The aim of glaucoma medical therapy is to slow the progression of optic neuropathy and visual field loss. Primary open-angle glaucoma (POAG) inevitably progresses in the absence of treatment, and lowering IOP is currently the only treatment approach that can slow progression. All current interventions for POAG, whether pharmaceutical or surgical, are aimed at reducing IOP. As demonstrated in several large clinical trials, IOP reduction can prevent progression of optic nerve damage and visual field loss in both early and late stages of the disease.^1-5 According to the American Academy of Ophthalmology’s (AAO) 2016 Preferred Practice Pattern for management of POAG, the goal of therapy is to lower IOP enough to slow or stop disease progression in order to maintain good functional vision.⁶

Available medications can lower IOP effectively for many patients, but not all, and little has changed in the ophthalmologist’s medical armamentarium in the past 20 years.

Common IOP-Lowering Therapies

Currently, five classes of IOP-lowering agents, which work by mechanisms affecting aqueous production and outflow, are available. These include: prostaglandin analogs (PGAs), β-blockers, carbonic anhydrase inhibitors (CAIs), α-2 adrenergic agonists, and miotics (also known as parasympathomimetics).⁶ Combination medications are also available. Eye drops may combine an α-2 adrenergic agonist and a β-blocker; a CAI and a β-blocker; or an α-2 adrenergic agonist and a CAI.

As my first-line treatment for glaucoma therapy, I offer PGAs or laser trabeculoplasty (ALT or SLT) if the glaucoma progression is not rapid. Some patients know they can’t tolerate putting drops in their eyes and opt for laser surgery immediately. For those who elect medication, I choose a PGA as my first-line therapy.

If a patient doesn’t respond well to or cannot tolerate PGAs, I typically move them to a β-blocker or add a β-blocker to their course of treatment. PGAs are used once daily, and I’ve found that patients are more compliant with a once-a-day medication schedule. If needed, I would next move patients to an α-agonist or CAI. The typical treatment goal with these medications is an IOP of less than 21 mmHg, and to lower the pressure by at least 20% for patients with mild glaucoma and by as much as 40% or 50% for those with moderate to severe glaucoma.⁷

But even with these therapies, many patients still don’t have their IOP lowered enough to stop disease progression. Why?

Medication Noncompliance

Many patients don’t adhere to their glaucoma treatment regimen, which results in failure to lower IOP to their target pressure. Studies across a range of populations show that medication nonadherence and dosing errors are widespread among patients being treated for glaucoma. In 2009, a prospective study assessing adherence with PGA monotherapy observed patients (N=196) for 3 months using an electronic dose-monitoring dispenser.⁸ Nearly 45% of patients took less than 75% of their doses, and almost 20% of patients took less than 50% of their doses, even when they knew they were being electronically monitored.⁸

A 2017 study of glaucoma medication prescription refill rates from two pharmacy dispensing databases in a total of 3,615 patients indicated unsatisfactory adherence for glaucoma patients. Satisfactory adherence (defined as medications available at least 80% of the time) over a 12-month period ranged from 30% to 37% in this analysis.⁹ In addition, a 2015 retrospective study evaluating patterns of glaucoma medication adherence over 4 years of follow-up found that of 1,234 newly diagnosed open-angle glaucoma patients, 7.5% of enrollees were never adherent, 14.9% had persistently very poor adherence, and 9.5% had declining adherence in the first year. What’s more, for most patients newly started on glaucoma medications, adherence patterns observed in the first year of treatment reflected adherence patterns over the subsequent 3 years.¹⁰

Patients may not understand that glaucoma requires lifelong therapy, unlike, for example, systemic hypertension, in which patients may be able to decrease the use of medication through dietary and lifestyle modifications. Other patients may understand the need to maintain a schedule of prescribed medication but are unable to keep to that schedule for various reasons. They may have arthritis, poor hand-eye coordination, muscle weakness, or another medical condition that keeps them from being able to squeeze a dropper or steady their hand to instill the drops in their eyes. In addition, patients may fail to reach the target dose of their medication if they develop side effects that prevent them from using their medication regularly as prescribed.

A 2017 review identified risk factors for poor adherence to medical glaucoma therapy, including, as discussed, lack of understanding among patients about their disease, as well as the cost, complexity, or side-effect profile of the medication regimen.¹¹ Researchers have been challenged to definitively link nonadherence to outcomes such as IOP or visual field loss, which may have to do with problems in study design or simply the difficulty of directly demonstrating how poor adherence affects this slowly progressing disease.¹¹

Need for Adjunctive Therapy

Despite the advantages of PGAs and the availability of multiple drug options, data shows that a significant proportion of glaucoma patients may not reach target IOP with a single-agent course of treatment: in one large cohort study of a claims database (n=5,933), 42% of patients prescribed a PGA required adjunctive therapy within 30 days.¹² Adjunctive therapy for additional pressure reduction is relatively common and often necessary for patients to achieve their individual target IOP levels.

Of course, additional medications increase the complexity of treatment and dosing schedules and can become another factor that can lead to noncompliance.¹¹ The use of multiple drops also can increase the risk of side effects, which, again, become an issue for patient noncompliance.¹²

Targeting Aqueous Outflow

Anatomically, two pathways are generally understood to be responsible for aqueous humor outflow: the trabecular meshwork (TM), or so-called conventional pathway, and the uveoscleral, or non-conventional, pathway.¹³ Today, we lower IOP primarily by decreasing aqueous humor production or enhancing uveoscleral outflow.

Of the several classes of glaucoma medications now in common clinical use, three — CAIs (systemic or topical), α-2 adrenergic agonists, and β-blockers — are secretory suppressants that decrease aqueous humor production, and one — PGAs — lower IOP primarily by enhancing uveoscleral aqueous outflow.⁶ Alpha-2 adrenergic agonists are also associated with decreased episcleral venous pressure or increased uveoscleral outflow.⁶

With the exception of miotics, none of the currently available drugs work by primarily enhancing aqueous outflow through the trabecular meshwork (TM). In adults, the majority of aqueous outflow moves through the TM, which is compromised in glaucoma patients.¹⁴ This may account for why so many glaucoma patients require more than one class of IOP-lowering medication, and why some require surgical intervention. SLT, for example, treats the TM directly to enhance its outflow capability, which results in lowered IOP. However, the efficacy of SLT is roughly equivalent to monotherapy with a PGA, thus adjunctive medication or incisional surgery may still be necessary to achieve the IOP goal.^6,15

Sustained Delivery

Because patients don’t always adhere to their medical therapy regimen, sustained-release platforms for IOP-lowering drugs, which would take the responsibility of adhering to a dosing regimen out of a patient’s hands, are being investigated.

Some of the sustained-release platforms for IOP-lowering currently in development include intraocular delivery, such as injectable depots to the intravitreal, intracameral, or subconjunctival space; and extraocular delivery, such as conjunctival inserts placed into the fornices, and punctal plugs. Under the sustained-release model, patients would potentially see their physician every 3 to 6 months, depending on the method used, to have the device removed and replaced.

Looking Ahead

Challenges to the medical management of glaucoma center around inadequate long-term IOP-lowering for some patients and difficulty with medication adherence, arising from a host of factors, in others. Taken together, studies on strategies to improve adherence (e.g., robust patient education, simplified drug regimens, or electronic reminder systems) suggest that an individualized approach, tailored to each patient’s needs, is most likely to be effective.¹¹ In the future, such strategies, combined with innovations in pharmacology, drug delivery, and even surgery, could improve the situation for glaucoma therapy considerably.¹¹ GP

Editor’s note: Medical writing support was provided by Jean Thilmany of Ethis Communications and funded by Bausch + Lomb.

References

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3. Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E; Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48-56.
4. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126(4):487-497.
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12. Schmier JK, Hulme-Lowe CK, Covert DW. Adjunctive therapy patterns in glaucoma patients using prostaglandin analogs. Clin Ophthalmol. 2014;8:1097-1104.
13. Goel M, Picciani RG, Lee RK, Bhattacharya SK. Aqueous humor dynamics: a review. Open Ophthalmol J. 2010;4:52-59.
14. Stamer WD, Acott TS. Current understanding of conventional outflow dysfunction in glaucoma. Curr Opin Ophthalmol. 2012;23(2):135-143.
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Dr. Miller-Ellis is professor of clinical ophthalmology at the Perelman School of Medicine at the University of Pennsylvania, and director of the Glaucoma Service at the Scheie Eye Institute. She specializes in the diagnosis and medical/surgical management of complex glaucoma. She also treats patients with glaucoma secondary to other diseases of the eye or systemic disease, as well as patients with both cataracts and glaucoma. Dr. Miller-Ellis is on the advisory board for Alcon, is a consultant for Inotek Pharmaceuticals, and has received research funding from Allergan and Aerie Pharmaceuticals.