Article

Partnering With Patients to Foster Optimal Care

The healthcare burden carried by individuals with diabetes is substantial. Largely due to multiple comorbidities, people with diabetes visit doctors’ offices and emergency rooms more frequently than people without diabetes and are more likely to be admitted to the hospital or a nursing home and to receive home health care.1

Working-age patients with diabetic macular edema (DME) have been shown to have an average of 25.5 healthcare visits per year — 10 more than those who have diabetes but not DME.2 The costs associated with diabetes, for individuals and society, are burdensome as well. (For more information on the costs of diabetes treatment, see “Responding to the Economic Impact of Diabetes on Patients and Practices,” page 22.)

At the same time, people with diabetic eye disease may not be receiving optimal care. In a cross-sectional analysis of 699 adults with diabetic retinopathy (DR) who participated in a National Health and Nutritional

Examination Survey, even those with the most severe forms of DR were not fully utilizing appropriate preventive healthcare services, specifically nutrition education or dilated ophthalmic exams.3 According to Behavioral Risk Factor Surveillance System data, 23.5% of adults age 40 and older who have diabetes are noncompliant with the recommendation to have a yearly dilated eye exam, with “cost or lack of insurance” and “no need” most commonly given as the reasons.4

Diabetic patients are also at high risk of being “lost to follow-up.” In one study, patients with DME had increased odds of canceling or not showing to appointments with retina specialists versus patients with age-related macular degeneration (AMD).5 Furthermore, for established DME patients, utilization of anti-VEGF injections in clinical practice is lower than in randomized clinical trials.6-9

To serve patients with diabetes appropriately, it is important that eyecare practitioners and practices recognize the challenges these patients face while taking steps to foster compliance with both treatment and monitoring recommendations.

Provide and Reinforce Education

For patients to comply with treatment recommendations and help protect their vision, they must understand the risk diabetes poses to their eyesight. Many do not. A literature review identifying 10 emerging trends in the epidemiology of DR cited the fourth as “patchy and low” awareness of the risks of diabetes in most populations.10 Retina practices can reinforce the basics of diabetes control, such as the importance of a healthy lifestyle and blood pressure and glucose management.

Says Nancy Holekamp, MD, director of retina services for Pepose Vision Institute in Chesterfield, MO, “The best tool I have for education is color fundus photographs. When patients see bleeding in their own retinas, it’s striking, and the idea of treatment makes much more sense. I also explain to patients their OCT when we discuss DME, and I always take baseline photographs so they see the remarkable improvement after a series of anti-VEGF injections. Showing the before and after leads to buy-in, and then we can practice shared decision-making in which the patient understands the purpose of treatment, sees the benefits of treatment, and agrees with continued treatment. Shared decision-making is gaining ground in the practice of ophthalmology, particularly with medication.”

Intervene Early to Regress Diabetic Retinopathy

With the solid body of evidence that has emerged showing the ability of ranibizumab (Lucentis 0.3 mg, Genentech) and aflibercept (Eylea 2 mg, Regeneron) to improve diabetic retinopathy severity scores (DRSS) by two or more steps, particularly from baseline moderately severe to severe nonproliferative DR (NPDR), shared decision-making increasingly includes consideration of earlier treatment. (See “Is Watching and Waiting Yesterday’s Approach to Diabetic Eye Disease?,” page 12.)

According to David Eichenbaum, MD, a partner with Retina Vitreous Associates of Florida, “The data are showing that if we treat moderately severe to severe NPDR with anti-VEGF injections, we’re far more likely to avoid advancement to the worse stages of disease, such as DME and PDR. Based on the results of the Protocol S11 and PANORAMA12 trials, it appears that non-DME patients achieve DR regression and protection from disease advancement without very frequent injections. This different, lower treatment burden for DR patients without DME is important when we’re considering initiating therapy in the setting of DR alone.”

Improvement in DRSS may make a significant difference in patients’ quality of life. DR, particularly at vision-threatening stages, can negatively affect overall vision-dependent functioning as well as specific activities, such as cooking, seeing street signs, and reading the newspaper.13 Approximately half of people with severe NPDR or PDR have reported difficulty performing at least one visual task from among reading, a visuospatial action, mobility, and driving.14 Furthermore, vision-related functional burden has been found to be significantly greater with severe NPDR or PDR than when no retinopathy was present,14 and severe NPDR and PDR have been independently associated with depressive symptoms.15 A post hoc analysis from the phase 3 RIDE and RISE clinical trials of Lucentis for the treatment of DME also supports the importance of DRSS improvement.16 Most patients (56.8%) treated with Lucentis in the trials achieved a one-step or more improvement in DRSS from baseline to month 24. Those who remained stable or improved had greater mean changes in best-corrected visual acuity (BCVA) (+15.1, +14.2, +11.3, and +11.2 letters for ≥3-step improvement, ≥2-step improvement, 1-step improvement, and no DRSS change, respectively) compared with +5.0 letters for those who had any DRSS worsening. An improvement in BCVA of ≥15 letters was more common with a 2-step or 3-step or more DRSS improvement (51.9% and 44.6%, respectively) than with a 1-step improvement, no change, or worsening. Resolution of macular edema was also more common in patients with DRSS improvement.

Recognize All Available Treatment Modalities and Protocols

For DME patients undergoing anti-VEGF treatment, a rigorous injection schedule as was used in phase 3 clinical trials is expected to produce the best results. However, a treat-and-extend approach may be appropriate for some patients. In the RETAIN study, two treat-and-extend strategies with Lucentis (with and without laser) produced similar BCVA results as a prn approach at 24 months, and patients in the treat-and-extend groups had 46% fewer clinic visits and maintained their BCVA with treatment intervals of ≥2 months.17 Treat-and-extend for DME has been secondarily supported in some smaller prospective series, with a trend toward fewer visits and equivalent vision when treat-and-extend is utilized versus monthly RISE/RIDE-style dosing.18

With careful consideration of the known side effects, sustained-release steroid implants can also be used to reduce injection burden for patients with DME.

“Patients known to be noncompliant may be especially better off with a sustained therapy on board,” notes Michael A. Singer, MD, director of clinical research at Medical Center Ophthalmology Associates in Texas.

Two recent studies — USER and PALADIN — involving use of the fluocinolone acetonide 0.19 mg intravitreal implant (Iluvien, Alimera Sciences) in clinical practice showed the implant favorably impacts treatment burden without compromising vision or anatomical results.19 In USER, patients had received some type of treatment (anti-VEGF injection, laser, or steroid injection) every 2.9 months prior to receiving Iluvien. After Iluvien, treatment frequency decreased significantly across all visual acuity (VA) groups. For example, among patients with 20/40 or better VA, treatment frequency decreased to 22 months.

Laser treatment for either DME or PDR can always be considered as a way to reduce patients’ injection burden.

Ensure Injection Pain is Not an Issue

Most patients tend to be leery, or downright afraid, of receiving intraocular injections. To be sure injection fear doesn’t compromise compliance, Dr. Eichenbaum has focused on patient comfort and made periodic changes to his injection procedure.

“I no longer use a lid speculum for most patients,” he explains. “In almost all of my patients, I’ve replaced topical and subconjunctival anesthetic with a pledget, which we prepare with 4% lidocaine each morning. The pledget is placed in the lower fornix for 20 to 40 minutes, used with or without additional lidocaine gel depending on the patient. Sensitive patients also receive ointment in the eye afterward. Injecting down near 6 o’clock is also helpful because the eye has a natural tendency to Bell’s reflex upward.”

Therapies in Development Aim to Reduce Treatment Burden

As new therapies for diabetic eye disease are developed, reducing the treatment burden patients must endure is a primary objective.

“Faricimab (Roche/Genentech), a bispecific antibody that binds VEGF as well as angiopoietin-2, showed better regression in DR and greater durability than ranibizumab in patients with DME in the BOULEVARD20 phase 2 trial,” says Arshad Khanani MD, MA, managing partner and director of clinical research at Sierra Eye Associates in Reno, NV. “The phase 3 YOSEMITE and RHINE studies of faricimab are ongoing. Also, gene therapy may play a role in addressing treatment burden in the future by significantly reducing or eliminating the need for injections in patients with diabetic retinopathy.”

A clinical trial is being planned to evaluate the Lucentis refillable Port Delivery System (PDS, Genentech) in DR and DME. In a phase 2 AMD clinical trial, PDS produced vision results similar to monthly Lucentis injections, and the majority of patients went 6 months or longer before the PDS required refilling.21

“The PDS could be another game-changer,” notes Dr. Singer.

Dr. Holekamp agrees, adding, “In addition to lower treatment burden, the fact that the PDS will be disease-modifying should really help us with our DR and DME patients.” ■

References

  1. McEwen LN, Herman WH. Health care utilization and costs of diabetes. In: Cowie CC, Casagrande SS, Menke A, et al., Eds. Diabetes in America, 3rd ed. Bethesda, MD: National Institutes of Health, NIH Pub No. 17-1468; 2018:40/1-40/78.
  2. Wallick CJ, Hansen RN, Campbell J, Kiss S, Kowalski JW, Sullivan SD. Comorbidity and health care resource use among commercially insured non-elderly patients with diabetic macular edema. Ophthalmic Surg Lasers Imaging Retina. 2015;46(7):744-751.
  3. Willis JR, Doan QV, Gleeson M, et al. Self-reported healthcare utilization by adults with diabetic retinopathy in the United States. Ophthalmic Epidemiol. 2018;25(5-6):365-372.
  4. Chou CF, Sherrod CE, Zhang X, et al. Barriers to eye care among people aged 40 years and older with diagnosed diabetes, 2006-2010. Diabetes Care. 2014;37(1):180-188.
  5. Jansen ME, Krambeer CJ, Kermany DS, et al; Compliance Study Group. Appointment compliance in patients with diabetic macular edema and exudative macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2018;49(3):186-190.
  6. Fong D, Luong T, Jimenez J, Contreras R, Campbell J, Patel V. Visual acuity outcomes in patients treated with anti-VEGF therapy for diabetic macular edema in a US integrated healthcare system. Presented at: Macula Society Annual Meeting; Feb. 2015; Scottsdale, AZ.
  7. Kiss S, Liu Y, Brown J, et al. Clinical utilization of anti-vascular endothelial growth-factor agents and patient monitoring in retinal vein occlusion and diabetic macular edema. Clin Ophthalmol. 2014;8:1611-1621.
  8. Holekamp N, Campbell J, Cole A, et al. Real world vision outcomes in DME treated with anti‐VEGF injections — An analysis of EMR data from a large health system. Presented at: American Society of Retina Specialists Annual Meeting; Aug. 2014; San Diego, CA.
  9. Holekamp N, Dugel P, Yep T, et al. Utilization of anti-VEGFs for diabetic macular edema in US clinical practice – an analysis of the Vestrum Health database. Presented at: Retina Society Annual Meeting; Oct. 2015; Paris, France.
  10. Sabanayagam C, Yip W, Ting DS, Tan G, Wong TY. Ten emerging trends in the epidemiology of diabetic retinopathy. Ophthalmic Epidemiol. 2016;23(4):209-222.
  11. Gross JG, Glassman AR, Liu D, et al. Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy. JAMA Ophthalmol. 2018;136(10):1138-1148.
  12. Regeneron press release. One-year results from positive phase 3 Eylea trial in diabetic retinopathy presented at angiogenesis symposium. Available at: https://investor.regeneron.com/news-releases/news-release-details/one-year-results-positive-phase-3-eylea-trial-diabetic ; accessed Feb. 28, 2019.
  13. Gupta P, Liang Gan AT, Kidd Man RE, et al. Impact of incidence and progression of diabetic retinopathy on vision-specific functioning. Ophthalmology. 2018;125(9):1401-1409.
  14. Willis JR, Doan QV, Gleeson M, et al. Vision-related functional burden of diabetic retinopathy across severity levels in the United States. JAMA Ophthalmol. 2017;135(9):926-932.
  15. Rees G, Xie J, Fenwick EK, et al. Association between diabetes-related eye complications and symptoms of anxiety and depression. JAMA Ophthalmol. 2016;134(9):1007-1014.
  16. Ip MS, Zhang J, Ehrlich JS. The clinical importance of changes in diabetic retinopathy severity score. Ophthalmology. 2017;124(5)596-603.
  17. Prunte C, Fajnkuchen F, Mahmood S, et al; RETAIN Study Group. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol. 2016;100(6):787-795.
  18. Eichenbaum DA, Duerr E, Patel HR, Pollack SM. Monthly versus treat-and-extend ranibizumab for diabetic macular edema: a prospective, randomized trial. Ophthalmic Surg Lasers Imaging Retina. 2018;49(11):e191-e197.
  19. Holekamp N. 2 real-world analyses of treatment burden associated with intravitreal injections for DME prior to 0.2 µg/day fluocinolone acetonide (FAc). Presentation at: American Society of Retina Specialists Annual Meeting; July 2018; Vancouver, BC, Canada.
  20. Regillo C. Anti-VEGF/anti-angiopoietin-2 bispecific antibody faricimab in diabetic macular edema. Paper presented at the annual meeting of the Retina Society; San Francisco, CA; Sept. 15, 2018.
  21. Genentech press release. Genentech unveils positive phase II results for the Port Delivery System with ranibizumab (PDS). July 25, 2018. Available at: https://www.gene.com/media/press-releases/14739/2018-07-25/genentech-unveils-positive-phase-ii-resu ; last accessed March 1, 2019.