A riddle stands at the center of glaucoma care. Research indicates that, when intraocular pressure (IOP) is substantially lowered, disease progression can be halted.1 Yet, multiple studies show that, despite adequate lowering of IOP, disease progression still occurs.2,3 How do we reconcile this apparent paradox? Why do medicated patients continue to progress despite IOPs that are low enough to theoretically halt the process? A 2020 study may help elucidate the answer.4 That research carried out a subanalysis of the landmark collaborative initial glaucoma treatment study and was able to demonstrate that patients who never missed a glaucoma medication dose (about 47% of the medicated group), experienced no visual field progression in a span of 8 years. For the patients that did have visual field progression, a decrease in medication adherence resulted in a direct and significant increase in the rate of visual field worsening. 

This patient was treated with a bimatoprost implant previously in her right eye. The improved hyperemia in her right eye is clear compared with the significant hyperemia in her left eye, which was being treated with a prostaglandin-analog at the time of this photograph. 

Have you ever had to take medicine multiple times a day? You could imagine that it can be difficult, but doable if for a short period of time. But how about maintaining this level of compliance indefinitely? Long-term adherence to glaucoma treatment is notoriously low.5  One study demonstrated that adherence to glaucoma medication drops precipitously with time, with only 50% of patients still on their prescribed topical therapy at 6 months of treatment.6 More alarming, only 37% persisted on therapy past 3 years.6 Adherence to prostaglandin-analog (PGA) therapy was substantially higher than all other classes of glaucoma therapy, clearly emphasizing the importance of once-a-day dosing.6 The addition of medication to existing glaucoma monotherapy further decreases compliance and adherence.7

Glaucoma is initially a symptom-free disease. Instilling eye drops multiple times a day introduces deleterious ocular symptoms, such as tearing, burning, stinging, as well as systemic side effects such as headaches, fatigue, exercise intolerance, and light sensitivity, amongst others.8 Patients with multiple topical medications report worse ocular discomfort compared with patients who use only a single topical medication.9 And research shows ocular surface disease and discomfort worsens as the frequency of glaucoma drop usage increases throughout the day.10 For patients, it seems like an awful lot to deal with for a disease they haven’t even symptomatically noticed yet.  


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All this points to the same solution. To improve medication adherence and reduce ocular discomfort, it is prudent for clinicians to minimize the number of glaucoma medications needed, and to choose medications that have the least frequent dosing throughout the day. Once-a-day treatments or drop-free options would achieve this goal. It is unsurprising then that PGAs, which are dosed nightly, have been our first line option since the 1990s.11 Nevertheless, 50% of patients may need more than 1 glaucoma medicine to control their IOP adequately.12 The potential to improve the quality of life for patients by reducing the quantity of medication while maintaining IOP control has spurred innovative new medications and therapeutics. Here, we review 4 options that are helping to both keep IOPs low and patients happy and compliant.

Topical Medications

In 2017, 2 new glaucoma medications arrived on the market after a 20-year drought. Both build on the existing platform of a PGA, providing once-a-day dosage while improving efficacy. Latanoprostene bunod consists of a latanoprost molecule attached to a nitric oxide (NO)-donating moiety.13 When in the anterior chamber, the NO dissociates and travels to the trabecular meshwork, where it helps to dilate the trabecular beams and improve trabecular outflow. With the addition of NO, latanoprostene bunod was proven superior to latanoprost, providing an additional average of 1.2 mm Hg IOP lowering.14 With regards to long term therapy, every 1 mm Hg in IOP lowering is vital, as it directly reduces the rate of glaucoma progression by 10%, according to a 2003 study.15 The greatest advantage of latanoprostene bunod is that its side effect profile is nearly identical to latanoprost, therefore you have improved efficacy without any additional adverse effects to encounter. 

The second new medication is netarsudil, a Rho-kinase inhibitor. Rho-kinases promote a contractile and stiff trabecular meshwork, and by inhibition of these proteins, the trabecular meshwork molds into a more relaxed and porous architecture, improving trabecular outflow16. Netarsudil is dosed nightly and was shown to be noninferior to timolol.16 

One available formulation, which combines netarsudil 0.02% and latanoprost 0.005%, provides a powerful single bottle treatment, dosed nightly. The therapeutic effect of these combined drugs is substantial, with a third of patients achieving more than a 40% drop in IOP.17 This degree of efficacy was previously unattainable without multiple bottles of topical medicines dosed multiple times a day. There is a significant downside of this option, though, which is that the rate of conjunctival hyperemia can be as high as 58%.17 Although the majority of hyperemia was mild, counseling the patient on this side effect is advisable to promote adherence. 

While all these options are effective, some patients may require you to remove the burden of treatment off of them altogether. A dropless treatment delivered by the ophthalmologist would have 100% compliance, substantially lowering the risk of glaucoma progression and would, ideally, reduce ocular discomfort. 

Selective Laser Trabeculoplasty

Selective laser trabeculoplasty (SLT) has been around for a while but was typically used as an adjunct for glaucoma treatment.18 The LIGHT study investigated the outcomes of SLT used as a first-line treatment in direct comparison with eyes that were started on a PGA first.19 The LIGHT trial confirmed what previous studies had indicated, in that SLT can achieve similar efficacy as a PGA. But, what the LIGHT trial elucidated was that long-term outcomes between the 2 cohorts were not the same. Despite similar efficacy, 11 patients using drops continued to have glaucoma progression and needed incisional glaucoma surgery. Zero patients required incisional glaucoma surgery in the SLT treatment group. This outcome clearly emphasizes the inherent risk of lower compliance with drops, since successful SLT would yield 100% compliance. Based on these studies, SLT as a first-line treatment may be in the best interest of many patients., specifically those in the milder spectrum of glaucoma disease.18

Injectable Medication

Researchers have investigated implantable glaucoma medication options for decades.20-24 From drug-eluting punctal plugs, contact lenses to medicated ocular ring inserts and injectables, clinical research has shown significant interest in creating a drop-free therapy for glaucoma.20 Fortunately, the intense amount of research has finally brought forward a drop-free option that the US Food & Drug Administration (FDA) has approved. That option is a bimatoprost-eluting implant. Bimatoprost is a PGA that has a long track record of proven efficacy, but with a side effect of increased conjunctival hyperemia.21 Bypassing the ocular surface and delivering bimatoprost into the anterior chamber was shown to lower the IOP similarly to topical bimatoprost while reducing the rate of conjunctival hyperemia.22 The implant itself is made of a biodegradable polymer that dissolves slowly and releases bimatoprost for 4 to 6 months. Research even shows significant IOP lowering in 40% of patients up to 1 year, with a subset of patients achieving 2 years of drop-free management from just 1 injection.23 A possible reason for the prolonged effect is thought to be due to ciliary body remodeling that occurs secondary to continuous prostaglandin exposure, promoting long-term uveoscleral outflow.24 With 3 injections spaced 4 months apart, a majority of patients did not need another injection for up to 1 year after the third injection. While this option is currently FDA-approved for only 1 injection, the agency is currently collecting long-term data on endothelial cell outcomes before approving for repeat injections. 

Despite this limitation, I have heard great interest from patients who are either symptomatic from PGA use or are yearning for a break from taking it nightly. As an example, a recent patient’s family was very happy with the bimatoprost implant, since the patient’s daughter had to drive every evening to her 90-year-old father’s house to help instill his eye drop. This option gave her a break for 4 to 6 months, and potentially up to a year or more. 

Cataracts and MIGS

About 20% of patients undergoing cataract extraction (CE) have concomitant glaucoma.25 Prior to 2012, there were no safe, minimally invasive, and effective options to provide IOP control in glaucomatous eyes undergoing CE. Fortunately, in the past decade, a new therapeutic category was introduced, coined minimally invasive glaucoma surgery (MIGS). MIGS, which includes trabecular stents and incisions, were designed to provide therapy for glaucomatous eyes undergoing CE, typically to reduce glaucoma medication burden. Instead of putting the patient back on glaucoma eye drops after CE, as was typically done, performing MIGS during CE is a window of opportunity to control glaucoma without topical therapy. Randomized, prospective, controlled studies have clearly demonstrated that trabecular stents can provide a greater than 70% chance of achieving glaucoma drop freedom for up to 2 years.26,27 What’s more striking is that in eyes that underwent implantation with a trabecular stent, researchers saw an 85% reduction in risk of necessitating incisional glaucoma surgery for 3 years, compared with control eyes, which were put back on drops.28 This strongly emphasizes the important role that trabecular stents have in stabilizing glaucoma and the superiority of surgical management of glaucoma instead of a medicated approach. 

Another category of MIGS includes nonstent options, such as canaloplasty, trabeculotomy, and excisional goniotomy. These procedures have become popular thanks to MIGS devices that facilitate an ab-interno surgical approach. Unlike trabecular stents, these procedures are approved for use with or without cataract surgery and therefore are more versatile in treating glaucoma. As stand-alone, sequential canaloplasty and trabeculotomy (used in concert with the appropriate device) successfully reduced eye drop burden and lowered IOP in eyes with mild-to-moderate glaucoma.29 Excisional goniotomy had similar outcomes, with a significant proportion of eyes achieving fewer drops and lower IOP compared to baseline.30 Long-term outcomes are necessary to see the effect these procedures have on preventing glaucomatous disease progression, but as emphasized previously with trabecular stent and SLT studies, surgical management may yield superior outcomes compared with medicated treatment of glaucoma.

Fewer Meds, Better Outcomes 

Adherence rates and compliance are significant factors that explain why some glaucomatous eyes continue to worsen despite seemingly controlled IOPs measured in the clinic. Reducing the frequency of eye drops by utilizing once-a-day options would help reduce the rate of ocular discomfort, improve patient adherence and ultimately reduce the risk of glaucoma progression. Eliminating the need for topical administration altogether, using either intracameral injections, SLT, or MIGS may yield the highest success rate in controlling glaucoma and could likely improve long-term quality of life for patients, especially those who currently use multiple drops a day. We must perform our duty and educate glaucoma patients on the surgical options available, including the superior outcomes associated with them, to help empower them to choose the option that is the best fit. 

References

1. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000;130(4):429-40. doi:10.1016/S0002-9394(00)00538-9 

2. Musch DC, Gillespie BW, Lichter PR, et al. Visual field progression in the Collaborative Initial Glaucoma Treatment Study the impact of treatment and other baseline factors. Ophthalmol. 2009;116(2):200-7. doi:10.1016/j.ophtha.2008.08.051.

3. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trialArch Ophthalmol. 2003;121(1):48–56.

4. Newman-Casey PA, Niziol LM, Gillespie BW, Janz NK, Lichter PR, Musch DC. The association between medication adherence and visual field progression in the collaborative initial glaucoma treatment study. Ophthalmol. 2020;127(4):477-483. doi:10.1016/j.ophtha.2019.10.022

5. Feehan M, Munger MA, Cooper DK, et al. Adherence to glaucoma medications over 12 months in two us community pharmacy chains. J Clin Med. 2016;5(9):79. doi:10.3390/jcm5090079 

6. Nordstrom BL, Friedman DS, Mozaffari E, Quigley HA, Walker AM. Persistence and adherence with topical glaucoma therapy. Am J Ophthalmol. 2005 Oct;140(4):598-606.

7. Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmol. 2005;112(5):863-8. doi:10.1016/j.ophtha.2004.12.026.

8. Inoue K. Managing adverse effects of glaucoma medicationsClin Ophthalmol. 2014;8(5):903-913.. doi:10.2147/OPTH.S44708

9. Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6):618-21. doi:10.1097/ICO.0b013e3181c325b2

10. Rossi G, Pasinetti G, Scudeller L, Raimondi M, Lanteri S, Bianchi PE. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol. 2013;23(3):296-302. doi:10.5301/ejo.5000220

11. Hogg H, Connor A. 10-year trends in English primary care glaucoma prescribing. Eye. 2020;34(11):192–196. doi:10.1038/s41433-019-0656-z

12. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-13; discussion 829-30.

13. Fingeret M, Gaddie IB, Bloomenstein M. Latanoprostene bunod ophthalmic solution 0.024%: a new treatment option for open-angle glaucoma and ocular hypertension. Clin Exp Optom. 2019;102(6):541-550. doi: 10.1111/cxo.12853.

14. Weinreb RN, Ong T, Scassellati Sforzolini B et al. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER studyBr J Ophthalmol. 2015; 99(5):738–745. doi:10.1136/bjophthalmol-2014-305908 

15. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trialArch Ophthalmol. 2003;121(1):48–56. 

16. Mehran NA, Sinha S, Razeghinejad R. New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprostEye (Lond). 2020;34(1):72-88. doi:10.1038/s41433-019-0671-0

17. Asrani S, Bacharach J, Holland E, et al. Fixed-dose combination of netarsudil and latanoprost in ocular hypertension and open-angle glaucoma: pooled efficacy/safety analysis of phase 3 MERCURY-1 and -2Adv Ther. 2020;37(4):1620-1631. doi:10.1007/s12325-020-01277-2

18. Garg A, Gazzard G. Selective laser trabeculoplasty: past, present, and future [published correction appears in Eye (Lond). 2020;34(8):1487]. Eye (Lond). 2018;32(5):863-876. doi:10.1038/eye.2017.273

19. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019 Apr 13;393(10180):1505-1516. 

20. Kesav NP, Young CEC, Ertel MK, Seibold LK, Kahook MY. Sustained-release drug delivery systems for the treatment of glaucomaInt J Ophthalmol. 2021;14(1):148-159.  doi:10.18240/ijo.2021.01.21

21. Aptel F, Cucherat M, Denis P. Efficacy and tolerability of prostaglandin analogs: a meta-analysis of randomized controlled clinical trials. J Glaucoma. 2008;17(8):667-73. doi:10.1097/IJG.0b013e3181666557. 

22. Craven ER, Walters T, Christie WC, et al. 24-month phase i/ii clinical trial of bimatoprost sustained-release implant (bimatoprost sr) in glaucoma patientsDrugs. 2020;80(2):167-179. doi:10.1007/s40265-019-01248-0

23. Medeiros FA, Walters TR, Kolko M, et al. Phase 3, randomized, 20-month study of bimatoprost implant in open-angle glaucoma and ocular hypertension (ARTEMIS 1). Ophthalmol. 2020;127(12):1627-1641. doi:10.1016/j.ophtha.2020.06.018.

24. Richter M, Krauss AH, Woodward DF, Lütjen-Drecoll E. Morphological changes in the anterior eye segment after long-term treatment with different receptor selective prostaglandin agonists and a prostamide. Invest Ophthalmol Vis Sci. 2003;44(10):4419-26. doi:10.1167/iovs.02-1281. 

25.Shrivastava A, Friedman, D, Singh, K et al., Prevalence of glaucoma in a cataract surgery population; Presented at: 2016 ASCRS-ASOA Symposium and Congress, New Orleans, US, May 6–10, 2016.

26. Samuelson TW, Chang DF, Marquis R, et al. A Schlemm canal microstent for intraocular pressure reduction in primary open-angle glaucoma and cataract: the HORIZON study. Ophthalmol. 2019;126(1):29-37. doi:10.1016/j.ophtha.2018.05.012

27. Samuelson TW, Sarkisian S, Lubeck D, et al. Prospective, randomized, controlled pivotal trial of an ab interno implanted trabecular micro-bypass in primary open-angle glaucoma and cataract: two-year results. Ophthalmol. 2019;126(6):811-821. doi:10.1016/j.ophtha.2019.03.006.

28. Ahmed IIK, Rhee DJ, Jones J, et al. Three-year findings of the horizon trial: a Schlemm canal microstent for pressure reduction in primary open-angle glaucoma and cataract. Ophthalmol. Published online November 5, 2020. doi:10.1016/j.ophtha.2020.11.004 

29. Vold SD, Williamson BK, Hirsch L, et al. Canaloplasty and trabeculotomy with the OMNI system in pseudophakic patients with open-angle glaucoma: the ROMEO study. Ophthalmol Glaucoma. 2021;4(2):173-181. doi:10.1016/j.ogla.2020.10.001

30. Berdahl JP, Gallardo MJ, ElMallah MK, Williamson BK, et al. Six-month outcomes of goniotomy performed with the Kahook dual blade as a stand-alone glaucoma procedure. Adv Ther. 2018;35(11):2093-2102. doi:10.1007/s12325-018-0803-0