Physician perspective: Glaucoma eye drops are here to stay

For as long as I can recall, there has been ongoing discussion about the drawbacks of initiating glaucoma therapy with IOP–lowering medications. This narrative has been amplified in recent years with the advent of early procedural interventions, particularly minimally invasive glaucoma surgery (MIGS) and implanted sustained-release devices. Laser trabeculoplasty has remained a reasonable first-line option for patients with newly diagnosed primary open-angle glaucoma (POAG), supported by multiple clinical trials, most recently the Laser in Glaucoma and Ocular Hypertension (LiGHT) trial (ISRCTN32038223) conducted in the UK.¹

One might ask why topical eye drop medications remain the mainstay of glaucoma therapy in the US and worldwide. The reason is straightforward: When patients with newly diagnosed glaucoma are started on eye drops and followed at appropriate intervals—with medical and surgical therapy escalated as needed—most will do well. This treatment paradigm is supported by numerous clinical trials, ranging from the Collaborative Initial Glaucoma Treatment Study (NCT00000149) to the UK Glaucoma Treatment Study (ISRCTN96423140).^2,3

Market data indicate that the glaucoma pharmaceutical market, even in a heavily genericized environment, is approximately 5 times the size of the interventional glaucoma market.⁴ Topical glaucoma medication therapy is here to stay. However, the pace of innovation in developing new molecular entities that provide safer and more effective IOP-lowering via topical delivery has slowed in recent decades, perhaps due to increased attention on surgical glaucoma interventions and neuroprotective candidate therapies.

Last year, I delivered the Carl B. Camras, MD, Memorial Lecture at the 31st Annual Gifford-Truhlsen Conference at the University of Nebraska Medical Center in Omaha.⁵ About 50 years ago, Camras (Figure)—then an undergraduate majoring in molecular biophysics and biochemistry at Yale University—conceived the idea that low-dose prostaglandins could safely and effectively treat glaucoma by lowering IOP. He continued this work at Columbia University during medical school and collaborated with his professor, László Bitó, PhD, and researchers at Pharmacia Corporation in Uppsala, Sweden, to develop latanoprost, which was introduced as Xalatan in 1996.⁶ Several other classes of glaucoma medications, including topical carbonic anhydrase inhibitors and α-adrenergic agonists, were also introduced in the 1990s.^7,8

Over the past few decades, the development of novel topical glaucoma therapeutics has been limited. At the same time, topical medications remain widely used in real-world practice. Despite challenges with drug delivery, adverse effects, and adherence, eye drops continue to be a mainstay of therapy.

One reason is the epidemiology of POAG. Most patients—particularly those diagnosed early—experience slow or minimal disease progression, even if therapy is not fully optimized. Observational and interventional studies, including real-world data, indicate that only a small subset of patients (approximately 4% to 10%) are fast progressors, losing more than 1 dB of mean deviation per year.^9,10

Furthermore, in large, randomized, well-controlled clinical trials, between one-third and two-thirds of subjects who received a placebo or no treatment showed no progression.^3,11 Twenty-year follow-up data from the Ocular Hypertension Treatment Study (OHTS) (NCT00000125) revealed that only 25% of subjects followed for 2 decades developed any visual field change from baseline.¹² These data should be sobering to those advocating for an early interventional approach to glaucoma care. If half or more of individuals who qualify for IOP-lowering treatment are destined to do well even without therapy, the safety and reversibility of medical therapy become particularly attractive.

Why do we treat so many people who may not ultimately need treatment? The reason, of course, is that we cannot prospectively identify which patients will worsen, and glaucomatous vision loss is generally irreversible. Fortunately, glaucomatous disease most often progresses slowly, and clinicians usually have multiple opportunities to intervene before patients develop symptoms, particularly when the disease is diagnosed early.

Tailoring therapy: Monitoring, progression, and patient outcomes

Longitudinal disease surveillance is likely the single most important factor in determining whether a patient will do well. For example, if a patient is started on IOP-lowering therapy and shows no disease progression over the next 2 years, this should be considered a successful outcome, regardless of whether the patient consistently adheres to the medication regimen. Conversely, if the patient shows progression over this period, the current therapy—whether taken or not—is insufficient, and escalation of treatment, including surgical options, should be considered.

The wide variability in the natural history of glaucoma among patients—even among those with similar risk factors—makes regular follow-up essential, rather than relying on one-time interventions that may or may not be effective long term. The current debate in glaucoma care is not between eye drops and procedural interventions, but rather about practitioners’ commitment to follow patients carefully and accept that patients should be subjected to the minimum harm necessary to preserve vision.

It is also noteworthy that procedural interventions may, in some cases, reduce a patient’s likelihood of returning for careful follow-up—perhaps due to a false sense of security that the intervention will provide permanent control. In such individuals, the risk of vision loss may be higher than in those who receive regular surveillance. Therapy cannot be advanced if the patient does not return for follow-up, and adherence to medications does not necessarily correlate with adherence to follow-up appointments.^13,14

Finally, it is important to note that procedural interventions, including MIGS and drug-delivery devices, provide limited efficacy. Many patients undergoing these procedures will ultimately require additional medications. Among currently available surgical options, only trabeculectomy is associated with a reasonably high likelihood of keeping patients off medications in the long term. Most patients receiving MIGS, minimally invasive bleb-forming procedures, or long-tube glaucoma implants will require supplemental IOP-lowering medications to maintain safe IOP levels.

Among drug-delivery platforms, only prostaglandin analogues are commercially available for intraocular delivery, and large clinical trials have shown that a single class of medication is generally insufficient to control IOP over the long term in many patients who demonstrate disease progression. Topical glaucoma medications, therefore, remain essential, and innovators should continue to pursue new molecular entities that lower IOP more effectively than—and/or synergistically with—currently available agents, whether delivered as eye drops or through other drug-delivery approaches.

Missing the mark

Overtreatment of patients who do not truly have progressive glaucomatous disease—and who would be better classified as glaucoma suspects or ocular hypertensives—is undoubtedly an important problem for several reasons. However, a potential glaucoma public health crisis in the US may be emerging not from overtreatment of the many, but from undertreatment of the few—less than 10%—who are destined to go blind from glaucoma and are receiving minimal therapy.

Over the past 5 years, I have seen more patients with advanced glaucomatous disease who were either not offered trabeculectomy or were discouraged from undergoing the procedure than in the preceding quarter-century. Some of these patients presented after already losing vision, sometimes in tears as they described undergoing a series of MIGS procedures and being told that trabeculectomy was an outdated operation that is no longer used.

Unfortunately, much of this narrative appears to be driven by transactional care, in which certain practitioners may perceive greater revenue potential with MIGS and insufficient reimbursement for the time and effort required for traditional procedures such as trabeculectomy.¹⁵ Denying patients meaningful interventions could ultimately become a major cause of increased blindness from glaucoma in future generations. Ironically, this could be an unintended consequence of an interventional glaucoma mindset imposed on patients with advanced or rapidly progressive disease who are denied the ultimate intervention: trabeculectomy, the procedure most likely to prevent blindness.

The future of glaucoma therapy: Novel drugs and continued innovation

Returning to medical therapy—which is here to stay for the treatment of most patients with glaucomatous disease—there are several promising novel therapeutics at various stages of the innovation cycle. For example, one compound (QLS-111; Qlaris Bio, Inc) may represent a first-in-class agent that lowers IOP by reducing episcleral venous pressure. We need drugs that are better tolerated and that can meaningfully reduce IOP when used adjunctively with prostaglandin analogues, the most commonly prescribed first-line glaucoma medications.

My wish list for a new glaucoma drug includes one with no systemic adverse effects and excellent ocular tolerability, with low rates of allergic reactions, hyperemia, or ocular pain and discomfort. A drug that could consistently lower IOP by an additional 2 to 3 mm Hg beyond what is achieved with a prostaglandin analogue—and that has ocular tolerability similar to timolol and systemic tolerability similar to latanoprost—would be a major win for our patients.

Selective laser trabeculoplasty (SLT) should, and will, continue to play an important role as an initial or adjunctive treatment option for OAG. However, SLT is not a panacea, and the disease of most patients who live one or more decades after diagnosis will not be adequately controlled with SLT alone, even if the procedure is repeated. Topical medications will continue to play an essential role, and we should continue to pursue novel molecular entities that safely and effectively lower IOP. To put this in perspective, if anti-VEGF therapy could be delivered safely and effectively with topical eye drops, I doubt many patients would choose to return every few months for intraocular injections.

In the mid-1990s, when several new classes of glaucoma medications were introduced over 5 years, most major glaucoma meetings focused on medical therapy, with little discussion of surgery. The pendulum has now swung to the other extreme, with little, if any, recent discussion of topical glaucoma medications. One unforeseen consequence of this shift is that trainees and young practitioners may be misled into thinking that glaucoma eye drops will soon become obsolete. If this misperception reduces training in the characteristics of glaucoma drugs—such as optimal dosing regimens, peak and trough effects, contraindications, and stepwise treatment algorithms—patients will be poorly served. Continued innovation in glaucoma pharmaceuticals to safely lower IOP, along with training the next generation of ophthalmologists in the nuances of prescribing topical glaucoma medications, remains as essential today as it has been in the past.

Physicians and their patients with glaucoma have benefited from many novel procedural approaches that have emerged over the past 25 years. I am grateful to have these options available in my practice, as they have helped improve care for many patients. Gratitude is owed to pioneering individuals—including James B. Wise, MD; Douglas E. Gaasterland, MD; Thom J. Zimmerman, MD, PhD; George Baerveldt, MD; Mary G. Lynch, MD; Reay H. Brown, MD; and many others—who envisioned and developed safer interventions than traditional glaucoma surgeries. Procedural interventions, however, will not replace the importance of glaucoma pharmaceuticals, including eye drops. Procedural and pharmaceutical innovation can—and should—coexist to optimize care for future generations of patients with glaucoma.

Kuldev Singh, MD, MPH

E: [email protected]

Singh is a professor of ophthalmology and director of the glaucoma division in the Department of Ophthalmology at Stanford University School of Medicine in Palo Alto, California. He is a consultant to Alcon, Bausch + Lomb, Elios, Novartis, Oculis, Ocular Therapeutix, Qlaris Bio, Radiance Therapeutics, and Sight Sciences.

The thoughts and opinions expressed are those of Singh and do not necessarily represent the opinions of this publication.

References

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10. Jackson AB, Martin KR, Coote MA, et al. Fast progressors in glaucoma: prevalence based on global and central visual field loss. Ophthalmology. 2023;130(5):462-468. doi:10.1016/j.ophtha.2023.01.008

11. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268-1279. doi:10.1001/archopht.120.10.1268

12. Kass MA, Heuer DK, Higginbotham EJ, et al; Ocular Hypertension Study Group. Assessment of cumulative incidence and severity of primary open-angle glaucoma among participants in the Ocular Hypertension Treatment Study after 20 years of follow-up. JAMA Ophthalmol. 2021;139(5):1-9. doi:10.1001/jamaophthalmol.2021.0341

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