Barriers to Care in Diabetic Eye Disease
Roger A. Goldberg, MD, MBA
Diabetic eye disease comprises diabetic macular edema (DME) and diabetic retinopathy (DR); DR can be subtyped to proliferative DR (PDR) or nonproliferative DR (NPDR). A 2021 estimate of DR prevalence revealed that DR rates are much higher than previously estimated: approximately 26% (9.6 million) of Americans with diabetes have DR, and 5% (approximately 1.8 million) of patients with diabetes have vision-threatening DR.1 Approximately 746,000 Americans have DME.2
A clear connection exists between long-term HbA1c levels and risks of diabetes-related complications. The Diabetes Control and Complications Trial showed that lower hemoglobin A1c levels correlated with lower risks of diabetes-related complications.3 A 1% decrease in HbA1c levels can reduce the risk of progression by up to 50% for second-order effects such as retinopathy, nephropathy, and neuropathy.4 Patients in the UK Prospective Diabetes Study who were observed over a 10-year period were 25% less likely to require photocoagulation for DR if the mean HbA1c levels were 7.0% compared with 7.9%.5
Risk factors for DR include duration of diabetes, poor control of diabetes, high blood pressure, coexistent nephropathy or kidney disease, obesity, hyperlipidemia, smoking, and pregnancy.6-10 Of course, smoking cessation and control of blood sugar, blood pressure, and cholesterol are key to successful management of diabetes. Medical management using those key tactics should always be recommended to patients with diabetes.
Optometrists and ophthalmologists play an important role in educating patients about the importance of medical management of diabetes, and successful efforts may yield fewer instances of vision-threatening disease for patients. As primary eye care providers, optometrists have a unique opportunity to discuss medical management of diabetes with patients in its earliest stages; indeed, many retina specialists don’t encounter patients with diabetes until their visual disruption has reached the point that it requires therapy, at which point A1c control has typically been poor for some period of time. In contrast, optometrists often see patients for routine care before disease manifestations adversely affect vision. For patients, reiterated instruction on medical management of diabetes is important, and when all providers (eg, primary care providers, endocrinologists, etc.) are on the same page, the patient receives a single, clear message.
SCREENING CHALLENGES
Early detection of DR is key to thorough monitoring and treatment, but challenges to disease detection persist. The DR Barometer Study, which was a survey comprised of 4,340 patients with diabetes in 41 countries, found that 65% of patients with DR present when visual disruption is already present.11 Intuitively, this makes sense: many patients make an appointment with an eye care provider when they notice visual changes. The same study also found that 6% of patients with DR present after disease has advanced so far that treatment is ineffective, and that 29% of patients present before the manifestation of visual disruption (Figure 1).
Closer adherence to screening guidelines may be an effective means by which to detect DR in patients before it affects vision. The most recent American Academy of Ophthalmology DR Preferred Practice Pattern Guidelines suggests different screening practices for patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).12 Patients with T1DM, sometimes called early-onset diabetes or juvenile diabetes, should be screened for DR 5 years after diagnosis, and annually thereafter. Patients with T2DM should be screened promptly at diagnosis of T2DM, with follow-up each year (Table). It is advised that patients with T2DM are screened promptly because it is assumed that they have been living with T2DM for an undetermined period prior to diagnosis.
We must stress to patients that follow-up is needed even if they are not experiencing visual symptoms: we cannot detect disease early if they don’t present as suggested. In 2016, Ziemer et al found that patients with diabetes who are already in the care of a provider are most likely to be screened for DR—but also found that 71% of patients with diabetes do not receive DR screening.13 Further, 50% of patients do not follow up with eye care providers as recommended.
Figure 1. Nearly two-thirds of patients with DR are screened for disease when they present to an eye care provider after experiencing visual decline, per the DR Barometer Study. Only 29% of patients present before the onset of visual disruption. If more patients experienced earlier DR diagnosis due to enhanced screening protocols, then the risk of ocular complications and visual compromise may be reduced. Adapted from: Cavan D, Makaroff L, da Rocha Fernandes J, et al. Diabetes Res Clin Pract. 2017;129:16-24.
TREATMENT CHALLENGES
Even after patients are diagnosed with DR or DME, they still face significant hurdles to compliant treatment. Retina specialists administering anti-VEGF injections to treat these diseases recognize that monthly injections—despite being the standard dosing regimen described in the earliest entries into the literature14,15—are too burdensome on patients. Among real-world patients, as illustrated by Ciulla et al, the number of injections in the first year correlates in a near-linear fashion with better vision outcomes (Figure 2).16
In an effort to alleviate the burden associated with monthly injections, retina specialists have evaluated quarterly,17 prn (ie, as-needed),18 and treat-and-extend (TAE) regimens.19 In the United States, 57% of retina specialists employ TAE regimens,20 and in real-world settings evaluating TAE regimens for DME, it has been shown to be noninferior to monthly dosing.21
Debating the merits of various dosing regimens is beyond the scope of this discussion. Rather, we should see the number of arrows in a retina specialist’s quiver as a sign that DR is a heterogenous disease that responds variously according to any number of factors.
One of those factors, of course, is patient compliance to dosing recommendations. It is difficult to pin down any single factor linked to patient noncompliance, but Baumal et al identified several factors as existing within the matrix of nonadherence to therapy. They can broadly be grouped as socioeconomic (eg, high out-of-pocket costs for care, lack of education), practical (eg, lack of transportation, vacation), psychologic, (eg, fear of injections, fear of poor prognosis, depression/anxiety), and medical (eg, other illnesses that take priority, lost mobility).22
Despite the scientific advances that the first generation of anti-VEGF therapies represent, these innovations are useless if the barriers to care prevent patients from visiting the clinic. The advent of treatments that allow longer durations between visits could significantly mitigate the barriers outlined above without sacrificing the quality of care delivered to the patient. Prompt referral from an optometrist to a retina specialist will be key getting patients in the chair, but referral alone is insufficient: optometrists must arm their patients with urgency and education to ensure that they receive the highest level of care with the greatest likelihood of efficacy.
Figure 2. During the first year of treatment for DME, the number of anti-VEGF injections correlates with mean change in visual acuity from baseline. Still, frequent anti-VEGF injections are burdensome, and patients face various barriers to receiving consistent monthly therapy. Reproduced from Ciulla TA et al. Br J Ophthalmol. 2021;105:216-221; with permission from BMJ Publishing Group Ltd.1. Lundeen EA, Burke-Conte Z, Rein DB, et al. Prevalence of diabetic retinopathy in the US in 2021. JAMA Ophthalmol. 2023;141(8):747-754.
2. 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.
3. DCCT 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.
4. Diabetes In Control. Reduction in risk of diabetic complications per 1% decrease in. Updated April 22, 2002. Accessed March 1, 2024. Available at: http://www.diabetesincontrol.com/reduction-in-risk-of-diabetic-complications-per-1-decrease-in.
5. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853. Erratum in: Lancet. 1999;354(9178):602.
6. Zhang X, Zeng H, Bao S, et al. Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci. 2014;14:4:27.
7. Ko F, Vitale S, Chou C, et al. Prevalence of nonrefractive visual impairment in US adults and associated risk factors, 1999–2002 and 2005–2008. JAMA. 2012;308:2361-2368.
8. International Council of Ophthalmology (ICO) guidelines for diabetic eye care (updated 2017). Available at: www.icoph.org/downloads/ICOGuidelinesforDiabeticEyeCare.pdf. Updated 2017. Accessed June 13, 2023.
9. ADA. Standards of medical care in diabetes. Diabetes Care. 2005;28:S4-S36.
10. Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care. 2003;26:2181-2188.
11. Cavan D, Makaroff L, da Rocha Fernandes J, et al. The Diabetic Retinopathy Barometer Study: global perspectives on access to and experiences of diabetic retinopathy screening and treatment. Diabetes Res Clin Pract. 2017;129:16-24.
12. American Academy of Ophthalmology (AAO) DR preferred practice pattern, 2022 Update. Available at: www.aao.org/education/preferred-practice-pattern/diabetic-retinopathy-ppp. Accessed February 27, 2024.
13. Ziemer DC, Neema PK, Mojonnier A, et al. Improving diabetic retinopathy screening is a complex challenge. ADA 2016 Congress, poster 617-P.
14. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
15. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
16. Ciulla TA,Pollack JS, Williams DF. Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28 658 patient eyes. Br J Ophthalmol. 2021;105:216-221.
17. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145(2):239-248.
18. Martin DF, Maguire MG, Ying, G, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
19. Gupta OP, Shienbaum G, Patel AH, et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology. 2010;117(11):2134-2140.
20. Hahn P, ed. ASRS 2021 Preferences and Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2021.
21. Payne JF, Wykoff CC, Clark WL, et al; TREX-DME Study Group. Randomized trial of treat and extend ranibizumab with and without navigated laser versus monthly dosing for diabetic macular edema: TREX-DME 2-year outcomes. Am J Ophthalmol. 2019;202:91-99.
22. Baumal CR. Wet age-related macular degeneration: treatment advances to reduce the injection burden. Am J Manag Care. 2020;26(5):S103-111.
Longer Duration Therapies as a Potential Solution for Diabetic Eye Disease
A. Paul Chous, MA, OD, FAAO
In the 2023 American Society of Retina Specialists (ASRS) Preferences and Trends (PAT) survey, 43% of US retina specialists said that administrative and insurance burdens were the leading socioeconomic challenge for treating patients with diabetic macular edema (DME).1 The second-leading challenge (35%) to treating patients was frequent loss to follow-up (LTFU).
Research on the matter backs up retina specialists’ response. Approximately 25% of patients with nonproliferative diabetic retinopathy (NPDR) and DME did not return for a follow-up visit following a single injection of anti-VEGF in a 2019 study.2
Among patients with proliferative diabetic retinopathy (PDR), 25% of patients were LTFU over a 4-year period, with researchers noting older patients, White and Asian patients, and patients with higher adjusted gross incomes more likely to return for follow-up care.3 Another study tracking PDR follow-up rates found the LTFU rate as high as 52% at 1 year, and identified having government and private health insurance (as opposed to being a self-pay patient) as a risk factor for LTFU status.4 Patients with PDR who received anti-VEGF therapy and are LTFU for at least 6 months may be at increased risk for developing a tractional retinal detachment (TRD) compared with LTFU patients who receive panretinal photocoagulation, with one study finding an incidence of TRD 10 times higher among anti-VEGF patients.5 With cautionary statistics such as that in mind, eye care providers must educate patients that failure to follow up as directed could result in significant complications and vision loss.
The 2023 ASRS PAT survey asked US retina specialists about their most important metrics for success when employing anti-VEGF therapy for any disease (Figure 1).1 A majority of US respondents cited vision improvements (81% of US respondents), longer treatment duration (66%), functional and anatomic stability (63%), and decreased treatment burden (51%) as their most important success metrics; the percentage of respondents who said that fewer injections could be used as a metric for success fell slightly under a majority (49%).
In short, eye care providers authorized to administer treatment want it all: reduced treatment burden that does not sacrifice the visual and structural gains that first-generation anti-VEGF agents have realized with no increased safety risk. Three of the most recent innovations in retina therapy aim to accomplish those goals: faricimab, which is approved by the FDA for the treatment of DME6; aflibercept 8 mg, which is approved for the treatment of diabetic retinopathy (DR) and DME7; and brolucizumab, which is approved for DME.8 All three of these therapies also have indications for non-diabetic eye diseases, but that is beyond the scope of this discussion.
Figure 1. The 2023 ASRS PAT survey found that vision improvements, extended treatment duration, anatomic and functional stability, decreased treatment burden, and reduced number of injections were all popular metrics for success when using anti-VEGF therapy for retinovascular diseases.Faricimab for DME
Faricimab is a bispecific antibody that inhibits both VEGF-A and angiopoietin-2 (Ang-2). The safety and efficacy of faricimab for the treatment of DME was assessed in the phase 3 Yosemite and Rhine studies, a pair of randomized, double-masked, active comparator–controlled phase 3 clinical trials.9 Patients in those studies were randomly assigned to aflibercept 2 mg every 8 weeks after 5 monthly loading doses, faricimab every 8 weeks after 6 monthly loading doses, faricimab up to every 16 weeks after 4 monthly loading doses; this final arm was called the personalized treatment interval (PTI) arm, which is an approximation of real-world TAE regimens and permitted extension of the time between faricimab injections beginning in year 1, after loading doses were delivered, based on prespecified visual acuity and OCT thresholds. The primary endpoint for the Yosemite and Rhine studies was the mean change in BCVA from baseline as averaged over weeks 48, 52, and 56 (Figure 2).
The study met its primary endpoint.9 At 2 years, patients in the faricimab arms demonstrated noninferior BCVA gains from baseline compared with the aflibercept 2 mg arm. Further, the faricimab arms showed comparable anatomic outcomes to the aflibercept 2 mg arm as measured by central subfield thickness (CST) reductions from baseline at 2 years.10
Durability was observed with faricimab treatment. In both trials, 78.1% of patients achieved at least Q12 week dosing at week 96, with a majority (60.0% and 64.5%) achieving 16-week dosing intervals (Figure 3).10 Among those who achieved 16-week intervals in 1 year, 76% maintained that dosing schedule through 2 years.10
Faricimab was well tolerated through 2 years, and no instances of retinal vasculitis or occlusive retinal vasculitis were reported.10
Figure 2. The study design for the phase 3 Yosemite and Rhine studies assessed faricimab dosed every 8 weeks, faricimab dosed on a PTI regimen up to every 16 weeks, and aflibercept 2 mg dosed every 8 weeks.
Figure 3. Among patients in the PTI arms, 78.1% in both Yosemite and Rhine achieved dosing intervals of at least 12 weeks, with a majority of PTI patients achieving 16-week treatment intervals. Adapted from: Lim JI, et al. Presented at: ARVO 2022; May 1-4, 2022; Denver, CO.
High-Dose Aflibercept for DR and DME
High-dose aflibercept (8 mg) has a molar dose that is four times greater than that of aflibercept 2 mg. The safety and efficacy of high-dose aflibercept for the treatment of DME was assessed in the phase 3 Photon study.11 Patients were randomly assigned to high-dose aflibercept every 12 weeks after 3 monthly doses, high-dose aflibercept every 16 weeks after 3 monthly doses, or aflibercept 2 mg every 8 weeks after 5 monthly doses. Patients in the high-dose aflibercept arms could have their intervals shortened during years 1 and 2, and could have their intervals extended during year 2.11
The primary endpoint for this noninferiority study was mean change in BCVA from baseline at week 48. The study met its primary endpoint at week 48, with mean observed BCVA improvement from baseline measured at 8.8 letters, 7.9 letters, and 9.2 letters in the high-dose aflibercept 12-week arm, high-dose aflibercept 16-week arm, and aflibercept 2 mg 8-week arm, respectively (P < .01).11 At week 96, mean observed BCVA improvement from baseline measured at 8.8 letters, 7.5 letters, and 8.4 letters in the high-dose aflibercept 12-week arm, high-dose aflibercept 16-week arm, and aflibercept 2 mg 8-week arm, respectively (P < .01).11 Other efficacy findings for both timepoints can be seen in Figure 4.
Anatomic findings were comparable among the three treatment arms in Photon, with reductions in CST ranging from 148 µm to 171 µm at week 48 and ranging from 144 µm to 187 µm at week 96.11
At week 96, 89% of patients randomized to high-dose aflibercept maintained at least 12-week dosing, and 84% of those randomized at baseline to 16-week intervals with high-dose aflibercept maintained that regimen at week 96.
Figure 4. Outcomes data at weeks 48 and 96 in the Photon study. Note that the mean number of injections for the 16-week high-dose aflibercept arm was 5.0 at week 48 and 7.8 at week 96.Brolucizumab for DME
The safety and efficacy of brolucizumab for the treatment of DME was assessed in the randomized, double-masked, multicenter, active-controlled phase 3 Kestrel and Kite studies.12 In Kestrel, patients were randomly assigned 1:1:1 to brolucizumab 3 mg, brolucizumab 6 mg, or aflibercept 2 mg; in Kite, patients were randomly assigned 1:1 to brolucizumab 6 mg or aflibercept 2 mg. The primary endpoint in both studies was BCVA change from baseline at week 52.
Patients who were assigned to the brolucizumab arms in Kestrel and Kite received five doses every 6 weeks before they were shifted to 12-week dosing; if prespecified criteria were met, they could be dosed as frequently as every 8 weeks. Patients in the aflibercept 2 mg arms received 5 monthly doses and were then shifted to fixed 8-week dosing.
At week 52, patients who received brolucizumab 6 mg showed noninferior visual outcomes compared with patients in the aflibercept 2 mg arms, which meant the study met its primary endpoint (Figure 5). After a series of real-world intraocular inflammation events with brolucizumab for the treatment of wet age-related macular degeneration, some retina specialists have been hesitant to use this particular anti-VEGF agent.13 Still, it is approved by the FDA, and patients that optometrists refer may initiate therapy with brolucizumab if a retina specialist feels that it fits their needs and the patient can be safely monitored for complications.
Figure 5. At week 52, patients who were randomly assigned to brolucizumab 6 mg dosed as infrequently as every 12 weeks in Kestrel and Kite had noninferior outcomes to patients who were dosed with aflibercept 2 mg every 8 weeks. Brown DM, et al. Am J Ophthalmol. 2022;238:157-172. Under a Creative Commons BY-NC-ND license.1. Hahn P, ed. ASRS 202 Preferences and Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2023.
2. Gao X, Obeid A, Aderman CM, et al. Loss to follow-up after intravitreal anti-vascular endothelial growth factor injections in patients with diabetic macular edema. Ophthalmol Retina. 2019;3(3):230-236.
3. Obeid A, Gao X, Ali FS, et al. Loss to follow-up in patients with proliferative diabetic retinopathy after panretinal photocoagulation or intravitreal anti-VEGF injections. Ophthalmology. 2018;125(9):1386-1392.
4. Suresh R, Yu HJ, Thoveson A, et al. Loss to follow-up among patients with proliferative diabetic retinopathy in clinical practice. Am J Ophthalmol. 2020;215:66-71.
5. 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.
6. Prescribing information for faricimab. Available at: https://www.gene.com/download/pdf/vabysmo_prescribing.pdf. Updated October 2023. Accessed February 28, 2024.
7. Prescribing information for aflibercept 8 mg. Available at: https://www.regeneron.com/downloads/eyleahd_fpi.pdf. Updated December 2023. Accessed February 28, 2024.
8. Prescribing information for brolucizumab-dbll. Available at: https://www.novartis.com/us-en/sites/novartis_us/files/beovu.pdf. Updated September 2023. Accessed February 28, 2024.
9. Wykoff CC, Abreu F, Adamis AP, et al; YOSEMITE and RHINE Investigators. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet. 2022;399(10326):741-755.
10. Lim JI, et al. Presented at: The Association for Research in Vision and Ophthalmology (ARVO) 2022 Meeting; May 1-4, 2022; Denver, CO.
11. Do DV. Aflibercept 8 mg for Diabetic Macular Edema: 2-Year Results of the Phase 2/3 PHOTON Trial. Presented at ASRS Annual Meeting 2023; July 28 – August 1, 2023; Seattle, WA.
12. Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52-week results from two phase III pivotal trials of brolucizumab for diabetic macular edema. Am J Ophthalmol. 2022;238:157-172.
13. Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology. 2020;127(10):1345-1359.
A Look at the Pipeline: Can Future Therapies Extend Duration Even Further?
Joseph Sowka, OD, FAAO, Diplomate
Various therapies are under investigation for the treatment of diabetic eye disease, many of them focusing on enhancing the duration of therapy.
Port Delivery System with Ranibizumab
The Port Delivery System with Ranibizumab (PDS) is a surgically implanted reservoir that dispenses a continuous low dose of a customized formulation of ranibizumab. During a refill-exchange procedure, any remaining ranibizumab is removed from the PDS and a fresh payload is delivered.1 Researchers evaluated the safety and efficacy of the PDS for two diabetic eye disease indications in two phase 3 trials: diabetic retinopathy (DR) without diabetic macular edema (DME) in the Pavilion study and with DME in the Pagoda study.
In Pavilion, patients with treatment-naïve DR without DME were randomly assigned 5:3 to PDS or control arms.2 Patients in the PDS arm received a dose of intravitreal ranibizumab 1 month prior to PDS implantation and received a refill-exchange at week 36. Patients in the control arm were treated at investigator discretion with intravitreal ranibizumab at each monthly visit. Pavilion was a superiority study, with a primary endpoint of superior efficacy of the PDS compared with intravitreal ranibizumab treatment based on the proportion of patients with improvements in Early Treatment DR Study-DR Severity Score (ETDRS-DRSS) scoring of at least 2 steps at week 52.
Pavilion met its primary endpoint, with 80% of patients in the PDS arm experiencing a 2-step ETRDS-DRSS improvement compared with 9% of control patients (P < .01). The proportion of patients whose ETDRS-DRSS score worsened by 2 steps favored the PDS, with 2% of PDS patients experiencing a 2-step drop compared with 46% of patients in the control arm. No patients in the PDS arm needed supplemental treatment through 1 year.
The PDS was generally well tolerated. Further, a significantly higher percentage of patients in the control arm experienced vision-threatening complications or center-involved DME (CI-DME) at week 52 compared with the PDS arm. Specific statistics can be seen in Figure 1.
Researchers in the Pagoda study randomly assigned patients with DME who had undergone at least a 6-month treatment-free period in a 3:2 ratio to the PDS or to monthly intravitreal ranibizumab. Patients in each arm received 4 monthly doses, with those in the PDS arm receiving an initial PDS implantation at week 16 and a refill-exchange at week 40. The primary endpoint of the study was noninferiority of PDS compared with monthly intravitreal ranibizumab, based on change in BCVA score from baseline averaged over weeks 60 and 64.3
The study met its primary endpoint. Averaged over weeks 60 and 64, patients in the PDS arm gained mean 9.6 letters from baseline and patients in the monthly ranibizumab arm gained mean 9.4 letters from baseline. Patients in the PDS arm experienced a drop on letters gained after PDS implantation, as expected, but rebounded to pre-surgical vision approximately 12 weeks later (Figure 2). During the first refill-exchange interval (ie, between the first and second refill-exchange), 96% of patients did not require rescue therapy; during the second interval, 97% of patients did not require rescue therapy.4
Figure 1. More patients in the control arm of Pavilion experienced a vision-threatening complication (VTC), defined as proliferative DR (PDR), anterior segment neovascularization (ASVN), or CI-DME. Adapted from: Pieramici D. Presented at Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration 2023 Virtual; February 10-11, 2023.
Figure 2. In Pagoda, patients with DME who received the PDS demonstrated similar visual gains to patients who received monthly ranibizumab injections. The drop in vision seen in the 3 months after PDS implantation was expected by the investigators. Presented at the ASRS Annual Meeting; July 28-August 1, 2023; Seattle, WA.Gene Therapy
Gene therapy options for diabetic eye disease remain under investigation. Although exciting from a scientific standpoint, recent safety issues with gene therapy for diabetic eye disease have derailed some programs.
ABBV-RGX-314 is a recombinant adeno-associated viral vector (AAV) encoding a soluble monoclonal anti-VEGF.5 In the phase 2 Altitude study, patients with DR without diabetic macular edema (DME) have received ABBV-RGX-314 via suprachoroidal delivery. Through year 1, the therapy has been well tolerated.6 The study is ongoing.
ADVM-022 is an AAV encoding aflibercept that is delivered via intravitreal injection.7 In 2021, following safety issues observed in the Infinity trial, the company announced that they would halt plans for further investigation in DME.8
1. Holekamp NM, Campochiaro PA, Chang M, et al. Archway randomized phase 3 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Ophthalmology. 2022;129(3):295-307.
2. Pieramici D. Port Delivery System With ranibizumab in patients with diabetic retinopathy: primary analysis results of the phase 3 Pavilion trial. Presented at Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration 2023 Annual Meeting; Virtual; February 10–11, 2023.
3. Marcus DM. Port Delivery System with Ranibizumab (PDS) for continuous treatment in DME and DR: Additional results from the phase 3 Pagoda and Pavilion trials. Presented at the American Society of Retina Specialists Annual Meeting; July 28–August 1, 2023; Seattle, WA.
4. Khanani A. Port Delivery System with Ranibizumab in patients with Diabetic Macular Edema: Primary analysis results of the phase 3 Pagoda trial. Presented at Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration 2023; Virtual; February 10–11, 2023.
5. Dhoot DS. Suprachoroidal delivery of RGX-314 for diabetic retinopathy: the phase II ALTITUDE study. Ophthalmol Vis Sci. 2022;63(7):1152.
6. Barakat MR. Suprachoroidal delivery of investigational ABBV-RGX-314 for diabetic retinopathy: The phase II ALTITUDE study dose levels 1 and 2: One year results. Paper presented at: American Academy of Ophthalmology Annual Meeting; November 3, 2023; San Francisco, CA.
7. Khanani A. Presented during Angiogenesis, Exudation, and Degeneration 2021 Virtual Meeting. February 12-13, 2021.
8. Adverum Biotechnologies. Adverum provides update on ADVM-022 and the INFINITY trial in patients with diabetic macular edema [press release]. July 22, 2021; Adverum Biotechnologies; Redwood City, CA.
Real-World Cases From the Optometric Clinic
Discussions about eye care in a vacuum satisfy our academic instincts, but reviews of real-world cases transform conceptual discussions into practical ones. Here, Drs. Sowka and Chous share cases from their respective optometric practices, both of which illustrate the dynamics at play in patients with diabetic eye disease.
CASE 1: Patient Lost to Follow-up After Initial Treatments
Joseph Sowka, OD, FAAO, Diplomate
A 62-year-old man with type 2 diabetes was referred to my clinic by his primary care provider following a report of 4 years of blurred vision OS. His medical history includes use of insulin, hypertension, hypercholesterolemia, seizure disorder, anemia, and end-stage renal disease that requires dialysis three times per week.
The patient’s most recent ocular exam was 4 years ago. BCVA is 20/30- OD and 20/150 OS. A clinical examination revealed a grade-2 cataract OD and a grade-3 cataract OS. Scattered retinal and vitreous hemorrhages were observed OU (Figure 1). OCT imaging revealed diabetic macular edema (DME) in both eyes, and a tractional retinal detachment OS (Figure 2). No active proliferative diabetic retinopathy was observed.
I referred him to my practice’s in-house surgeon. A retina specialist began treatment with ranibizumab OU, and the patient was instructed to return in 4 weeks. The patient was also cleared for cataract surgery, as the cataracts were advanced enough to realize visual disruption. The surgeons planned to assess the patient for retinal surgery after cataract surgery.
He never presented for cataract surgery. The patient was lost to follow up (LTFU) for a period of 2 years. Upon his return, the patient reported worsening vision. BCVA was 20/40 OD and count fingers at 6 feet OS. During the examination, it was unclear if the patient was still under the care of a primary care physician. The patient’s fundus imaging did not depict many changes, but his cataracts had worsened significantly. The patient was referred for another cataract evaluation, which advised cataract surgery. He was again LTFU.
Given his history of noncompliance, a therapy with a longer duration could have helped this patient had he presented to the clinic for retinal care following cataract surgery.
Figure 1. Bilateral hemorrhages were observed on color fundus photography in a patient with a long history of visual disruption. Despite the presence of disease in both eyes, the patient’s BCVA was 20/30- OD. The patient’s contralateral eye, however, had a 4-year history of blurred vision and 20/150 BCVA. Courtesy of Joseph Sowka, OD, FAAO, Diplomate.
Figure 2. OCT imaging in the same patient depicted DME OU and a tractional retinal detachment OS. Courtesy of Joseph Sowka, OD, FAAO, Diplomate.
CASE 2: Illustrating the Need for More Durable Treatments
A. Paul Chous, MA, OD, FAAO
A 62-year-old Black woman with a 7-year history of type 2 diabetes presented to the clinic with complaints of reduced vision OD. Ocular examination revealed BCVA 20/50 OD, 18 mm Hg IOP OD, and central subfield thickness (CST) 426 µm OD. The patient’s HbA1c was measured at 8.0% and reported being prescribed a continuous glucose monitor (CGM), but said she does not use it. She also reported use of a continuous positive airway pressure (CPAP) device for sleep apnea and a history of early diabetic kidney disease.
The patient was diagnosed with moderate nonproliferative diabetic retinopathy and center-involved DME (Figure 3). I sent a letter to her primary care provider with my findings, and referred her to a retina specialist. I also instructed her to make an appointment at my office at 2 months. I find that re-appointing patients to return to the optometric clinic at 2 months is a useful means by which to assure that they keep their visit with a retina specialist.
The patient returned to my clinic in 3 months for a follow-up refraction. She had received 3 monthly injections of bevacizumab, which was required by her insurance carrier before a branded drug could be administered. BCVA OD was 20/30 and her DME had significantly improved (Figure 4).
The patient was scheduled for a fourth bevacizumab injection in 8 weeks. After congratulating the patient on her diligent follow-up, I counseled her to continue with the recommended intravitreal injections, reminding her that she had a chronic condition that requires ongoing care.
The patient returned 3 months later (ie, a total of 6 months since her first presentation) and reported that she had missed her follow-up appointments with the retina specialist: As her husband’s primary caretaker, she had to skip her own appointments as she drove him to his. Upon examination, I observed a recurrence of fluid and 20/100 BCVA OD (Figure 5).
I re-emphasized the importance of follow-up with the retina specialist for this patient, and strongly encouraged that she use her CGM. A growing body of evidence shows that CGM improves glycemic control in type 2 diabetes patients treated with insulin while also reducing the risk of hypoglycemia.1,2 The latter point was made in light of data from the Fremantle Diabetes Study, which found that severe hypoglycemia was a major risk factor for losing vision during follow-up in patients with type 2 diabetes as a consequence of ophthalmic complications.2
I educated the patient that ocular therapies with longer duration of action are available, and recommended she speak with her retina specialist about them to learn more. Of course, I did not recommend a specific treatment—that is up to the retina specialist and the patient—but I did mention in my notes to the retina specialist that I spoke to the patient about longer duration treatments. This way, if the patient broaches the topic, the retina specialist can begin the conversation knowing that this is not the first time the patient has heard of options for extending treatment intervals without sacrificing efficacy.
Figure 3. Upon presentation, a significant volume of retinal fluid was observed on OCT imaging. The patient’s CST was 426 µm. She was diagnosed with moderate nonproliferative diabetic retinopathy and center-involved DME. Courtesy of A. Paul Chous, MA, OD, FAAO.
Figure 4. After 3 monthly injections of bevacizumab, fluid resolution was obvious on OCT. BCVA was 20/30 at this visit. Courtesy of A. Paul Chous, MA, OD, FAAO.
Figure 5. Although this patient presented for her first three bevacizumab injections, she was LTFU due to life circumstances. BCVA OD was 20/100 and recurrence of retinal fluid was observed on OCT. Courtesy of A. Paul Chous, MA, OD, FAAO.
1. Grace T, Salyer J. Use of real-time continuous glucose monitoring improves glycemic control and other clinical outcomes in type 2 diabetes patients treated with less intensive therapy. Diabetes Technol Ther. 2022;24(1):26-31.
2. Drinkwater JJ, Davis TME, Davis WA. Incidence and predictors of vision loss complicating type 2 diabetes: The Fremantle Diabetes Study Phase II. J Diabetes Complications. 2020;34(6):107560.
