label treatment. In the DRCR Protocol T trial, 660 patients with diabetic macular edema were randomly assigned to receive intravitreal injections of aflibercept (n = 224), bevacizumab (n = 218), ranibizumab (n = 218) for one year (as frequently as every 4 weeks), with a primary outcome of change in visual acuity.

Key Points:  

• The mean improvement in the visual acuity at 1 year was greater with aflibercept (+13.3 letters) than with bevacizumab (+9.7) or ranibizumab (+11.2)
• At better presenting visual acuities (20/40 or better), the difference between injection agent was not statistically significant; however, when presenting vision was 20/50 or worse, the difference was more pronounced
• Central subfield thickness reduced in all groups, but the difference was greatest for aflibercept (169±138 μm), then ranibizumab (147±134 μm), and bevacizumab (101±121 μm)

Overall, the DRCR T is a landmark study because it highlighted the safety and efficacy of bevacizumab as a cost effective (~$50 compared to >$1000) initial anti-VEGF agent. In the study, all three treatments were all found to be effective and safe for the treatment of diabetic macular edema vision impairment. Still, it is worth noting that aflibercept (Eylea) did have superior outcomes for both visual acuity and central subfield thickness than did bevacizumab (Avastin). 

Can ranibizumab pull its weight? How does the monoclonal antibody compare to PRP?

In the 2015 DRCR S study, patients with proliferative diabetic retinopathy were randomized to treatment with PRP (n = 191 eyes) and ranibizumab (n = 203 eyes) to determine if anti-VEGF therapy was a reasonable alternative to PRP.

Key Points:  

• Ranibizumab was non-inferior to PRP treatment for best corrected visual acuity at two-year follow-up (+2.8 letters vs. +0.2 letters, P = .11)
• Patients in the PRP group had more peripheral visual field loss than the Ranibizumab group (P < .001)
• Patients in the PRP group had more vitrectomies than patients in the Ranibizumab group (15% vs. 4%, P < .001)

Overall, the DRCR S study is a landmark study because it showed that ranibizumab was theoretically non-inferior to PRP for the treatment of PDR. In fact, the study showed that it might have superior visual outcomes (visual acuity and visual field measurements at 2 years). It is important to note that a key concern for long-term anti-VEGF therapy instead of PRP is that it requires high patient compliance and repeated interventions. As such, while the clinical study showed non-inferiority, clinicians must be wary about how these factors would impact the care of their patients and cost of care.

Sometimes the best intervention is none at all. The DRCR.net Protocol V study sought to determine the optimal management of center-involving diabetic macular edema. In this randomized controlled trial, 702 individuals (n=702 study eyes) with type 1 or type 2 diabetic with baseline visual acuity of 20/25 or better were enrolled. Participants were placed into 3 study groups: initial observation (n=236), initial laser photocoagulation (n=240), and initial aflibercept (n=226). Aflibercept was initiated in the observation and laser groups as needed based on reduced vision and worsened macular edema.

Key Points:  

• At 2 years, there was no significant difference in the rate of vision loss (5-letter reduction) between the observation (19%), laser photocoagulation (17%), and aflibercept group (16%)
• There was a small increase in the proportion of patients that were 20/20 at year 2 for the Aflibercept group (77%) compared to initial observation (66%) (P = 0.03); this was not true for Aflibercept versus laser

Overall, the DRCR V is a landmark study because it was the first large RCT to evaluate management outcomes in diabetic macular edema after the development of anti-VEGF treatments. Anti-VEGF treatments provided ophthalmologists with a new option for diabetic macular edema; however, there was no evidence prior to this study to demonstrate that early treatment initiation improved visual acuity outcomes for these patients. This study demonstrated that individuals with good baseline visual acuity did not require initiation of treatment with anti-VEGF intravitreal injections or laser photocoagulation.